Conditions: Hypertension
Keywords: Hypertension Cardiovascular outcomes Pragmatic clinical trial Point of care research
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20723
Healthy volunteers: no

Brief summary:
The Diuretic Comparison Project aimed to evaluate whether chlorthalidone, as compared with hydrochlorothiazide, would reduce the risk of major nonfatal cardiovascular disease outcomes and non-cancer-related deaths in older patients with hypertension who were receiving hydrochlorothiazide at baseline. The investigators incorporated the pragmatic methods used by the Department of Veterans Affairs (VA) Healthcare System to provide a real-world assessment of the effectiveness of chlorthalidone as compared with hydrochlorothiazide in routine clinical care.

Detailed description:
Thiazide-type diuretics have been in use for more than 50 years and are considered as the first-line treatment for hypertension. Of the more than 1 million Veterans prescribed a thiazide-type diuretic each year, more than 95% receive hydrochlorothiazide, and fewer than 2.5% receive chlorthalidone. However, indirect evidence has been accumulating for many years that chlorthalidone may be more effective than hydrochlorothiazide at preventing cardiovascular events.

The Diuretic Comparison Project was conducted with a clinically integrated design (termed a "point of care" or "pragmatic embedded" trial). The key feature of our design was that, instead of employing local investigators, the investigators developed centralized trial procedures and implemented into the VA electronic health record (EHR) and healthcare delivery systems. This approach enabled us to conduct trial-related interactions and randomization with the use of data in the EHRs, centralize recruitment efforts without the use of site staff, eliminate the need for trial-related visits and procedures, and centralize data capture from administrative databases.

This study was performed to answer a question of whether chlorthalidone is more effective than hydrochlorothiazide at preventing cardiovascular outcomes. Consent was obtained from eligible participants who were willing to participate and their primary care providers. With provider assented to the patient undergoing randomization, 3,523 older patients with hypertension were randomized across 72 VA health care systems. Patients across the US (including Puerto Rico and District of Columbia) were enrolled. Participants were randomly assigned to continue with existing hydrochlorothiazide treatment regimen (25/50mg daily) or switch to a dose equivalent chlorthalidone (12.5/25 mg daily).

The primary outcome was the first occurrence of a composite outcome consisting of a nonfatal cardiovascular event or non-cancer related death. Nonfatal cardiovascular events included nonfatal myocardial infarction, stroke, hospitalization for heart failure, or urgent coronary revascularization for unstable angina.

Arms:
arm 1: Participants remained on the existing hydrochlorothiazide treatment regimen (a daily dose of 25 or 50 mg). arm 2: Participants switched to an equivalent dose of chlorthalidone (a daily dose of 12.5 or 25 mg). arm 3: Providers were enrolled in order to contact their potentially eligible patients and were not included in the results

Interventions: intervention 1: Hydrochlorothiazide (HCTZ) intervention 2: Chlorthalidone (CTD)
Intervention descriptions: intervention 1: Trial activities following study randomization were considered as usual care. Prescriptions of the allocated drug were managed by the primary care providers and patients would receive the prescribed mediations through the VA outpatient pharmacy services. intervention 2: Trial activities following study randomization were considered as usual care. Prescriptions of the allocated drug were managed by the primary care providers and patients would receive the prescribed mediations through the VA outpatient pharmacy services.

Protocol document:
SAP_003.pdf: 
 
 
 
 
CSP597: Diuretic Comparison Project (DCP) 
Statistical Analysis Plan (SAP) 
V1.1 
 
October 27, 2022 
 
NCT02185417 


MAVERIC Study  
Specific 
Documents 
DATE OF ISSUE 
DOCUMENT DESCRIPTION 
 
10/27/2022 
This document describes the statistical analysis 
plan for the CSP597. 
AUTHORS:  Robert Lew, PhD 
Sarah Leatherman, PhD 
                      Cynthia Hau, MPH 
 
SUBITTED BY: 
CSP597 Biostatistician 
DOCUMENTS/ RECORD HISTORY: 
 
DATE 
VERSION 
RECORD HISTORY 
12/14/2016 
 
 
8/29/2017 
 
 
10/17/2022 
 
Initial Version for 
review at DMC meeting 
 
Version 1.0 
 
 
Version 1.1 
 
 
 
Finalized comments generated after DMC 
meeting 
 
Minor modification to calculation of medication 
possession ratio and average daily dose per 
discussion with CSP597 study committees on 
9/8/2022 
 
Added competing risks analysis for secondary 
and safety outcomes 
 
Minor revision to the description of study 
overview to match language with study protocol 
 
AUTHORIZATION SIGNATURE 
 
NAME 
FUNCTION TITLE 
SIGNATURE 
DATE 
 
 
Robert Lew, PhD 
 
Biostatistician 
 
 
 
 
 
 
ROBERT LEW
Digitally signed by ROBERT 
LEW 
Date: 2022.10.27 12:33:34 
-04'00'


Page 2 of 18 
 
Table of Contents 
1. 
Introduction .......................................................................................................................................... 5 
1.1 Overview of the Study Design and Objectives .............................................................................. 5 
2. 
Investigational Plan ............................................................................................................................... 6 
2.1 Description of the Study Population ............................................................................................. 6 
2.1.1 
Inclusion Criteria .............................................................................................................. 6 
2.1.2 
Exclusion Criteria ............................................................................................................. 6 
2.2 Description of the Intervention Strategy ...................................................................................... 7 
2.2.1 
Randomization ................................................................................................................. 7 
2.2.2 
Study Intervention ........................................................................................................... 7 
2.2.3 
Follow-Up Assessment .................................................................................................... 7 
3. 
Statistical Methods ............................................................................................................................... 8 
3.1 Primary Data Analysis ................................................................................................................... 8 
3.1.1 
Primary Objective ............................................................................................................ 8 
3.1.2 
Primary Endpoint ............................................................................................................. 8 
3.1.3 
Primary Hypothesis .......................................................................................................... 8 
3.1.4 
Statistical Methods for Primary Data Analysis ................................................................ 8 
3.2 Secondary Data Analysis ............................................................................................................... 9 
3.2.1 
Secondary Objectives ...................................................................................................... 9 
3.2.2 
Secondary Endpoints ....................................................................................................... 9 
3.2.3 
Statistical Methods for Secondary Data Analyses ......................................................... 10 
3.3 Tertiary Data Analysis ................................................................................................................. 10 
3.3.1 
Tertiary Objective .......................................................................................................... 10 
3.3.2 
Tertiary Endpoints ......................................................................................................... 10 
3.3.3 
Statistical Methods for Tertiary Data Analysis .............................................................. 11 
3.4 Exploratory Data Analysis ........................................................................................................... 11 
3.4.1 
Exploratory Objective .................................................................................................... 11 
3.4.2 
Statistical Methods for Exploratory Data Analysis ........................................................ 11 
4. 
Sample Size and Power ....................................................................................................................... 13 
4.1 Interim Analysis ........................................................................................................................... 13 
4.2 Futility Analysis ........................................................................................................................... 13 


Page 3 of 18 
 
5. 
General Considerations ...................................................................................................................... 14 
5.1 Definition of Intention to Treat Sample ...................................................................................... 14 
5.2 Definition of Per-Protocol Sample .............................................................................................. 14 
5.3 Missing and Miscoded Data ........................................................................................................ 14 
5.4 Baseline Characteristics .............................................................................................................. 15 
5.4.1 
Demographics ................................................................................................................ 15 
5.4.2 
Clinical factors................................................................................................................ 15 
5.5 Safety Evaluation and Reporting ................................................................................................. 15 
5.4 Outcome Adjudication ................................................................................................................ 16 
6. 
Data Monitoring Committee Report................................................................................................... 17 
6.1 Analytic Sample for DMC Report ................................................................................................ 17 
6.2 Algorithm .................................................................................................................................... 17 
6.3 Outline of DMC Report ............................................................................................................... 17 
6.3.1 
Section A:  Subject Disposition ...................................................................................... 17 
6.3.2 
Section B:  Baseline and Follow-Up Measures .............................................................. 17 
6.3.3 
Section C:  Outcome Measures ..................................................................................... 18 
6.3.4 
Section D:  Safety Assessment ....................................................................................... 18 
 
 
 


Page 4 of 18 
 
Abbreviations 
ACME 
Automated Classification of Medical Entitles 
ADD 
Average Daily Dose 
BMI 
Body Mass Index 
CDW 
Corporate Data Warehouse 
CMS  
Centers for Medicare & Medicaid Services 
CPRS 
Computerized Patient Record System 
CSP 
Cooperative Studies Program 
CSPCC 
Cooperative Studies Program Coordinating Center  
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DCP 
Diuretic Comparison Project 
DMC 
Data Monitoring Committee 
ED 
Erectile Dysfunction 
eGFR 
estimated Glomerular Filtration Rate 
EMR 
Electronic Medical Record 
GEE 
Generalized Estimating Equation 
ICD 
International classification of disease 
ITT 
Intention To Treat 
MI 
myocardial infarction  
MPR 
Medication Possession Ratio 
MSM 
Multistage Model 
PCP 
Primary Care Provider 
POC 
Point-Of-Care 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SOP 
Standard Operating Procedure 
VA 
Veterans Affairs 
VHA 
Veterans Health Administration 
 
 
 
 
 
 
 
 
 
 


Page 5 of 18 
 
1. 
Introduction 
This document outlines the statistical methods for the analysis of the data collected in 
the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) study #597 
entitled “Diuretic Comparison Project (DCP)”.  The purpose of this document is to 
provide guidelines from which the analysis will proceed.   
 
 
1.1 
Overview of the Study Design and Objectives 
The present study is an open-label, blinded-endpoint, multicenter, prospective 
randomized two-arm controlled clinical trial.  This trial is designed to compare the 
effects of two thiazide-type diuretics, hydrochlorothiazide and chlorthalidone, on 
cardiovascular (CV) events and non-cancer death.  A randomized trial comparing the 
effectiveness of the two drugs has never been conducted, primarily for reasons of cost.  
Consequently, a less-expensive study design (termed a “point-of-care (POC)” trial) is 
utilized to answer the question of whether chlorthalidone is more effective than 
hydrochlorothiazide at preventing CV events and non-cancer death among older 
patients with hypertension. 
 
This study aims to enroll 13,500 patients (up to 13,700 patients) over 3 years. Based on 
the feasibility analysis, we anticipate this can be accomplished by randomizing an 
average of 270 patients from 50 Veterans Affairs (VA) medical centers. The participants 
will be randomized with equal probability into one of the treatment arms.  Based on 
time of enrollment, participants can be followed for a maximum of 4.5 years.  Assuming 
a uniform rate of enrollment over time (90 patients per medical center each year), the 
average follow-up time will be approximately 3 years among all participants. 
 
 
 
 


Page 6 of 18 
 
2. 
Investigational Plan 
 
2.1 
Description of the Study Population 
Patients who satisfy the inclusion and exclusion criteria are considered eligible to be 
enrolled in this study. 
 
2.1.1 Inclusion Criteria 
Patients who meet the following criteria are considered eligible:  
 
I. 
Over 65 years of age 
II. 
Receiving hydrochlorothiazide from the VA pharmacy at a daily dose of 25 or 50 
mg 
III. 
Have a most recent systolic blood pressure (SBP) ≥120 mmHg, with no SBP <120 
mmHg recorded in CPRS over the past 90 days  
 
2.1.2 Exclusion Criteria 
Patients with any of the following conditions are excluded from enrollment: 
 
I. 
Impaired decision-making capacity rendering the patient unable to provide 
informed consent.  (Indicated in medical chart or determined by the primary 
care provider (PCP)) 
II. 
Death expected within 6 months (inferred by PCP permission to randomize) 
III. 
Potassium <3.1 or <3.5 (if on digoxin) meq/L over the past 90 days  
IV. 
Sodium <130 meq/L over the past 90 days  
V. 
Enrolled in Medicare Part C (extracted from administrative data or obtained 
from patients through consent phone call) 
 
 


Page 7 of 18 
 
2.2 
Description of the Intervention Strategy 
 
2.2.1 Randomization  
Participants will be randomized with a 1:1 allocation ratio to:  
I. 
Continue receiving hydrochlorothiazide at current daily dose (25 or 50 mg), or 
II. 
Switch to chlorthalidone at half dose (12.5 or 25 mg, respectively)   
 
Both stratification and blocking will be employed to control for potential imbalance in 
randomization.  The randomization scheme will be stratified by participating medical 
centers to account for possible regional differences in clinical practice, and the 
treatment allocation will be performed within blocks of size 6. 
 
2.2.2 Study Intervention 
We will obtain informed consent from patient for study participation. Prior to the start 
of the intervention, we will obtain approval from his/her associated PCP for randomizing 
the particular patient.  Participants of this study will be randomly allocated to either the 
hydrochlorothiazide or chlorthalidone arm.  The administration of the allocated 
treatment will be managed by his/her PCP.  There are no study-specific clinic visits or 
assessments.  During the entire study period, participants will be monitored by their 
health care providers through usual clinical care.  Data collection of this study will be 
performed by extracting relevant study data from electronic medical records.  A series 
of pre-defined algorithms will be developed to identify study outcomes and safety 
events.  The overall compliance of study medications will be determined indirectly using 
medication possession ratio (MPR) and average daily dose (ADD) based on electronic 
pharmacy records. 
 
2.2.3 Follow-Up Assessment 
Participants will be followed passively through the VA electronic medical record (EMR) 
system.  The pre-defined extraction algorithms will be performed and collect relevant 
follow-up data from the VHA Corporate Data Warehouse (CDW), Centers for Medicare & 
Medicaid Service (CMS) database, and the National Death Index.   
 
Assuming a uniform rate of enrollment over time, the first patient entered will have 4.5 
years of follow-up and the last patient entered will have 1.5 years of follow-up, yielding 
an average follow-up time of 3 years on 13,500 subjects.  
 
 


Page 8 of 18 
 
3. 
Statistical Methods 
3.1 
Primary Data Analysis 
 
3.1.1 Primary Objective 
The primary objective is to determine whether chlorthalidone is superior to 
hydrochlorothiazide for the prevention of CV events and non-cancer death over time.   
 
3.1.2 Primary Endpoint 
The primary endpoint is time to a composite outcome involving CV events of interest 
and non-cancer death.  The CV events of interest are defined as hospitalization for 
stroke, myocardial infarction (MI), urgent coronary revascularization due to unstable 
angina, and acute decompensated heart failure.  Time to event will be measured as time 
from study enrollment to the first occurrence of the composite outcome.   
 
3.1.3 Primary Hypothesis 
We posit a 4.5-year event rate of 13.5% in the hydrochlorothiazide arm and a 17.5% 
reduction of CVD events in the chlorthalidone arm to inform our primary hypothesis 
stated below: 
 
H0:  The 4.5-year event rate will be 13.5% (or 578 primary events) in both treatment 
arms  
 
H1:  The 4.5-year event rate will be 11.1% (or 477 primary events) in the chlorthalidone 
arm  
 
In theory, if the primary events occurred as projected, the relative percent change will 
be 17.5% ((578 – 477)/ 578 *100%).  The hazard ratio (chlorthalidone hazard rate/ 
hydrochlorothiazide hazard rate) will be approximately 0.81, which will be midway 
between the odds ratio of 0.80 (11.1(100 –13.5)/13.5(100 – 11.1)) and the risk ratio of 
0.82 (11.1/13.5).  
 
3.1.4 Statistical Methods for Primary Data Analysis 
The effect of treatment on the primary study outcome will be assessed by means of a 
two-sided log-rank test and Cox proportional hazards models based on intention-to-
treat (ITT) principles. Both unadjusted and adjusted models will be used. The adjusted 
Cox model will account for baseline characteristics such as demographics (e.g., age, sex) 
and clinical factors (e.g., blood pressure, medications, history of disease, and body mass 
index (BMI)).  A time-treatment interaction term will also be included to test the 


Page 9 of 18 
 
proportional hazards assumption. The final study results will present both unadjusted 
and adjusted hazard rates and corresponding hazard ratios with 95% confidence 
intervals.  
 
3.2 
Secondary Data Analysis 
 
3.2.1 Secondary Objectives 
The secondary objectives are to compare the treatment effects 1) across pre-specified 
subgroups, 2) on individual components of the primary outcomes, and 3) on additional 
outcomes of interest. 
 
Differential treatment effects will be evaluated in the following baseline characteristics: 
 
I. 
gender 
II. 
age (dichotomized at the median) 
III. 
baseline SBP (dichotomized at the median) 
IV. 
history of MI or stroke 
V. 
black race vs. not 
VI. 
diabetes vs. not 
VII. 
eGFR <60 mL/min/1.73m2 
VIII. 
good compliance (medication possession ratio ≥ 80%) with hydrochlorothiazide 
over the year before randomization 
 
3.2.2 Secondary Endpoints 
 
Individual components of the primary outcome will be examined: 
I. 
stroke 
II. 
MI 
III. 
urgent coronary revascularization due to unstable angina  
IV. 
hospitalization for acute decompensated heart failure 
V. 
non-cancer death 
 
Treatment effects will be evaluated for additional outcomes below: 
I. 
all-cause mortality 
II. 
the composite outcome substituting all deaths for non-cancer deaths 


Page 10 of 18 
 
III. 
“possible vascular deaths” defined as all deaths caused by vascular diseases, 
diabetes, external causes, and unknown causes 
IV. 
the composite outcome substituting “possible vascular deaths” for non-cancer 
deaths 
V. 
any revascularization of an artery 
VI. 
erectile dysfunction (ED), defined as first prescription of PDE5 inhibitor or 
referral for ED 
 
3.2.3 Statistical Methods for Secondary Data Analyses 
Cox regression modeling will be used to explore variation in treatment efficacy across 
the pre-specified subgroups.  The components of the primary outcomes will be 
examined individually using log-rank, Cox proportional hazards, and competing risks 
models.  Both unadjusted and adjusted analyses will be performed.  Covariate 
adjustment will be similar to that used in the primary data analysis.    
  
 
3.3 
Tertiary Data Analysis 
 
3.3.1 Tertiary Objective 
The tertiary objective is to examine the occurrence of expected adverse events (defined 
as common events related to diuretics), and their associations with the assigned 
treatment regimens.   
 
3.3.2 Tertiary Endpoints 
The expected adverse events of this study are: 
 
I. 
hospitalization for primary diagnosis of hypokalemia, hyponatremia, or renal 
failure 
II. 
renal failure, defined as dialysis, vascular access for dialysis, or renal transplant 
III. 
other recorded hypokalemia (<3.5 meq/L) or hyponatremia (<130 meq/L) 
IV. 
new diabetes, defined as first use of medication for diabetes 
V. 
acute gout episodes 
VI. 
new allergic reaction to thiazide-type diuretics 
 


Page 11 of 18 
 
3.3.3 Statistical Methods for Tertiary Data Analysis 
The expected adverse event will be examined individually using log-rank, Cox 
proportional hazards, and competing risks models.  Both unadjusted and adjusted 
analyses will be performed.  The adjustment for baseline covariates will be similar to 
that used in the primary data analysis.    
 
3.4 
Exploratory Data Analysis 
 
3.4.1 Exploratory Objective 
The ITT analyses take no account of post-baseline changes in study medications. Thus, 
exploratory analyses may be performed to examine the primary, secondary, and tertiary 
endpoints in a per-protocol subset, which defined as participants who persistently 
receive the allocated medication prescriptions throughout the duration of the study. 
 
Other exploratory analyses may be performed to evaluate the treatment efficacy with 
considerations of protocol deviations and time-varying repeated measures, as well as 
treatment interruptions due to hospitalization and other clinical factors.  We may also 
explore the between-group difference in SBP, which will be measured repeatedly over 
the disease-free intervals (free of component events).  
 
3.4.2 Statistical Methods for Exploratory Data Analysis  
The per-protocol analysis will be performed following statistical procedures used in the 
ITT cohort.  Other exploratory analyses may be conducted using a generalized 
estimating equation (GEE) to account for varying time intervals and treatment 
interruptions, with potential modeling of time-dependent effects of protocol deviations.  
We may also explore censoring patterns such as models that assume not missing-at-
random using a Bayesian approach to the pattern mixture model (Missing Data in 
Longitudinal Studies Chapman and Hall Boca Raton 2008).  In addition, a change in 
medication may alter the subsequent risk of a cardiovascular event.   Therefore, we may 
add time-dependent covariates to the Cox model, such as binary indicators of 
medication switching (from chlorthalidone to hydrochlorothiazide, or vice versa).  To 
directly estimate subsequent risk, we may use a multistage model (MSM) to assess the 
hazard rate of a major cardiovascular event after a switch.  MSM models extend the 
time-to-first-event models to second, third, and more events.   This extension of the Cox 
model allows direct estimation of the hazard rate associated with any transition 
adjusted for previous history and baseline characteristics.  Within MSM, we may carry 
out a competing risks analysis to assess the effect of cancer deaths.   
 
In addition, a mixed effects model for repeated measures may be used to test whether: 
1) SBP increases/decreases over time among participants receiving chlorthalidone, 2) 
SBP increases/decreases over time among participants receiving hydrochlorothiazide, 


Page 12 of 18 
 
and 3) SBP is statistically significant different between study arms.  The model will allow 
for irregular time intervals and a random effect will be included for both intercept and 
linear time. 
 
 
 
 
 
 
 


Page 13 of 18 
 
4. 
Sample Size and Power 
The annual primary outcome occurrence rate is projected to be 3% (578 events over 4.5 
years) in the hydrochlorothiazide arm.  With the goal of enrolling 13,500 patients (6,750 
in each study arm for an overall type-I error of 5%), the two-sided test will have a 90% 
power to detect a 17.5% reduction in CV events among participants receiving 
chlorthalidone.  Thus, this study will have a 90% power to detect a hazard ratio of less 
than 0.82 or greater than 1.22 in the chlorthalidone arm.  However, if the annual 
occurrence rate is between 2% and 2.5% (rather than the posited 3%), the study will 
have a power of 75% to 84%. 
 
4.1 
Interim Analysis 
This study will have one interim analysis, which will be performed when the 500th 
primary outcome event occurs (approximately 3.5 years after initiation of enrollment).  
Assuming a uniform rate of enrollment over time, the first patient entered will 
potentially have 3.5 years of follow-up and the last patient entered will potentially have 
0.5 years of follow-up. Thus, we will have an average follow-up time of approximately 2 
years on 13,500 subjects.  
 
Using the O-Brien Fleming procedure, this interim analysis will have a type I error of 
0.1%, which negligibly decreases the overall type I error and has virtually no effect on 
the power to show that chlorthalidone is different from hydrochlorothiazide.  Given the 
potential inflation factor, the increase in sample size of 1.001 will result in 14 more 
subjects per arm.  We will confer with the Data Monitoring Committee (DMC) members 
and the program leadership for potential stopping guidelines based on findings from the 
interim analysis. 
 
4.2 
Futility Analysis 
If requested by the DMC, a futility analysis that includes conditional probability 
estimation will be conducted to determine the probability of observing a significant 
result assuming the distribution of future event rates from additional data from the 
second half of the study follow three scenarios.  These scenarios are: 
 
1) No-change – future event rates are the same as the currently observed event rates, 
2) Expected – future event rates are as proposed in the protocol, and 
3) Extreme – all new events at the currently observed event rate are in the control 
group. 
 
 


Page 14 of 18 
 
5. 
General Considerations 
 
5.1 
Definition of Intention to Treat Sample 
All consented and randomized subjects will be accounted for and reported in the 
CONSORT diagram.  However, only those consented subjects for whom a randomized 
drug order is entered will be considered as ITT subjects and included in the DMC reports 
and primary efficacy analysis.  An analytic sample data file consisting of only the ITT 
subjects will be created and maintained throughout the study period.   
 
5.2 
Definition of Per-Protocol Sample 
Participants categorized as protocol compliant will make up the per-protocol subset.  
The overall compliance to the randomly assigned medication will be measured over the 
entire follow-up period using MPR and ADD defined as follows:  
 
ܯܴܲ= 
ܦܽݕݏ ݋݂ ܿℎ݈݋ݎݐℎ݈ܽ݅݀݋݊݁ ݋ݎ ℎݕ݀ݎ݋ܿℎ݈݋ݎ݋ݐℎ݅ܽݖ݅݀݁ ݏݑ݌݌݈ݕ 
ܾ݁ݐݓ݁݁݊ ݐℎ݁ ݀ܽݐ݁ ݋݂ ݎܽ݊݀݋݉݅ݖܽݐ݅݋݊ ܽ݊݀ ݐℎ݁ ݏݐݑ݀ݕ ݁݊݀ ݀ܽݐ݁ 
ܦܽݕݏ ܾ݁ݐݓ݁݁݊ ݎܽ݊݀݋݉݅ݖܽݐ݅݋݊ ܽ݊݀ ݌ܽݐ݅݁݊ݐᇱݏ ݏݐݑ݀ݕ ݁݊݀ ݀ܽݐ݁ 
 
ܱݒ݁ݎ݈݈ܽ ܣܦܦ= ܶ݋ݐ݈ܽ ܿݑ݉ݑ݈ܽݐ݅ݒ݁ ݀݋ݏ݁ ݋݂ ܿℎ݈݋ݎݐℎ݈ܽ݅݀݋݊݁ ݋ݎ ℎݕ݀ݎ݋ܿℎ݈݋ݎ݋ݐℎ݅ܽݖ݅݀݁
ܦܽݕݏ ܾ݁ݐݓ݁݁݊ ݎܽ݊݀݋݉݅ݖܽݐ݅݋݊ ܽ݊݀ ݌ܽݐ݅݁݊ݐᇱݏ ݏݐݑ݀ݕ ݁݊݀ ݀ܽݐ݁
 
 
ܣܦܦ ݋݂ ݌ݎ݁ݏܿݎܾ݅݁݀ ݀ݎݑ݃= ܶ݋ݐ݈ܽ ܿݑ݉ݑ݈ܽݐ݅ݒ݁ ݀݋ݏ݁ ݋݂ ܿℎ݈݋ݎݐℎ݈ܽ݅݀݋݊݁ ݋ݎ ℎݕ݀ݎ݋ܿℎ݈݋ݎ݋ݐℎ݅ܽݖ݅݀݁
ܽݒ݈ܾ݈ܽ݅ܽ݁ ݀ܽݕݏ ݋݂ ݏݑ݌݌݈ݕ
 
 
 
5.3 
Missing and Miscoded Data 
A related issue is the possibility that patients who suffer a cardiac or non-cardiac event 
during the study will have the wrong ICD10 code assigned despite review of the 
electronic patient record by cardiologists in our study.  If this appears to be a major 
issue we will apply Carroll Ruppert and Stefanski’s methods as implemented in the 
r_langauge package DECON (2013).  While this will not correct any errors it will increase 
the standard errors and thereby assess the robustness of our conclusions. 
 
Changes in medication may also prove to be a major issue of missing data.  Subjects in 
this study will not have frequent clinic visits wherein our staff asks them about their 
current medications.  Instead, we will passively detect changes by review of electronic 
charts including pharmacy data.   A systematic change in medication, if not detected, 
would bias study results.   Thus, we will intensively review electronic data for any 
evidence of such changes.   This vigilance is more a matter of study protocol than 
statistical adjustment. 


Page 15 of 18 
 
 
5.4 
Baseline Characteristics 
With the use of all available data stored in the CDW, baseline measurements will be 
recorded as the closest date before randomization.  The baseline measurement will be 
evaluated among the entire study cohort, between study arms, and stratified by 
enrollment sites.  The number of observations, mean, median, standard deviation, 
minimum, and maximum will be calculated for continuous variables.  The categorical 
results will be reported as frequencies and percentages. 
 
Distribution of continuous variables and proportions of categorical variables will be 
tabulated by intervention group, and t-test and chi-square tests will be performed to 
evaluate if these variables are balanced across the two intervention groups. 
 
5.4.1 Demographics 
Baseline demographics including age, sex, race, ethnicity, marital status, military service, 
height, weight, and BMI will be determined before the start of the study intervention. 
 
5.4.2 Clinical factors  
Critical clinical factors such as medical history, comorbidities, medication history, vital 
signs, and key laboratory values will also be extracted. 
 
5.5 
Safety Evaluation and Reporting 
The CSPCC staff will collect safety data from the medical record from the time of 
consent through the end of the study period.  If the subject withdraws from the study 
prior to study end, collection of safety data will cease on the date of withdrawal.   
 
Pre-defined safety events of interest will be identified through data extraction from the 
VA CDW and CMS database.  In brief, participants’ health care providers will identify, 
monitor, and treat (as necessary) adverse events that occur during the course of the 
study.  Informatics staff at the Boston CSPCC will extract EMR data routinely with pre-
defined algorithms including, but not limited to, International Classification of Disease 
(ICD) 10 codes, Current Procedure Terminology (CPT) codes, medication names, and 
laboratory test name with critical values.  In addition to data culled from the EMR, the 
trial will allow for spontaneous reporting of events by study participants.  There are no 
unanticipated safety events for this study.  However, participants will be given a study-
specific information sheet with relevant contact information for communicating safety 
concerns with the study team. 
 


Page 16 of 18 
 
All safety data will be reported with aggregated data tables detailing the frequencies of 
these events by treatment arms.   The expected adverse events will be reported to in 
the DMC report as secondary and tertiary outcomes. 
 
5.4 
Outcome Adjudication 
In cases where the outcome diagnosis is not clear based on the electronic adjudication, 
we will resort to manual adjudication to determine the validity of the diagnosis.  Please 
refer to the study protocol for more details regarding the process of outcome 
adjudication. 
 
 


Page 17 of 18 
 
6. 
Data Monitoring Committee Report  
Data and study progress will be monitored by the study executive committee and by the 
DMC.  The DMC will review the study progress and safety semi-annually with additional 
meetings and communications as needed.   
 
6.1 
Analytic Sample for DMC Report 
All subjects randomized more than four weeks prior to the DMC meeting date will be 
included in the analytic cohort for the upcoming DMC report.   
 
6.2 
Algorithm 
Shell tables with annotated algorithms for creating aggregated tables in the DMC report 
are kept securely on the CSP597 SharePoint site and/or study data storage network.  
Only authorized study personnel will have access to the secured SharePoint site/data 
storage network.   
 
6.3 
Outline of DMC Report 
The DMC report is divided into four sections to cover subject disposition, baseline & 
follow-up Measures, outcome measures, and safety events.  Following is the list of 
tables/figures to be included within each of these sections.  Revision to this list, if any, 
will be discussed at the first DMC meeting. 
 
6.3.1 Section A:  Subject Disposition 
 
Table A1. Consort Diagram for CSP 597 
 
Table A2. Enrollment by Sites 
 
Table A3. Protocol Deviation 
 
6.3.2 Section B:  Baseline and Follow-Up Measures 
 
Table B1. Baseline information 
 
Table B2. Medical History 
 
Table B3. Compliance to study medication  
 
Figure B4. Current prescription status of study medication  
 
Table B5. Systolic blood pressure and other use of antihypertensive Agents 
 
 


Page 18 of 18 
 
6.3.3 Section C:  Outcome Measures 
 
Table C1. Occurrence of Study Outcomes 
 
6.3.4 Section D:  Safety Assessment 
Table D1. Expected Safety Events 
Table D2. List of Unanticipated Serious Adverse Events  
 
 
 
 
 

Prot_000.pdf: 
 
 
 
 
 
 
Department of Veterans Affairs Cooperative Studies Program 
 
 
 
CSP#597: Diuretic Comparison Project (DCP) 
A proposal from the Point of Care Program 
 
 
Study Chair: Areef Ishani, MD 
 
 
 
Version 4.5 
 
 
 
 
 
 
This document contains confidential material that is privileged. Please do not disseminate this 
document, or sections thereof, beyond its limited original distribution 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             2 
 
 
Table of Contents 
I. 
Abbreviations and Acronyms ................................................................................................................ 4 
II. 
Study Question ...................................................................................................................................... 7 
III. 
Background and Rationale ................................................................................................................ 7 
IV. 
The Point of Care Program within the VA’s Office of Research and Development ........................ 14 
V. 
Relevance of our trial design to current needs of VA healthcare ....................................................... 16 
VI. 
Study Design.................................................................................................................................... 18 
VII. 
Study Population ............................................................................................................................. 18 
VIII. 
Study Intervention .......................................................................................................................... 19 
IX. 
Study Procedures ............................................................................................................................ 20 
X. 
Outcome Measures ............................................................................................................................. 24 
XI. 
Biostatistical Considerations ........................................................................................................... 31 
XII. 
Feasibility and Recruitment Plan .................................................................................................... 37 
XIII. 
Data Collection and Data Sources ................................................................................................... 38 
XIV. 
Data Management and Data Security Plans ................................................................................... 39 
XV. 
Human Subjects .............................................................................................................................. 41 
XVI. 
Quality Control Procedures ............................................................................................................. 43 
XVII. 
Study Monitoring Plan .................................................................................................................... 44 
XVIII. 
Study Organization and Administration ...................................................................................... 46 
XIX. 
Publications ..................................................................................................................................... 49 
XX. 
Provider Experience Survey ............................................................................................................ 50 
XXI. 
References ...................................................................................................................................... 50 
 
 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             3 
A. Executive Summary  
Thiazide-type diuretics have been in use for more than 50 years and are considered in JNC-7 and VA 
guidelines to be the first-line treatment for hypertension. Of the more than 1 million veterans 
prescribed a thiazide-type diuretic each year, more than 95% receive hydrochlorothiazide, and fewer 
than 2.5% receive chlorthalidone. However, indirect evidence has been accumulating for many years 
that chlorthalidone may be more effective than hydrochlorothiazide at preventing cardiovascular 
events, by about 20% according to a recent network meta-analysis. Possible mechanisms for such an 
effect include longer duration of action, better nighttime blood pressure control, and pleiotropic effects 
of chlorthalidone. A randomized trial comparing the effect of the two drugs on cardiovascular outcomes 
has never been conducted, primarily for reasons of cost. 
We are proposing a new type of efficient, less expensive randomized trial (termed a “clinically 
integrated” or “point of care” trial) to answer the question of whether chlorthalidone is more effective 
than hydrochlorothiazide at preventing cardiovascular outcomes in older patients with hypertension. 
Our primary outcome will be a composite consisting of: stroke, myocardial infarction, non-cancer death, 
urgent coronary revascularization, and hospitalization for acute congestive heart failure. We plan to 
enroll patients over age 65 years currently prescribed hydrochlorothiazide 25 or 50 mg daily with no 
recent systolic blood pressure below 120 mm Hg, and randomize them to either continue on 
hydrochlorothiazide or receive open-label chlorthalidone at suggested doses of 12.5 or 25 mg, 
respectively.  
To have a 90% power with 2-sided α = 0.05 to detect a 17.5% reduction in the expected 3% per year 
primary outcome occurrence rate in the hydrochlorothiazide group, we plan to randomize 
13,700patients over 3 years and follow them for a mean of 3 years, for a total study duration of 4.5 
years.  
The key feature of our design is that, instead of employing local investigators, we substitute centralized 
study processes and rely on usual primary care. Specifically, this involves: 1) identification of eligible 
patients using the VA electronic medical record system (EMR), 2) centralized recruitment and 
enrollment, involving permission from the patient’s primary care provider, a patient recruitment letter, 
and informed consent obtained by telephone, 3) centralized placement of notes and orders using the VA 
EMR, 4) all patient care including the study drug to be managed by the primary care provider, and 5) 
centralized passive collection of outcomes and process variables using the VA EMR, Medicare, and other 
national VA and non-VA databases.  
 
 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             4 
I. 
Abbreviations and Acronyms 
ACCOMPLISH 
Avoiding Cardiovascular Events in Combination Therapy in Patients  
 
 
 
 
Living with Systolic Hypertension 
ACCORD 
Action to Control Cardiovascular Risk in Diabetes Trial 
ACE 
 
Angiotensin Converting Enzyme  
ACEI  
 
Angiotensin Converting Enzyme Inhibitors 
ACME  
Automated Classification of Medical Entities 
AHA 
 
American Heart Association 
ALLHAT  
Antihypertensive and Lipid-Lowering Therapy to Prevent Heart Attack Trial 
ANBP2  
Second Australian National Blood Pressure Study 
ARB 
 
Angiotensin Receptor Blocker 
ARIC 
 
Atherosclerosis Risk in Communities 
BIRLS 
 
Beneficiary Identification and Records Locator Subsystem database  
CAC 
 
Clinical Application Coordinator 
CBOC  
Community Based Outpatient Clinics 
CDW 
 
Corporate Data Warehouse 
CFR 
 
Code of Federal Regulations 
CHD 
 
Coronary Heart Disease 
CHF 
 
Congestive Heart Failure 
CI 
 
Confidence Interval 
CPRS 
 
VA Computerized Patient Record System 
CPT 
 
Current Procedural Terminology 
CSP 
 
Cooperative Studies Program 
CSPCC  
Cooperative Studies Program Coordinating Center 
CSSEC  
Clinical Sciences Scientific Evaluation Committee 
CVD 
 
Cardiovascular Disease 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             5 
DM 
 
Diabetes Mellitus 
DMC 
 
Data Monitoring Committee 
DoD 
 
US Department of Defense 
ECG 
 
Electrocardiography 
EMR 
 
Electronic Medical Record 
EHR 
 
Electronic Health Record 
EXAMINE 
EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE  
 
 
in patients with type 2 diabetes mellitus and acute coronary syndrome 
FDA 
 
US Food and Drug Administration 
HCTZ 
 
Hydrochlorothiazide 
HDFP 
 
Hypertension Detection and Follow-up Program 
HF 
 
Heart Failure 
HIPAA  
Health Insurance Portability and Accountability Act 
HR 
 
Hazard Ratio 
ICD-9 
 
International Classification of Disease, 9th edition 
ICD-10  
International Classification of Disease, 10th edition 
ICD 
 
Internal Cardiac Defibrillator 
IRM 
 
Information Resource Management 
ISO 
 
Information Security Officer 
JNC-7  
Seventh Report of the Joint Committee on Prevention, Detection, Evaluation and  
 
 
Treatment of High Blood Pressure 
meq/L  
Milli-equivalents per liter 
mg 
 
Milligram 
MI 
 
Myocardial Infarction 
mmH 
 
Millimeters of Mercury 
MRFIT  
Multiple Risk Factor Intervention Trial 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             6 
NHLBI  
National Heart, Lung, Blood Institute 
NIH 
 
National Institutes of Health 
PACT 
 
Patient Aligned Care Team 
PBM 
 
VA Pharmacy Benefits Management 
PCP 
 
Primary Care Provider 
PEACE Trial 
Prevention of Events with Angiotensin-Converting Enzyme Inhibition 
PHI 
 
Protected Health Information 
POC-CT  
Point of Care Clinical Trial 
PROBE  
Prospective, Randomized, Open-label, Blinded-Endpoint Trial 
SBP 
 
Systolic Blood Pressure 
SHEP 
 
Systolic Hypertension in the Elderly Population Trial 
SPRINT  
Systolic Blood Pressure Intervention Trial 
SOP 
 
Standard Operating Procedure 
SME 
 
Subject Matter Expert 
TOMHS-T 
Treatment of Mild Hypertension Study 
TRACER 
Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes 
(TRA2°P)-TIMI 50   Thrombin Receptor Antagonist in Secondary Prevention of  
 
 
 
 
 
Atherothrombotic Ischemic Events Trial 
UK NICE 
United Kingdom National Institute for Health and Care Excellence 
VA 
 
US Department of Veterans Affairs 
VAMC  
VA Medical Center 
VIREC  
VA Information Resource Center 
VISN 
 
Veterans Integrated Service Network 
WHO 
 
World Health Organization 
 
 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             7 
II. 
Study Question 
Does treatment with chlorthalidone reduce cardiovascular outcomes compared with 
hydrochlorothiazide in older patients with hypertension? 
III. 
Background and Rationale 
A. 
Diuretics for hypertension 
Hypertension is the most common primary diagnosis in America (1), and 3 of the 10 most commonly 
prescribed drugs in the US are antihypertensive agents (2). Thiazide-type diuretics are recommended as 
first line therapy by VA/DoD hypertension guidelines (3) and by the Seventh Report of the Joint 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7). JNC-7 
noted that “diuretics have been virtually unsurpassed in preventing complications of hypertension” and 
as a result “should be used in drug treatment for most patients with uncomplicated hypertension” (4). In 
a network meta-analysis of 42 trials involving 192,478 patients randomized to active drug treatment for 
hypertension vs. placebo, low-dose diuretics (usually hydrochlorothiazide or the thiazide-type diuretic 
chlorthalidone) were “the most effective first-line treatment for preventing the occurrence of 
cardiovascular disease morbidity and mortality” (5).  
B. 
Hydrochlorothiazide and chlorthalidone  
Nearly all thiazide-type diuretic prescriptions in the U.S. are for hydrochlorothiazide. 
Hydrochlorothiazide is among the top 10 most commonly prescribed drugs in the US (2), with 135 
million prescriptions written annually (6). In the VA national outpatient prescription database, of the 
more than 1 million veterans prescribed a thiazide-type diuretic each year from 2003-8, more than 95% 
received hydrochlorothiazide, and fewer than 2.5% received chlorthalidone (7). From our own search of 
the subsequent 3-year period 2009-11, 1.5 million veterans received hydrochlorothiazide from the VA 
and 50,000 received chlorthalidone. 
The nearly universal use of hydrochlorothiazide has been attributed to a variety of factors, including 1) 
early aggressive marketing by its manufacturer (Merck) using “the largest pharmaceutical sales force in 
the world” (8), 2) its use in the early landmark VA hypertension treatment trials, 3) its early and frequent 
inclusion into combination pills, numbering at least 28 preparations (8), and 4) the ease of abbreviation 
to “HCTZ”, which may influence physician preference (9).  
Both drugs have been approved by the FDA and in use for more than 50 years, have long been available 
as generics, and are included in the VA national formulary in the same drug class: USP code CV 701, 
thiazide-related diuretics. There is no patient characteristic that influences the choice between these 
two drugs - it is based solely on physician preference. 
C. 
Drug dosages 
Both drugs were once commonly used at doses of 100 mg per day and higher, but by 1990, concern over 
the lack of reduction in coronary events from blood pressure reduction by thiazides (despite proven 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             8 
efficacy for stroke), and further concern that this might be due to competing harms (particularly 
ventricular arrhythmias) from thiazide-induced metabolic abnormalities, led to recommendations to use 
lower doses of diuretics, including suggestions to use 12.5 mg of hydrochlorothiazide (10).  
In the early 1990’s, publications of randomized dosing trials from the VA cooperative study group 
concluded that the doses of 25-50 mg of hydrochlorothiazide were nearly as effective as higher doses at 
controlling blood pressure with fewer adverse metabolic effects, favoring the use of 25 mg and a 
maximum dose of 50 mg (11,12). Several randomized dosing trials of chlorthalidone found 12.5 mg per 
day to be effective, and found 25 mg per day to be nearly as effective as higher doses with fewer 
adverse metabolic effects (13,14). Since then, doses of 12.5-25 mg per day have been widely used (15) 
and rarely exceeded for both drugs, with higher doses accounting for only 7% of VA prescriptions in 
2008 (7). However, several authors have pointed out that hydrochlorothiazide doses lower than 25 mg 
have not been shown to reduce cardiovascular outcomes and have performed poorly in randomized 
trials (6). As a result, JNC-8 recommends target doses of 25-50 mg per day for hydrochlorothiazide and 
12.5-25 mg per day for chlorthalidone (16). 
D. 
MRFIT – the first evidence that chlorthalidone may be more effective 
Despite the near universal use of hydrochlorothiazide in the U.S., evidence has accumulated over the 
past 30 years suggesting that chlorthalidone may be more effective at reducing cardiovascular 
outcomes. The first indication was from the Multiple Risk Factor Intervention Trial (MRFIT), a large 
randomized trial of a multi-component ‘special intervention’ to prevent cardiovascular events in which 
either hydrochlorothiazide or chlorthalidone could be used as first-line treatment of hypertension in the 
special intervention arm. During the study, clinics that used hydrochlorothiazide were noted to have 
44% more coronary heart disease deaths than those using chlorthalidone.  In 1980, the MRFIT Policy 
Advisory Board changed the protocol, recommending chlorthalidone over hydrochlorothiazide for initial 
therapy, and lowered the maximum dose to 50 mg. Mortality in the former hydrochlorothiazide clinics 
subsequently dropped 28% (which could, of course, partially reflect regression to the mean). A recent 
analysis of the use of chlorthalidone and hydrochlorothiazide within MRFIT reported significantly fewer 
cardiovascular events with chlorthalidone, though the findings of this non-randomized comparison are 
confounded by large differences in dosage, randomized group, and lipid lowering (17). A separate non-
randomized analysis of MRFIT data concluded that chlorthalidone was associated with less left 
ventricular hypertrophy than hydrochlorothiazide (18).  
E. 
Indirect comparisons of randomized trial data 
Because of the MRFIT observations, most subsequent NIH-funded blood pressure trials have used 
chlorthalidone, including the Hypertension Detection and Follow-up Program (HDFP), the Systolic 
Hypertension in the Elderly Program (SHEP), the Treatment of Mild Hypertension Study (TOMHS), and 
the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), and in the 
ongoing Systolic Blood Pressure Intervention Trial (SPRINT), it is ‘preferred’. The use of chlorthalidone in 
these trials and of hydrochlorothiazide in many other trials has enabled indirect comparisons of the 
effects of the two drugs against a third drug or class. Thus, hydrochlorothiazide resulted in worse 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             9 
outcomes than an ACE inhibitor (enalapril) in men in the Second Australian National Blood Pressure 
Study (ANBP2)  (19), and worse outcomes than amlodipine (with all patients receiving benazepril) in the 
Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension 
(ACCOMPLISH) trial (6), whereas in ALLHAT, chlorthalidone was found to be superior to an ACE inhibitor 
(lisinopril) or amlodipine “in preventing 1 or more major forms of CVD” (though there was no difference 
in the primary outcome) (20). These and other indirect comparisons have recently been combined into a 
focused network meta-analysis that estimated a 21% risk reduction (p< .0001) in cardiovascular events 
with chlorthalidone relative to hydrochlorothiazide that persisted (as 18%, p=.024) in an analysis 
adjusted for attained blood pressure (21). 
F. 
Relative Potency 
Several studies have found chlorthalidone to have about twice the potency of hydrochlorothiazide 
(22,23,24) and this is reflected in the VA Pharmacy Benefits Management (PBM) 2009 evidence review 
(25). Two indirect meta-analyses have reported similar conclusions. Ernst et al (26) found that at 
identical doses, chlorthalidone had a greater effect than hydrochlorothiazide on lowering blood 
pressure. Pederzan et al (27) considered the 2 drugs to have equivalent effects at equally potent doses, 
which they considered to be 3 to 1. Despite these indications of greater potency, in practice 
chlorthalidone is not used in lower doses than hydrochlorothiazide (7,28,29). This may reflect greater 
awareness of appropriate thiazide dosing by the small proportion of prescribers who use chlorthalidone, 
rather than widespread belief that the potencies are equivalent. There is essentially universal 
agreement among experts that chlorthalidone at 12.5 or 25 mg is equipotent to hydrochlorothiazide at 
25 or 50 mg (respectively). 
G. 
Possible differences between the two diuretics 
No randomized trials have been conducted that directly compare clinical (e.g., cardiovascular) outcomes 
of chlorthalidone and hydrochlorothiazide, but several short-term randomized trials have examined 
blood pressure and metabolic effects. Two recent short-term (10 and 12 weeks) randomized double-
blind trials of 609 and 1071 patients (respectively) compared blood pressure control and adverse effects 
when taking chlorthalidone 25 mg or hydrochlorothiazide 25 mg in patients also taking an angiotensin 
receptor blocker (ARB) (30,31). In both studies, chlorthalidone resulted in lower systolic blood pressure 
by at least 5 mmHg in clinic and, in the larger study, by 24 hour ambulatory recording. 
Chlorthalidone is known to have a longer duration of action than hydrochlorothiazide. The elimination 
half-life of chlorthalidone is 50-60 hours compared with 9-10 hours for hydrochlorothiazide (32). Ernst et 
al (23) randomized 30 patients to either chlorthalidone 12.5mg/day, titrated to 25 mg/day or 
hydrochlorothiazide 25 mg/day, titrated to 50mg/day. After 8 weeks, there was no significant difference 
in office systolic blood pressure (SBP), but 24-h ambulatory SBP favored chlorthalidone over 
hydrochlorothiazide: -12.4 (± 1.8) vs. -7.4 (± 1.7) mmHg, respectively, P = 0.054, an effect primarily 
driven by the lower nighttime SBP for chlorthalidone compared with hydrochlorothiazide: -13.5 (± 1.9) 
and -6.4 (± 1.8) mmHg, respectively, P = 0.009. Of note in this regard, large observational studies have 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             10 
found nighttime blood pressure to be a better predictor of cardiovascular outcomes than daytime blood 
pressure (33,34).  
A recent in vitro study reported that chlorthalidone reduced epinephrine-induced platelet aggregation 
and increased angiogenesis more than the thiazide bendroflumethiazide (35). There have been no 
reports of any related clinical effects (e.g., increased bleeding), but these mechanisms could help to 
explain differences between thiazides in reducing vascular events (36). 
In summary, given the longer duration of action, better nighttime blood pressure control, and possible 
pleiotropic effects of chlorthalidone, it is possible that chlorthalidone and hydrochlorothiazide could 
have different long-term effects on cardiovascular outcomes even at doses that result in similar office 
blood pressures. 
H. 
Drug costs 
Although both drugs are inexpensive generic products, chlorthalidone costs the VA seven times as much 
as hydrochlorothiazide. According to VA Pharmacy Benefits Management (PBM), the cost to the VA for 
hydrochlorothiazide 50 mg is 1.6¢ per tablet and for chlorthalidone 25mg is 11¢ per tablet (with half 
doses costing half as much). Thus if the approximately 1 million VA patients using hydrochlorothiazide 
(nearly all on 12.5 or 25 mg) were switched over to chlorthalidone 12.5 mg at an additional cost of 5¢ 
per day, the total increased cost would be about $18 million per year. 
I. 
Comparative metabolic effects 
Thiazide diuretics have a variety of metabolic effects. They generally lower serum sodium (36) and 
potassium (27,38) levels and increase blood sugar (39,40) and uric acid (27,41) levels. In a small 
randomized trial (42), hydrochlorothiazide 50 mg per day lowered potassium by a mean of 0.44 meq/L 
more than placebo, regardless of whether potassium supplements or triamterene were added. Perhaps 
the best source of information on the effect of thiazides comes from ALLHAT, which randomized 33,357 
patients with hypertension: 15,255 to chlorthalidone and 9000 each to amlodipine and lisinopril. 
Overall, chlorthalidone was considered superior to the other drugs in preventing cardiovascular events 
(20).  The year-1 incidence of hypokalemia (<3.5 meq/L) was higher with chlorthalidone (12.9%) than 
with lisinopril (1.0%) or amlodipine (2.1%), but only 3.5% of the chlorthalidone group had a level <3.2 
meq/L, and, in the chlorthalidone group, hypokalemia was associated with fewer cardiovascular 
outcomes than was normokalemia (38).  
According to UpToDate (43): “The severity of the manifestations of hypokalemia tends to be 
proportionate to the degree and duration of the reduction in serum potassium. Symptoms generally do 
not become manifest until the serum potassium is below 3.0 meq/L, unless the serum potassium falls 
rapidly or the patient has a potentiating factor, such as a predisposition to arrhythmia due to the use of 
digitalis. Symptoms usually resolve with correction of the hypokalemia. … Muscle weakness usually does 
not occur at serum potassium concentrations above 2.5 meq/L if the hypokalemia develops slowly. … In 
addition to causing muscle weakness, severe potassium depletion (serum potassium less than 2.5 
meq/L) can lead to muscle cramps, rhabdomyolysis, and myoglobinuria.”  In one study, occurrence of 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             11 
premature ventricular contractions was twice as common when serum potassium was below 3.0 meq/L 
(43). 
In ALLHAT (39,40), chlorthalidone was also associated with more incident diabetes (defined as any 
fasting blood sugar >125 mg/dL) than were the other drugs (chlorthalidone: 14%, amlodipine: 11.1%, 
lisinopril: 9.5%). While overall, those with incident diabetes had more cardiovascular deaths, incident 
diabetes in the chlorthalidone group had lower cardiovascular deaths than incident diabetes in other 
groups, leading the ALLHAT investigators to conclude that “there is no conclusive or consistent evidence 
that this diuretic-associated increase in DM risk increases the risk of clinical events” (39), so “concerns 
regarding potential adverse diabetic effects associated with thiazide-type diuretic therapy should not 
inhibit its use” (40). Roush et al (44) recently reviewed this literature and concluded that 
“Chlorthalidone-induced diabetes mellitus (DM) is “chemical diabetes” rather than DM leading to 
cardiovascular pathology.” 
Also in ALLHAT, chlorthalidone did not increase the rate of development of either end-stage renal 
disease or of a 50% or greater decrease in glomerular filtration rate compared with lisinopril or 
amlodipine (45,46).  
Sodium, uric acid, and gout were not followed in ALLHAT. Thiazides have been associated with 
hyponatremia in observational studies. In the Rotterdam study, about 50 of 3400 patients treated with 
thiazides over 6 years developed Na < 130 meq/L, 4.5 times as many as controls (36). However, in SHEP, 
patients randomized to chlorthalidone did not differ from those receiving placebo in sodium levels after 
1 year (47).  
Similarly, in the observational Atherosclerosis Risk in Communities (ARIC) study, thiazides were 
associated with an increased risk of incident gout mediated by increased uric acid levels (41). A recent 
systematic review concluded “There is a trend toward a higher risk for acute gouty arthritis attacks in 
patients on loop and thiazide diuretics, but the magnitude and independence is not consistent. 
Therefore, stopping these useful drugs in patients who develop gouty arthritis is not supported by the 
results of this review” (48). In HDFP, patients randomized to chlorthalidone had reduced mortality 
compared with usual care regardless of baseline uric acid level (49). In a matched sample comparison of 
national pharmacy records, new onset gout episodes occurred with similar frequency in the year 
following prescription for chlorthalidone or hydrochlorothiazide, despite the 2 drugs being used in equal 
milligram doses (50). 
The above comparisons involving thiazide vs. no thiazide demonstrate effects that are minor and of 
uncertain clinical importance. In addition, two studies from university (51) and VA (52) settings changed 
19 and 40 patients (respectively) on a stable dose of hydrochlorothiazide to an equal milligram dose of 
chlorthalidone. Both reported reduced blood pressure with no significant metabolic effects except for 
one instance of hypokalemia in the university study.  
Changing from hydrochlorothiazide to a roughly equipotent half dose of chlorthalidone (the intervention 
proposed in this study) should result in even smaller effects. In the randomized study by Ernst et al (23), 
hypokalemia < 3.5 meq/L occurred in nearly identical proportions at 2:1 doses: 50% of patients on 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             12 
hydrochlorothiazide 25/50mg and 46% on chlorthalidone 12.5/25mg. Within the commonly used dosing 
range of 12.5-25 mg per day, potassium reduction was found to be equivalent for the 2 drugs in one 
meta-analysis (26), whereas the other found it to mirror the potency results, i.e. greater for 
chlorthalidone at equal milligram doses (27). In a Dutch population-based case-control study, 
hyponatremia was twice as common with chlorthalidone compared with hydrochlorothiazide at equal 
doses, but no difference was observed comparing 2:1 dosing (53). In the short-term randomized trials of 
609 and 1071 patients that compared equal doses (25 mg) of the 2 drugs in patients also taking an 
angiotensin receptor blocker, hypokalemia was rare, occurring in 1-2% (30,31). Summarizing the 
metabolic data available for the 2 drugs, a recent review (54) concluded that “factors such as serum 
potassium, glucose, lipids, endothelial function, and oxidative status” “are either favorable to 
chlorthalidone or are neutral in arriving at a decision as to which drug is superior.”   
More recently, a population-based observational study from Ontario compared effects of starting 
treatment with chlorthalidone (10,384 patients) vs. hydrochlorothiazide (propensity matched sample of 
19489 patients) with a mean follow-up of about one year (29). Patients treated with chlorthalidone 
received higher doses (despite its greater potency), and were less likely to also be treated with an ACEI 
or ARB (drugs that raise potassium levels). Chlorthalidone was associated with a small non-significant 
reduction in the composite cardiovascular outcome, from 3.4 to 3.2 per 100 patient-years (adjusted HR 
0.93, CI: 0.81-1.06).  However, treatment with chlorthalidone was associated with significantly more 
hospitalizations with (not necessarily “for”) hypokalemia (0.69 vs 0.27 events per 100 patient-years, 
adjusted HR 3.06, CI: 2.04-4.58) and hyponatremia (0.69 vs 0.49 events per 100 patient-years, adjusted 
HR 1.68, CI: 1.24-2.28). The authors included hospitalizations that listed electrolyte abnormalities as 
secondary diagnoses noted during hospitalizations for other reasons. Hypokalemia and hyponatremia 
were each recorded as a secondary outcome noted during hospitalization less than once per 100 
patient-years. In response to a letter suggesting that the analysis should be restricted to hospitalizations 
“for” hypokalemia (as primary diagnosis), the authors responded that doing so would result in so few 
hospitalizations that “such an analysis would be severely underpowered” (55). So while it is not known 
whether chlorthalidone caused more hospitalizations “for” hypokalemia, it is clear that such 
hospitalizations were rare. 
The Ontario study had the advantages of large size and direct comparison of the two drugs in a 
population. The principal disadvantages were the observational design and the very small (and therefore 
potentially quite different) proportion taking chlorthalidone. Incomplete adjustment for known 
confounders (e.g., for dose and co-treatment) or from unrecognized confounders in the treated 
populations could have influenced the findings, as noted in a letter by the ALLHAT investigators (56). For 
example, chlorthalidone is likely used more often by hypertension specialists who might have been 
more attentive to recording electrolyte abnormalities on discharge summaries. Review of US data 
indicates that chlorthalidone is used in patients with more severe co-morbidities than those given 
hydrochlorothiazide (57). The Ontario study nevertheless raises questions regarding the possible 
superiority of chlorthalidone. In the correspondence following its publication, both the ALLHAT 
investigators and the Ontario authors stress the need for a randomized trial, such as the one we are 
proposing, to resolve this uncertainty (55,56). 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             13 
In summary, the metabolic effects of thiazides are minor and have little or no clinical effect. Evidence 
from a variety of studies indicates that substitution of an equipotent dose of chlorthalidone for 
hydrochlorothiazide can be expected to have no more metabolic effect than might occur if the patient 
remained on hydrochlorothiazide without the substitution. This is the basis for our assertion that this 
substitution constitutes minimal risk. 
J. 
Expert views on the choice of drugs and the need for a randomized trial 
The evidence summarized above is consistent with a substantial benefit from using chlorthalidone 
rather than hydrochlorothiazide, but is not compelling, as the Ontario study illustrates. Many of the 
studies describing a possible advantage of chlorthalidone were conducted by Ernst and colleagues at the 
University of Iowa (7,18,22,23,26,28), but those authors have stated that “we do not believe there is 
strong evidence to support the use of chlorthalidone over HCTZ” (22). Ernst and Marvin Moser (who 
pioneered thiazide use in the 1950’s) wrote in 2009: “Whether hydrochlorothiazide and chlorthalidone 
are interchangeable in reducing the risk of cardiovascular events is questionable”(32). On the other 
hand, Messerli et al reviewed the literature and concluded that “there is no evidence showing that HCTZ 
in the dose of 12.5-25 mg reduces myocardial infarction, stroke, or death” and argue that “if a thiazide-
type diuretic is indicated, either chlorthalidone or indapamide should be selected” (6). The 2011 UK 
National Institute for Health and Care Excellence (NICE) guidelines for hypertension (58) recommend “a 
thiazide like diuretic, such as chlorthalidone…, in preference to a conventional thiazide diuretic such as 
bendroflumethiazide or hydrochlorothiazide”, whereas the 2013 European Society guidelines dispute 
this and conclude that “no recommendation can be given to favor a particular diuretic agent” (59). 
A recent review from investigators at the New Mexico VA (15) concludes: “The available evidence 
therefore supports both HCTZ and chlorthalidone as safe and effective drugs for treating hypertension. 
Although there are favorable trends both in terms of antihypertensive efficacy as well as clinical 
outcomes data with chlorthalidone compared with HCTZ, the results are not conclusive, and as such may 
not be enough to shift the treatment paradigm in favor of chlorthalidone, given the comfort level that 
most prescribers have with HCTZ. A head-to-head study looking at hard clinical outcomes, which may or 
may not ever be performed, may be the only way to resolve the ongoing debate as to which is the 
preferred thiazide for treating hypertension.” Floyd and Psaty noted in 2012 (60) that “In the area of 
pharmacological drug treatment for high blood pressure, the current question of primary interest is 
whether health outcomes associated with the use of hydrochlorothiazide and chlorthalidone may differ. 
…Reliable and valid comparisons between hydrochlorothiazide and chlorthalidone will require a large, 
long-term clinical trial.”  
As suggested by the New Mexico authors, it is extremely unlikely that a randomized clinical outcomes 
trial of hydrochlorothiazide vs. chlorthalidone will ever be undertaken except by the inexpensive 
methodology we are proposing. Neaton and Grimm, University of Minnesota Professors who 
participated in MRFIT, SHEP, and subsequent NIH hypertension trials, have been lobbying for such a trial 
since the end of SHEP more than 20 years ago. They have discussed the idea with the NHLBI project 
office numerous times over conference calls and had a meeting in Bethesda about this issue. According 
to Dr. Grimm, NHLBI project officers have maintained that they will only consider a 5 year proposal 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             14 
capped at $1.5 million a year. The Director of the NHLBI Cardiovascular division has recently written that 
“we can no longer afford to undertake randomized effectiveness trials that cost tens or hundreds of 
millions of dollars” (61). Apart from a trial design such as we are proposing, which may be unique to the 
VA system, these investigators found it impossible to design a study for an amount close to this budget. 
Richard Grimm concluded a 7/29/13 email to the principal proponent (FAL) with: “It looks like the last 
chance of getting a definitive answer for this incredibly important question is your VA proposal.” 
K. 
Summary of evidence and potential impact of the proposed trial 
Direct evidence shows chlorthalidone to be more potent and longer-lasting than hydrochlorothiazide, 
and indirect interventional evidence from the Roush network meta-analysis (21) suggests that 
chlorthalidone may have a more beneficial effect on cardiovascular events, whereas the large Ontario 
observational study (29) did not find a significant reduction in adverse cardiovascular events. In 
comparing these 2 methodologies, the International Society for Pharmacoeconomics and Outcomes 
Research Indirect Treatment Comparisons Good Research Practices Task Force concluded that “a 
network meta-analysis must be considered observational evidence, but is arguably less prone to 
confounding bias than an observational comparative (prospective) cohort study” (62). 
Currently available data thus favor a likely substantial benefit from chlorthalidone compared with 
hydrochlorothiazide, but these data have had little effect on prescribing, which continues to 
overwhelmingly favor hydrochlorothiazide.  
If cardiovascular events were reduced by even a small amount by chlorthalidone, the public health 
effect would be considerable because of the large number of patients who take diuretics. For the VA, it 
would likely justify the effort and cost of implementing a national policy to change drugs. However, the 
evidence is not yet persuasive enough to justify active measures directed at increasing chlorthalidone 
use. A randomized head-to-head comparison of the effectiveness of these two drugs at reducing 
cardiovascular events is clearly necessary to determine whether chlorthalidone is superior and if so, to 
justify efforts to change practice. 
IV. 
The Point of Care Program within the VA’s Office of Research and Development 
A. 
Program Background 
Medical decision making is informed by clinical trials and observational studies.  While clinical trials are 
the gold standard in clinical research the high cost of conducting these studies combines with issues of 
generalizability to limit their contribution to changes in medical practice.  Observational studies are far 
less expensive and thus more numerous, addressing a broader scope of clinical issues.  However, their 
primary failing is that the lack of randomization often leaves open the possibility of bias due to selection 
by indication, and residual confounding of results due to unobserved prognostic factors that influence 
treatment decisions.   
Point of care (POC) randomization represents an intermediate strategy between these two approaches.  
The intent is to introduce the opportunity to randomize patients at decision points in clinical care where 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             15 
two or more alternatives are considered equivalent on average by the medical community (that is, 
clinical equipoise exists).  Patients who agree to be randomly assigned to treatment options will become 
subjects in the clinical experiment.     
POC randomization preserves the experimental quality of clinical trials without the cost of the clinical 
trial apparatus; recruitment and randomization is done at the point of care with minimal perturbation of 
work flow, and outcomes are assessed by automated extraction of data from the medical record.  
Reduction of the need for research staff interaction with potential subjects (limited to obtaining 
informed consent) greatly reduces cost and generates data that reflects the effectiveness (rather than 
efficacy) of experimental interventions in clinical care.   
To be effective, the additional burden on patients and health care providers imposed by POC 
randomization must be minimal.  The VA electronic medical record system (VistA) can be customized to 
identify, enroll and randomize patients and serve as the source of outcomes data and is thus well suited 
for such a trial design.  Subject recruitment and enrollment will be accomplished by embedding 
processes within the VistA system through a series of dialog boxes.  Furthermore, an external system 
will extract consent and randomization data from the databases supporting VistA. 
As noted in a recent editorial (63), “With optimal use of EMRs, the administrative costs of a trial need 
not increase with the sample size; this decoupling of costs and size facilitates large, simple, and 
inexpensive trials that have the potential to transform health systems into entities that learn and 
continuously improve.” 
As the VA system continues to lead in the development of EMR that support increasingly sophisticated 
monitoring for outcome-based evaluation of care, we anticipate that the methods we test using POC 
randomization will have even greater scope for application. The methods are also a natural fit for testing 
personalized and precision medicine strategies and for experimental comparative effectiveness 
research.  
B. 
POC Pilot Study 
The first implementation of POC randomization is a pilot study that was conducted at 3 VAMC across 2 
VISNs. The goal of the pilot was fivefold: 
 
1. To test the feasibility of the method for modification of VistA/CPRS screens and the ability to 
randomize within the system; 
2. To assess patient and provider acceptance of the new methodology; 
3. To assess the regulatory acceptance of: 
a. Informed consent procedures; 
b. Safety monitoring; 
c. Ethical considerations; 
4. To test the method for data extraction and passive collection of endpoint data using the EMR; 
5. To apply Informatics techniques to refine and improve efficiencies in the identification of 
endpoints, etc.  
 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             16 
The pilot is a comparison of two standard strategies of insulin administration for hospitalized patients 
and is designed as an open-label, randomized trial comparing sliding scale regular insulin (ssRI) to a 
weight based regimen for control of hyperglycemia in non-ICU inpatients. The strategy is to enroll 
patients into the study directly from the point of contact with clinical care within all inpatient facilities. 
All non-ICU patients who require in-hospital insulin therapy are eligible for this study.  Clinicians decide 
at the time of care (through the VistA order entry screen for insulin) whether or not they will allow their 
patient to be contacted by POC study staff.  If the treating clinician agrees, consenting patients are 
randomized to treatment arms and treated by their clinicians according to usual practices. All technical 
modifications necessary are executed within the “Clinical Alert” package. Consenting patients are then 
followed through VistA from randomization until 30 days post discharge.   Comparisons of effectiveness 
will be formally conducted using length of hospital stay measured in days as our primary outcome 
measure. 
The pilot has demonstrated the feasibility of the POC method as an alternative design to traditional 
trials. To date, 92% of eligible patients have accepted participation and have been consented into the 
pilot protocol. Additionally, 71% of all clinicians that are able to order medications have accepted 
randomization within the clinic and have referred their patients to the protocol.  All patient data has 
been extracted from the EMR and has been validated with chart review by a qualified clinician. There 
have been no significant safety events and no findings from regulatory audits or the local institutional 
review boards.  
C. 
The POC National Program 
The goal of POC program is to deliver state of the art treatments to patients simultaneously with 
enrolling them as subjects to redefine that care. By institutionalizing a process of statistically sound and 
efficient learning, and by integrating that learning with automatic implementation of best practice, the 
participating VA health care systems will accelerate improvements in the effectiveness of care for 
veterans.  With this goal in mind, Point of Care Research has been designated as one of the Secretary’s 
(SECVA) Transformational Initiatives within the VA and within the Office of Research and Development 
(ORD).  Accordingly, this initiative has a national scope and an operating budget of approximately 
$10.2Million (exclusive of study budgets).    
The Boston CSPCC has been tasked with leading the effort to implement POC randomization within the 
VA. To that end, our mission is to build the infrastructure necessary to support POC research; to educate 
providers, veterans and investigators on the initiative; to build consensus for support of the initiative 
among the VA community as a whole; and to explore the ethical, scientific, and regulatory aspects of the 
POC method itself.  In order to fulfill its mission, the Boston CSPCC collaborates with national leaders in 
the fields of medical ethics and pragmatic clinical trials to produce scholarly works and it will conduct 
focus groups of veterans, veteran service organizations, and providers in order to develop a national 
educational campaign for all VA stakeholders.   
V. 
 Relevance of our trial design to current needs of VA healthcare 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             17 
The most reliable way to learn if medical interventions provide more benefit than harm for our patients 
is through large randomized trials (64). However, large randomized trials that enroll thousands of 
patients can cost hundreds of millions of dollars, placing them out of range for most payers, including 
VA.  As a result, many important questions remain unanswered.  
We are proposing herein a ‘clinically integrated’ study design (65,66) that will incorporate and extend 
previously described VA ‘Point of Care’ Clinical Trial methodology (67,68). This is an efficient and 
inexpensive design, that will rely on a centralized processes involving mail, phone, and data extraction 
from the VA electronic medical records (EMR) , assisted by a designated study champion at each site 
(the Site Liaison) and by local Clinical Application Coordinators (CACs). These methods will allow us to 
avoid having to employ study personnel at each site to manage patients and collect data. As a result, the 
infrastructure costs typically dedicated to these activities can be reinvested to answer other questions 
for the healthcare system.  The goal, as Lauer and D’Agostino suggest, is “to design and conduct 
megatrials with what we have: bigger data and smaller budgets” (61). 
The following quotes, excerpted from the 2011 Institute of Medicine report “Learning what works best - 
the nation’s need for evidence on comparative effectiveness in health care”(69), provide support for our 
study objectives and design:  
“A core objective for the nation is achieving the best health outcome for every patient. This objective 
simply cannot be accomplished until we have better evidence on which to base healthcare decisions”; 
“the most rapidly growing problem is that of our inability to produce the needed evidence in a timely 
fashion”; “Estimates of the proportion of medical care in the United States that is based on, or 
supported by, adequate evidence range widely. However, given concerns about the extent to which this 
information may be generalized, and the quality of the evidence which is used, some place this figure at 
well below half.”; “Within the overall umbrella of clinical effectiveness research, the most practical need 
is for studies of comparative effectiveness, the comparison of one diagnostic or treatment option to one 
or more others.”; “issues in need of additional systematic evaluation … include issues related to the 
comparative evaluation of different drugs within a single class”; “A learning healthcare system is one in 
which the clinical research paradigm depends more judiciously on the serial conduct of randomized 
controlled trials—important, but often too expensive, untimely, and of limited applicability—and draws 
more heavily on electronic health records (EHRs) to generate evidence as a natural by-product of the 
clinical experience.” 
More recently, the FDA has launched a Clinical Trials Transformation Initiative intended to promote and 
enable the conduct of larger, simpler, less expensive randomized trials using streamlining methodologies 
such as use of electronic health records (70). 
In addition to addressing an important clinical question, our proposed trial is responsive to all these 
needs. This trial represents a new efficient methodology designed to provide reliable answers to 
practical clinical questions at a greatly reduced cost.  
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             18 
VI. 
Study Design 
The study design is a multicenter clinically integrated (65) [or “point of care” (67,68)] prospective 
randomized open-label blinded-endpoint (PROBE) trial (71).  
VII. 
Study Population 
A. Inclusion Criteria 
Eligible patients are those (including women and minorities) who: 
 
1.  Are over age 65 years 
2.  Are receiving hydrochlorothiazide from the VA pharmacy at a daily dose of 25 or 50 mg  
3.  Have a most recent SBP in EHR ≥ 120 mm Hg, with no SBP < 120 mm Hg recorded in  EHR in 
the previous 90 days 
B. Exclusion Criteria 
 
Patients will be excluded if they are known to have any of the following:  
1.  Impaired decision-making capacity rendering the patient unable to provide informed consent 
(i.e., if there is any question during the nurse’s EHR chart review that the individual does not 
have the ability to make an autonomous decision or the PCP declines permission to randomize)  
2.  Death expected within 6 months (inferred by PCP permission to randomize) 
3.  K< 3.1 meq/L (or 3.5 meq/L if on digoxin) in the past 90 days (assessed by EHR review) 
4.  Na < 130 meq/L in the past 90 days (assessed by EHR review) 
5.  Known to be enrolled in Medicare Part C (assessed through administrative data or on consent 
phone call). This exclusion will only be employed if we determine that we cannot obtain 
sufficient information from Part C data (see below under Rationale). 
Enrollment in another CSP interventional study is not an exclusion criteria for DCP.  Dual 
enrollment is addressed in Section IX. Study Procedures. 
C. Rationale  
We limit to age over 65 years to allow data collection through Medicare (which is only widely available 
starting at this age) [and will exclude known Part C enrollees (those enrolled in Health Maintenance 
Organizations), for whom usual encounter data is not available through Medicare if we determine that 
we cannot obtain sufficient information from Part C data].  
We limit randomization to patients receiving hydrochlorothiazide because a) 95% of thiazide-type 
diuretic prescriptions are for hydrochlorothiazide, b) there is little evidence to suggest that 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             19 
chlorthalidone is inferior to hydrochlorothiazide, and c) the few PCPs who have deliberately chosen to 
use chlorthalidone over the much more commonly used hydrochlorothiazide are less likely to be willing 
to change drugs.  
We limit to hydrochlorothiazide doses of 25 or 50 mg because lower doses may not be effective and 
cannot be easily converted to chlorthalidone (which is available only in 25mg tablets), and because 
higher doses are not recommended and are rarely used.  
We limit to SBP ≥ 120 mmHg primarily to minimize risk from hypotension, and also to avoid enrolling 
patients whose blood pressure is already low enough that a potentially more effective drug would not 
be expected to add benefit (72, 73). The cutoff point of 120 mmHg was selected, in part, because we are 
using routine clinic blood pressures recorded in EHR to determine study eligibility. These are obtained 
using a less rigorous measurement protocol than is normally used in randomized trials and that tends to 
overestimate blood pressure (74), in one study by a mean of 8 mmHg (75). 
We will attempt to exclude patients in Part C as long as it appears that we will not be able to obtain 
adequate data. Part C data have not been available for research purposes in the past, but CMS plans to 
make the Healthcare Effectiveness Data and Information Set (HEDIS) for the years 2006-2011 available 
sometime in 2015. We plan to check with CMS periodically, and if, before or during enrollment, 
adequate Part C data appear to be accessible, we will discontinue the exclusion and attempt to enroll 
these patients.  
VIII. 
Study Intervention 
Participants will be randomly assigned to remain on their current dose of hydrochlorothiazide (25 or 50 
mg), or to replace it with half that dose of chlorthalidone (12.5 or 25 mg, respectively), both changeable 
by the PCP. Chlorthalidone 12.5 mg will require tablet splitting, and a splitter will be mailed with the 
prescription. [Tablet splitting is a common procedure in VA pharmacy, sometimes including the splitting 
of hydrochlorothiazide 50 mg to get 25 mg. A recent review (76) concluded that “Tablet splitting does 
not seem to significantly affect clinical outcomes related to management of hypertension, cholesterol, 
or psychiatric disorders, nor influence overall patient adherence.”]  
Rationale for the default use of 1:2 chlorthalidone dose:  Because chlorthalidone is not used at lower 
doses than hydrochlorothiazide in practice (7,28,29), it could be argued that the most appropriate 
pragmatic comparison would be a 1:1 substitution. We selected the 1:2 dose default for 3 reasons: 1) as 
noted above, the use of similar doses in practice probably reflects greater awareness of appropriate 
thiazide dosing by the small proportion of prescribers who use chlorthalidone, rather than belief that 
the potencies are equivalent, 2) a 1:1 design would change the study question from assessment of a 
possible inherent difference between the two diuretics to an assessment whether low doses of 
hydrochlorothiazide are less effective, whereas our interest is in the former question , and 3) an equal 
dose of chlorthalidone would represent an intensification of diuretic therapy, resulting in increased 
effects on blood pressure and blood chemistries (51,52,53), whereas the 1:2 design results in virtually no 
change in blood pressure or metabolic effects (see Background and Rationale, parts F and I). 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             20 
IX. 
Study Procedures 
A. Procedures prior to patient enrollment 
We will attempt to identify a “Liaison” at each site, usually a physician in primary care and/or 
hypertension management whose role will be limited to identifying key personnel at the site and 
introducing the study by giving presentations to local Primary Care Providers (PCPS), pharmacy, the 
Information Resource Management service (IRM), Clinical Application Coordinators (CACs), and 
Information Security Officers (ISOs) and subsequently referring all questions and comments to Boston 
CSPCC. The Liaison will not be involved in recruitment or have patient interaction related to the study. 
Because we are introducing a new design and intend to evaluate its success, PCPs are also considered to 
be research subjects (see XI. Biostatistical Considerations, F. Secondary Data Analysis, 4. Primary Care 
Provider Metrics of Interest). 
Our procedures are summarized in a flow diagram (Appendix C). Working through the VA national ISO 
structure and local CAC’s and pharmacy personnel, we will obtain permission for Boston CSPCC to have 
the necessary access to local EHR systems to enter notes and post orders as View Alerts to PCPs and to 
collect the study data on enrolled patients. Research staff at the Boston CSPCC will be responsible for 
communicating with local PCPs, coordinating and implementing all patient recruitment activities and 
completing the enrollment process including randomization and placing assigned treatment orders for 
signature by the PCP in EHR.  The Boston CSPCC will partner with the Minneapolis VA Medical Centers to 
conduct centralized calling activities, including contacting potential participants and obtaining informed 
consent by telephone. 
We plan to roll out the study in blocks of sites. When a site starts up, the Boston CSPCC will generate a 
local list of PCPs along with their eligible patients. We will also identify local PCP and pharmacy email 
groups and obtain the PCPs’ and pharmacists VA Outlook email addresses. The Boston CSPCC will send 
an introductory letter (by mail and email) to local PCPs signed by the Study Chair providing information 
about the study (Appendix A.1, A.7).  Introductory emails (Appendix A.7) will be sent by the study team 
via ProjectFlow, while letters will be sent via external mail contractor. The Site Liaison or study team will 
present information about the study at primary care staff meetings and other forums (individual PACT 
meetings, video staff meetings for Community-Based Outpatient Clinics, etc.). If no meetings are 
available the study may use a video of slides accompanied by an audio track to conduct site education 
for providers.  This video can also be accessed at any time by consented providers that would like to 
review the study information.  To further provider education, a second reminder email with an attached 
summary document and a link to the video will be sent to providers prior to being contacted within the 
EHR system (Appendix A.8). The second email is to act as a brief reminder of the study to providers, not 
to act as an informed consent document.  
After these activities are completed, a View Alert ‘testpatient’ order will be sent to each PCP identified 
by the method above. The testpatient order will accompany a progress note containing the text of the 
Provider Information Sheet, which will contain the elements of informed consent and detail the study 
procedures (Appendix B.3).  By signing the ‘testpatient’ view alert order, the PCP is agreeing to 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             21 
participate in the study as a research subject and allowing the recruitment letter (Appendix A.2) to be 
sent to eligible patients. Alternatively, the PCP can “discontinue” the order, in which case that PCP will 
not be enrolled in the study and his/her patients will not be contacted at this time. As some PCPs may 
discontinue the order because they did not recognize the purpose of the ‘testpatient’ order we may 
send a second View Alert ‘testpatient’ order approximately 8 weeks later to PCPs who decline to give 
the PCP the opportunity to participate and/or confirm their desire not to participate.  
B. Enrollment procedures 
The procedures described below are summarized in a flowchart (Appendix C). Provider and patient mail 
will be sent primarily through an external mail contractor and also by the study team, as needed. The 
external contracted mailing vendor will receive participants’ names, addresses, information about 
treatment assignment, and other protocol procedures. No other patient health information will be sent 
to the mail vendor.  
Using the VA electronic medical record, the Boston CSPCC will identify eligible patients of PCPs who 
signed the testpatient order.  The mailing vendor or study staff will mail the study recruitment letter 
(Appendix A.2) with Informed Consent Information Sheet (Appendix B.2), which contains the text of the 
consent script (Appendix B.1), to these patients. The study team will attempt to send the letter 3-4 
months before the patient’s next planned appointment with the PCP to make it easier for the PCP to 
obtain any follow up on blood pressure and laboratory tests that the PCP might want. The VA Advanced 
Clinical Access/Recall system may prevent early detection of these appointments. The study Invitation 
Letter and the Informed Consent Information Sheet will provide information about the study and the 
opportunity for the patient to opt out of future contact from the study. Patients can opt out by leaving a 
voicemail with their name, date of birth, and the last four digits of their social security number. Patients 
that leave an opt-out message will only be contacted in the rare case that the their identity cannot be 
confirmed. Additional Spanish letters will be sent to all patients in Puerto Rico and any patients that 
request a Spanish version. Any Spanish speaking Veteran will speak to a Spanish speaking study team 
member, contact a voicemail box recorded in Spanish, and will consent in Spanish.  
If no ‘opt out’ call is received within 2 weeks after the Patient Information Letter is sent, the patient will 
be contacted to determine if they wish to participate. This will be done in majority by trained callers 
using a telephone line that displays the calling source as the VA on caller ID. Trained research staff may 
also consent patients and may also contact patients during follow-up calls. We will make multiple 
attempts to reach the patient, only leaving a maximum of 3 spaced out messages. More than 3 will only 
be left if the caller is returning the patient’s call. The U.S. National Health Interview Survey used a 
maximum of 15 call attempts and a 1994 study confirmed this number to be optimal (77). In 2 surveys 
conducted by Statistics Sweden, nonresponse rates stabilized at 15 and 20 maximum call attempts (78). 
In the Consumer Assessment of Health Plans Study, “most hard-to reach non-respondents were called 
10 or more times” (79). A recent study at the University of Minnesota (80) had an amendment approved 
by the UMN IRB in 2011 to increase the maximum number of call attempts from 6 to 12. Regarding left 
messages, Koepsell (81) “found that leaving a brief message about the study and promising a call-back 
improved the response rate by nearly 20 percentage points”. If a Veteran expresses interest on the last  
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             22 
call or leaves a voicemail after 15 calls, 3 additional call attempts will be made. On the phone call, the 
information included in the letter will be reviewed and the patient’s informed consent will be sought 
using a pre-approved Telephone Consent Script (Appendix B.1). Research staff and study nurses may 
occasionally call consented patients to evaluate consent call procedures, discuss any concerns the 
patient’s raise, and to complete withdrawal procedures. Additional study information may be 
transmitted to Veterans, per their request, in the format that best suits their needs (Appendix A. 12). All 
email communication between the study team and Veterans will occur over My Healthy Vet. The mail 
vendor or study staff may also re-send introductory study materials to Veterans if they have not been 
reached after 5 calls.  The mail vendor or study staff may also send a newsletters or reminder 
information to enrolled patients as needed (Appendix A.15, A.10, A.11). At the end of recruitment a 
letter (Appendix A.20) will be sent to any patient who has not been given a study status. Meaning they 
have not declined, agreed to participate, or were otherwise found to be ineligible in the study. This 
letter will not be sent to patients who have received 6 or more calls, to avoid confusion.  Study data will 
be dispersed to all randomized patients via an end of recruitment letter (Appendix A. 23), consented 
PCPs will receive a the same information via email (Appendix A.22) 
At the end of recruitment all consented providers will receive an email (Appendix A.24) inviting them to 
participate in a participation survey (Appendix A.21). In addition, Minneapolis providers will have the 
opportunity to take an in-person interview (Appendix A.25). The survey data will be aggregated to 
inform and improve future designs of pragmatic studies.  
After telephone consent is obtained, a preliminary eligibility check will be performed to prevent sending 
randomization View Alerts to providers for ineligible patients. If a patient is deemed eligible, a View 
Alert order will be sent to the PCP which, if signed by the PCP, will indicate permission to randomize that 
particular patient. If a patient is deemed ineligible at that time, a determination will be made whether 
they are temporarily or permanently ineligible.  Temporary ineligibility may be due to lab values or 
blood pressure measurements out of inclusion range that could change over the subsequent months.  
Temporarily ineligible patients may receive a letter indicating that they are not presently eligible, but 
will continue to be considered for randomization if their eligibility criteria change.  Eligibility will be re-
assessed for temporarily ineligible participants periodically.  If a patient becomes eligible again six 
months or more after consent, a study team member will attempt to call the patient to reaffirm 
consent.  After three attempts the study team will proceed with randomization. Randomization will yield 
a letter with study information allowing the Veteran to withdraw or contact the study if needed.  
Permanently ineligible patients will receive a letter indicating that they will no longer be considered for 
randomization.  Alternatively, if the PCP believes that patient should be excluded for any reason (e.g., 
incompetence or short life expectancy), the order can be “discontinued” and the patient will then 
receive a letter saying that their PCP declined their participation in the study (Appendix A.3). 
If an eligible patient is enrolled into another CSP interventional study prior to randomization in DCP, the 
DCP PI will initiate a conversation regarding dual enrollment with the other study’s PI.  If the 
investigators of both studies agree, they will sign a memo describing that agreement and any additional 
study activities or safety reporting requirements resulting from enrollment in both studies.  Additionally, 
this memo must be signed by the studies’ respective CSPCC directors prior to randomization into DCP. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             23 
DCP will dual enroll with CSP577: CONFIRM, CSP2005: VALOR, and CSP2016 per the guidance from the 
signed memos.  
C. Randomization 
After the PCP signs the order allowing the patient to be randomized, the patient will be randomized by 
the Boston CSPCC. Randomization will be to chlorthalidone or hydrochlorothiazide with equal 
probability. Randomized group will be open label, but allocation will be concealed before randomization 
and irrevocable afterwards. All randomized patients will be included in the analysis according to the 
intent-to-treat principle. Outcome assessment will be conducted by investigators blinded to treatment 
assignment.  
We are thus proposing a “prospective randomized open-label blinded-endpoint” (PROBE) trial (71). The 
rationale for our open-label design is several fold: 1) since there is no local coordinator, it is essential 
that the PCP manage the diuretic therapy, and we are concerned that this may not always occur if we 
use a blinded study drug, 2) there is no local investigator to assist with emergency unblinding, 3) we 
believe that keeping patients on open label therapy, being more familiar and straightforward from the 
patient’s perspective, will enhance recruitment, thereby improving both feasibility and generalizability, 
4) local pharmacy management of blinded drug would require a level of effort and local engagement in 
research incompatible with our streamlined study structure, 5) the expense of producing a study 
preparation that is identical for the two drugs, and then labeling and tracking each patient’s therapy, 
would greatly increase cost, defeating the purpose of our highly efficient clinically integrated design. A 
recent meta-analysis found PROBE trials to be comparable to blinded trials in terms of assessing 
antihypertensive drug effect on blood pressure measurements, though clinical outcomes were not 
examined (71). 
At the time of randomization, a templated text order placed by the Boston CSPCC will appear as a View 
Alert to the PCP. The order will indicate randomized assignment and reference the associated progress 
note that provides the following reminders: 1) when resolving the view-alert orders, the PCP can accept 
the order by signing as is or change the dose, 2) the PCP can discontinue the order to continue their 
patient on his/her current diuretic, 3) the PCP may wish to order any desired laboratory tests or blood 
pressure checks, and 4) the PCP should manage the diuretic in the future according to the patient’s 
needs.  
Patients will be sent a letter informing them of their randomized group (Appendix A.4). Patients 
assigned to hydrochlorothiazide will simply remain on their current prescription. For patients 
randomized to chlorthalidone, the Boston CSPCC will also generate View Alert orders to the PCP 
cancelling the hydrochlorothiazide prescription and replacing it with chlorthalidone. Patients 
randomized to chlorthalidone will be instructed to discard their hydrochlorothiazide pills, and will be 
reimbursed for their co-pay on the discarded pills. The change from hydrochlorothiazide to 
chlorthalidone is a typical pharmacy action in usual care and will otherwise be handled with usual 
pharmacy procedures and information at that medical center.  
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             24 
In the unlikely event that the PCP, having very recently signed the “permission to randomize” view alert 
order, does not sign (i.e., “discontinues”) the initial study drug order for chlorthalidone, the patient will 
still be analyzed in the randomized group according to intent to treat. In these instances, we may 
contact the PCP to ask the reason for the discontinuation of the order.  
We will monitor drug prescribing for study patients throughout the study. If the study drug is 
discontinued, a prescription is written for the other diuretic (cross-over), or the prescription is not 
refilled for 90 days after expected, a View Alert may be sent to remind the PCP about the study. If the 
situation persists after 2 weeks, we will review the chart to determine if the lapse was intentional and if 
so, try to determine the reason. If questions remain after the review, we may query the PCP. 
X. 
Outcome Measures  
A. Primary outcome 
The primary outcome measure will be time to a major cardiovascular event, defined as a composite 
outcome comprised of the first occurrence (after randomization) of any of the following:  
1. Stroke 
2. Myocardial infarction 
3. Urgent coronary revascularization (completed or attempted) because of unstable angina 
4. Hospitalization for acute congestive heart failure  
5. Non-cancer death  
B. Secondary outcomes  
 
Secondary outcomes will include:  
1. All deaths 
2. The composite outcome substituting all deaths for non-cancer deaths 
3. “Possibly vascular deaths” defined as all deaths caused by vascular diseases, diabetes, 
external causes, and unknown causes 
4. The composite outcome substituting “possibly vascular deaths” for non-cancer deaths 
5. Each of the 5 components of the composite primary outcome 
6. Any revascularization of any artery  
7. Erectile dysfunction, defined as first prescription for PDE5 inhibitor or referral for ED 
C. Process variables 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             25 
1. Mean blood pressure during the study (outpatient clinics only; excludes inpatient, 
Emergency Department and Operating Room) 
2. Time to discontinuation of the randomly assigned diuretic (defined as discontinue order or 
no prescription for ≥ 6 months at last observation during study period) 
3. Mean compliance with study drug using “Medication Possession Ratio” (82) (used by VA 
Pharmacy Benefits Management Services)  
4. Other antihypertensive drug use 
D. Tertiary Outcomes 
1. Hospitalization for primary diagnosis of hypokalemia, hyponatremia, or renal failure 
2. Renal failure. Defined as dialysis or renal transplant. (Doubling of serum creatinine from 
baseline will also be recorded and reported in the final analyses). 
3. Other recorded hypokalemia (< 3.1 meq/L), or hyponatremia (< 130 meq/L)  
4. New diabetes, defined as first use of a medication for diabetes 
5. Acute gout episodes   
6. New allergic reaction to thiazide-type diuretic to be found in EMR allergy data 
E.  Rationale for elements of composite primary outcome  
The elements of the composite primary outcome are intended to represent the clinically important 
effects of diuretic therapy for hypertension. Myocardial infarction and stroke are traditional outcomes 
for cardiovascular clinical trials and will not be further justified here.  
Stroke. Stroke is defined from the American Heart Association/American Stroke Association updated 
definition of stroke for the 21st century (83) and includes central nervous system infarction (brain, spinal 
cord, or retinal) attributable to ischemia based on neuropathological, imaging, and/or clinical evidence; 
ischemic stroke accompanied by overt symptoms; and stroke caused by intracerebral hemorrhage, 
subarachnoid hemorrhage, or cerebral venous thrombosis. Stroke also includes any episode of acute 
neurological dysfunction presumed to be caused by ischemia or hemorrhage, persisting ≥24 hours or 
until death, but without sufficient evidence to be classified as one of the above. We exclude silent 
central nervous system (CNS) infarction, silent cerebral hemorrhage, major brain trauma including 
subdural hematoma or hemorrhaging, intracranial neoplasm or metastasis, coma due to metabolic 
disorders or disorders of fluid or electrolyte balance, peripheral neuropathy, or central nervous system 
infections. 
Myocardial infarction. Myocardial infarction is defined from the third universal definition as evidence of 
myocardial necrosis in a clinical setting consistent with myocardial ischemia (84).  
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             26 
Urgent coronary revascularization. Urgent coronary revascularization is an important outcome because 
these events accurately reflect both the progression of underlying atherosclerotic vascular disease and 
represent an important contributor to cardiovascular morbidity and healthcare costs. Disease 
progression that formerly resulted in myocardial infarction now frequently results in revascularization 
that aborts the infarction. Furthermore, because of increasingly sensitive troponin assays, many patients 
having urgent coronary revascularization attributed to unstable angina actually have mild troponin 
positivity and would be classified as myocardial infarctions in a classic trial design with in-depth outcome 
review (Christopher P. Cannon, MD, personal communication, Aug 2013). Including urgent coronary 
revascularization in our study will prevent us from missing these infarctions. Urgent coronary 
revascularization is more restrictive than the revascularization outcome usually reported in previous 
trials and selects for the most clinically relevant events. For example, in the PEACE trial of patients with 
stable coronary artery disease and normal ejection fraction (85), “all coronary revascularizations” were 
more frequent than all the other events combined that make up our composite. On the other hand, in 
the (TRA2°P)-TIMI 50 trial of an antiplatelet agent in patients with vascular disease (86), urgent coronary 
revascularization because of unstable angina was less frequent than myocardial infarction and similar in 
frequency to cardiovascular death or stroke, and increased the composite rate in the placebo group 
from 10.5% for those 3 outcomes to 12.4% for those 3 outcomes plus urgent revascularization.  
Reductions in urgent coronary revascularization represent an important contribution to the overall 
effectiveness of therapy. The observed reductions in urgent revascularizations in randomized trials are 
concordant with changes in other major outcomes. In (TRA2°P)-TIMI 50 (86), the hazard ratio for the 
primary composite outcome of cardiovascular death, myocardial infarction, or stroke was 0.87, and for 
urgent coronary revascularization was 0.88.  Urgent coronary revascularization has also been used in 
TRACER (87) and is being used in EXAMINE (88). CSSEC recently approved a broader revascularization 
outcome for VA CSP #593, the VA Fenofibrate Intervention Trial (VA-FIT) (for which the indications 
included stable angina with a >50% target lesion). 
In summary, urgent coronary revascularization is a significant contributor to cardiovascular morbidity 
and health care costs, its inclusion will allow assessment of the full impact of therapy, and its relative 
contribution to overall endpoints is not anticipated to be disproportionate to that of other study 
outcomes. Our definition of urgent coronary revascularization will consider completed or attempted 
coronary revascularization procedures performed because of unstable angina. Unstable angina is further 
defined as any increase in angina, and/or inadequate response to increased anti-anginal therapy cited as 
the reason(s) for the procedure, and with the medical record citing that increased angina and/or 
inadequate response to increased anti-anginal therapy occurred within 30 days before the inpatient 
procedure code for coronary revascularization.    
Hospitalization for acute congestive heart failure.  Hospitalization for acute congestive heart failure is 
another important component of our primary outcome.  It will, in most instances, represent a new 
diagnosis of heart failure because most patients with established heart failure are maintained on a loop 
diuretic such as furosemide and are not treated with hydrochlorothiazide and thus would not be 
enrolled in our study.  We will seek to identify clinical exacerbations of symptoms (e.g., not 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             27 
hospitalization for ICD placement), which should be associated with intensification of treatment, which 
we will assess in our algorithm.  
Heart failure is a major public health problem with a profound impact on prognosis and also on costs, 
and is the most frequent cause of hospitalization among people older than 65 years (89). Its impact is 
summarized in the AHA 2013 update (90): “HF incidence approaches 10 per 1000 population after 65 
years of age”, …“approximately 50% of people diagnosed with HF will die within 5 years”, …“One in 9 
deaths has HF mentioned on the death certificate”, …“In 2009, HF any-mention mortality was 274 601” 
and “HF was the underlying cause in 56 410 of those deaths”.  
Heart failure and stroke are the two major cardiovascular outcomes most related to hypertension and 
most benefited by treatment of hypertension. Seventy-five percent of heart failure cases have 
antecedent hypertension (90). The Framingham Heart Study (91) found the highest risk ratio from 
hypertension to be for heart failure in men (Figure 1).  
  
Figure 1. A prospective analysis of the 36-year follow-up data from the Framingham Heart Study (91) 
demonstrates that hypertension (blood pressure ≥ 140/90 mmHg) predisposes to all major 
atherosclerotic cardiovascular disease outcomes, but the largest risk ratios are for cardiac failure and 
stroke in men. 
Diuretic-based treatment arms in outcome trials have reduced HF by an average of 50% over placebo 
(compared with 30-40% reduction for stroke), and more effectively than calcium channel blockers and 
ACE inhibitors in comparative trials (Figure 2) (5).  In ALLHAT (89), the alpha blocker doxazosin, the 
calcium channel blocker amlodipine, and the ACE inhibitor lisinopril were associated with 80%, 38% and 
19% higher risk of heart failure compared with chlorthalidone. Therefore, heart failure is likely to be one 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             28 
of the most sensitive outcomes for detecting a true difference in reducing cardiovascular disease 
between the two diuretics in our study. 
 
Figure 2. From a network meta-analysis of hypertension trials (5). Heart failure (CHF) can be seen to be a 
particularly effective outcome for discriminating between diuretics and other drugs. “CVD Events” 
include CHD, CHF, stroke and CVD deaths. 
Hospitalized heart failure is not disproportionately common compared with our other outcomes. In the 
principal ALLHAT report (20), there were 885 non-fatal MIs, 724 hospitalized or fatal heart failure 
events, and 675 strokes. Hospitalized heart failure events in ALLHAT attracted close scrutiny because 
they were reported by site investigators and not adjudicated. The authors undertook a separate study in 
which they successfully validated these events (89), and from which they concluded “Heart failure 
proved to be a common outcome in ALLHAT and one that was affected differentially by the randomized 
treatment assignments. In addition, patients who developed HF had significantly poorer survival than 
those who did not. Whether this poor prognosis can be altered presents an important clinical and public 
health question. Thus, in planning future hypertension treatment trials (and perhaps also treatment 
trials in other populations at high risk of HF, such as diabetics and survivors of acute coronary 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             29 
syndromes) serious consideration should be given to including HF in the primary end point, along with 
death, MI, and stroke” (italics added).  
Heart failure is reasonably well identified using discharge diagnoses. In a population-based study of 4537 
cases of heart failure from Olmsted County MN, ICD-9 code 428 constituted 80% of heart failure codes, 
and 82% of the cases coded as 428 met Framingham criteria for heart failure when records were 
reviewed by experienced abstractors (92). 
Identification of clinically important episodes can be improved by looking for evidence of treatment 
intensification. The draft report of the FDA expert panel on Cardiovascular Endpoints in Clinical Trials 
(93) recommends inclusion of the following criteria for determining a heart failure hospitalization event: 
“The patient receives initiation or intensification of treatment specifically for HF, including at least one 
of the following: a. augmentation in oral diuretic therapy, b. intravenous diuretic, inotrope, or 
vasodilator therapy, or c. Mechanical or surgical intervention, such as i. mechanical circulatory support 
(e.g., intra-aortic balloon pump, ventricular assist device) or ii. mechanical fluid removal (e.g., 
ultrafiltration, hemofiltration, dialysis).” We will employ these criteria and others, such as exclusion of 
admissions for ICD placement, in our algorithms to maximize the likelihood that the events we capture 
are clinically relevant. 
Non-cancer deaths. We include non-cancer deaths in our primary composite outcome as a compromise 
between total mortality, which includes many irrelevant events that dilute the effect of the intervention, 
and cardiovascular mortality, which is less accurately distinguished on death certificates and may miss 
relevant deaths. We exclude cancer deaths because they are numerous, relatively accurately identified 
on death certificates (94,95,96), and believed to be unrelated to diuretic use, so excluding them reduces 
“noise” relative to expected effects of the intervention. In the Physicians’ Health Study (95), cancer 
deaths in patients older than 65 years were identified from death certificates using standard nosology 
protocols and the Automated Classification of Medical Entities (ACME) Decision Tables with specificity 
well over 99% compared with an adjudication committee, meaning that the deaths excluded from our 
primary outcome will almost certainly be due to cancer.  
Prieto-Merino and colleagues (97) note: “If outcomes that are causally related to the trial treatment are 
combined with those that are not, the estimate of the treatment effect is diluted towards the null and 
we may fail to identify potentially important benefits or harms…. Because few treatments will be 
causally related to all causes of death, all-cause mortality is a composite outcome that combines 
causally related causes of death with those unrelated to the treatment.” We did not restrict to 
cardiovascular deaths because some other deaths may be relevant, such as accidents due to syncope 
from hypotension and deaths from unknown causes (which could have been cardiovascular), and other 
deaths (e.g., pneumonia, COPD) that are not accurately distinguished from cardiovascular deaths by 
death certificate diagnoses. Competing risk from cancer deaths will be considered in a secondary 
analysis. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             30 
F. Ascertainment of Outcome Data 
Data collection will be via electronic medical records, administrative data, Medicare and death records. 
We will use VA, CMS, and National Death Index data.  Assessment of outcomes and relevant data 
elements as well as adverse event is by passive collection of data in electronic health records; the study 
will not attempt to generate any additional tests or procedures. All outcome processing will be 
conducted by investigators at the Boston CSPCC unaware of treatment group. In this section we describe 
our approach to ascertainment and assessment of these outcomes.  
The Boston CSP Coordinating Center has 15 years of experience in ascertainment and assessment of 
cardiovascular outcomes using the VA electronic health record (EHR) and CMS data.  We will build on 
this extensive experience to refine a specific procedure for doing the same in this trial in order to 
accurately identify and assess outcomes.  The process involves several clearly defined steps.  First, we 
develop a method to screen the electronic medical records of all participants on a periodic basis for 
potential cases.  This screening consists of comparing discharge diagnosis and procedure codes for 
enrolled patients to a list of outcome-relevant ICD 10 and CPT codes.  Admissions that do not match 
codes on our list will be considered non-events.  The development of the screening process and the 
algorithms for confirming cases follows a systematic approach that we have used at the Boston CSPCC 
for a number of years.  The screening approach is used to identify all potential cases using key elements 
in the EHR.  The screening tool varies for each outcome (i.e. outcome-specific administrative diagnosis 
codes).   
Second, algorithms are developed to collect and analyze data elements that are used to confirm or 
refute the potential cases (e.g. presence of imaging during a stroke).  The algorithms are based on 
elements of the clinical definitions of the outcomes, and are applied to potential cases to determine if 
the case is confirmed, disconfirmed or deemed indeterminate.  Algorithms for cases are constructed 
using “gold standard” cases (identified by manual chart review) and data elements obtained from the 
medical record that are found in the outcome definitions, such as cardiac enzymes for MI.  Once the 
algorithm for a specific case is defined, the algorithm’s accuracy is checked by manual review of cases 
identified by the algorithm.    
Third, indeterminate cases will undergo manual adjudication. We expect to be left with a relatively small 
number of events that cannot be resolved by the algorithm, but all of these will be referred for 
adjudication to an outcomes committee. This will greatly lessen the workload for manual adjudication. 
All patients will be followed until death or the end of the study (even if the primary outcome is 
determined to have occurred) to collect secondary outcomes, including death.  
A pilot study using VA EHR was conducted to determine the availability of potential cases and core data 
elements that would be needed to develop algorithms to assess the primary outcomes.  A total of 150 
medical records were reviewed, 30 in each category for stroke, myocardial infarction and urgent 
coronary revascularization and 60 records of patients with a diagnosis of acute congestive heart failure.  
A medical record abstraction form for each outcome was developed based on standard diagnostic 
definitions that included information on symptom presentation, physical findings, critical laboratory 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             31 
values, radiographic or imaging findings, electrocardiographic results, hemodynamic data and 
administration of medications and therapeutic interventions (84, 98) During this study these data will be 
augmented with CMS data for all participants. Below we describe the approach to ascertainment of 
potential cases. Definition criteria and ICD diagnostic and procedure codes for each outcome can be 
found in Appendix F (Outcome Definitions)  
G. Adjudication of events 
In cases where the outcome diagnosis is not clear based on the screening mechanism and algorithms 
developed, we will resort to manual adjudication to determine the validity of the diagnosis.  Based on 
our 150 chart review, it is expected that fewer than 300 to 400 cases will require this form of 
adjudication.  The adjudication will consist of a chart review by qualified clinicians of medical records 
pertaining to the hospital admission for VA admissions and a chart review of VA inpatient and outpatient 
records as well as CMS data following the discharge date for non-VA hospitalizations. In some cases, we 
may query the PCP as to whether a possible event occurred. 
Additionally, we will also manually adjudicate 10% of all outcomes confirmed or refuted by our 
algorithms to serve as a quality check on the algorithms. We will develop near-final algorithms during 
the study and will continue to refine the algorithms and retrospectively apply these refinements to all 
data.  It is also important to note that between the time of study approval and study launch, the VA has 
transitioned to using the ICD-10 classification system.  We will be mapping the ICD-9 codes described in 
this protocol to the equivalent ICD-10 codes as we continue to develop our algorithms. 
H. Ascertainment of potential cases, adverse events and other case data  
Investigators at the Boston CSPCC unaware of treatment group will process potential cases and adverse 
events by collecting relevant codes, laboratory values, and prescription data from  EHR, the VA 
electronic medical record system, and Medicare (e.g., acute gout episode = ICD10 M10.00). Blood 
pressures will be collected from routine clinic visits, and not from emergency room visits or inpatient 
stays, and only the reading with the lowest SBP of the day will be retained (99).  Section XIII details the 
data sources and the data collection (i.e., data extraction) procedures that will be used. When the study 
drug is discontinued, we may query the PCP as to the reason if not clear from the chart.  
XI. 
Biostatistical Considerations 
A. Overview of the Study Design 
The proposed study is a prospective randomized open-label blinded-endpoint, multicenter, two arm 
intervention trial testing the effectiveness of chlorthalidone for prevention of cardiovascular events and 
non-cancer death among patients currently receiving hydrochlorothiazide.  The primary hypothesis is 
that chlorthalidone is superior to hydrochlorothiazide for the prevention of cardiovascular events and 
non-cancer death over time. 
The primary outcome measure is time from enrollment in the study to the first occurrence of a 
cardiovascular event or non-cancer death.  Cardiovascular (CVD) events are defined as stroke, 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             32 
myocardial infarction, urgent coronary revascularization, and hospitalization for acute congestive heart 
failure.  The results for CVD and non-cancer death event-free survival will be analyzed by means of a 
two-sided log-rank test. 
The study will have one interim analysis and one final analysis. 
1. Estimated Incidence of the Primary Endpoint 
This study will randomize up to 13,700 patients, in 50:50 allocation to hydrochlorothiazide and 
chlorthalidone, in order to achieve 1,055 primary outcome events.  .  All subjects will be followed 
through the end of the four and one-half (4.5) year study period yielding an estimated average follow-up 
time of three (3) years. We posit a four and one-half year rate of 13.5% of the composite outcome in the 
hydrochlorothiazide group and 11.1% in the chlorthalidone group.  We utilized the VA National data 
from fiscal years 2010 to 2012 to identify a subgroup of subjects who would be potentially eligible for 
the proposed study.  Details of the analysis can be found in Section XII. Feasibility and Recruitment 
Plan. 
The cardiovascular event rate, using a composite similar to that proposed here, was 2% per year in 
ALLHAT (20) and ACCORD (101), and is projected as 2% for the ongoing SPRINT. Unlike those studies, we 
are limiting enrollment to patients over age 65 years and are not excluding very old or seriously ill 
patients (unless life expectancy is known to be less than 6 months), and we are including all non-cancer 
deaths rather than only cardiovascular deaths, all of which would be expected to increase the event 
rate. For patients 65-79 years old with no serious illness (and creatinine <1.5 mg/dL) in ACCORD, the 
composite event rate (stroke, myocardial infarction, and cardiovascular death) was 2.8% per year (96). 
Our event rate should be higher because we include urgent revascularization, acute heart failure, and 
non-cancer deaths. ANBP2 enrolled patients over 65 years but included all deaths in the composite, and 
observed an event rate of >4% per year (19).  
We believe that the most relevant event rates for our study come from the Ontario observational study 
(29) comparing chlorthalidone with hydrochlorothiazide, discussed above. The Ontario study is both 
recent, published in 2013 and reporting data from 1993 to 2010, large (nearly 30,000 patients), and 
shares important features with our proposed trial, including: 1) study patients are aged 66 and older and 
taking diuretics for hypertension, 2) outcome data were collected passively from administrative 
databases, and 3) the primary outcome was a composite similar to the one we are proposing, with two 
differences: a) they did not include urgent revascularization, and b) they included all deaths whereas we 
do not include cancer deaths.  
We expect these 2 differences to very nearly cancel each other’s effect. The rate for the Ontario 
composite outcome was 3.4% per year in the hydrochlorothiazide group. The rate for all deaths was 
1.8% per year, or 45% of the total number of individual outcomes (some patients had more than one of 
the composite outcome elements). Many studies, such as the Physicians Health Study (95) have found 
that all deaths in this age group are comprised of roughly 1/3 each of deaths due to cardiovascular 
disease, cancer and other causes, suggesting that our exclusion of cancer deaths would reduce the 
composite rate by 15%. In the (TRA2°P)-TIMI 50 trial (86), urgent coronary revascularization was less 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             33 
frequent than myocardial infarction (0.82% in the Ontario study, or 20% of the total number of 
individual outcomes) and similar in frequency to stroke (0.46% in the Ontario study, or 11% of the total 
number of individual outcomes), suggesting that our inclusion of this outcome will raise the composite 
by 10-15%.  
These adjustments result in a best estimate for the expected composite rate of about 3.2% per year. For 
the proposed study, because event rates tend to decrease over time, we conservatively project a 3% per 
year event rate in the hydrochlorothiazide group.  
2. Effects of the Intervention 
Of 125,000 VA patients started on drug in routine practice in 2004, 72% of hydrochlorothiazide users 
and 62% of chlorthalidone users remained on the drug 1 year later (28). Onsite coordinators in standard 
trials may be able to maintain better drug adherence than occurs in usual practice. ACCORD (101) and 
SPRINT (84) considered a 20% relative reduction to be an appropriate minimum important difference for 
power calculations. Because the difference in outcomes in our study could be reduced by patients 
coming off drug more often than in previously published trials, we reduce the minimum important 
difference value to 17.5%.  A reduction in CVD events or non-cancer death of this magnitude or greater 
would be considered clinically significant. 
B. The Primary Analysis 
We posit a four and one-half event rate of 13.5% in the hydrochlorothiazide group and a 17.5% 
reduction of CVD events in the chlorthalidone group to inform our primary hypothesis. 
Formal statement of the primary hypothesis 
 
Under the null hypothesis: 
 
   The 4.5 year event rate will be 13.5% (or 578 primary events) 
 
Under the alternative hypothesis for study participants treated with chlorthalidone: 
 
   The 4.5 year event rate will be 11.1% (or 477 primary events) 
 
The reductions attributed to chlorthalidone may be viewed in several ways.  The absolute reduction 
from 13.5% to 11.1% is 2.4%, the relative reduction is (13.5 – 11.1)/13.5 = 17.5%, and the hazard ration 
(chlorthalidone hazard rate/hydrochlorothiazide hazard rate) of 0.81 is approximately midway between 
the simple odds ratio, 11.1(100-13.5)/13.5(100-11.1) = 0.80 and the risk ratio 11.1/13.5 = 0.82. 
 
Formally, the null hypothesis is that the two treatment groups do not differ in their time-to-event 
hazard rates.  The alternative hypothesis is that chlorthalidone has a lower or higher hazard rate than 
hydrochlorothiazide therapy with a hazard ratio for chlorthalidone compared to hydrochlorothiazide 
less than 0.82 or greater than 1.22.  We will test this hypothesis with a two-sided log-rank test.   
 
C. Sample Size and Statistical Power Considerations for the Primary Hypothesis 
The formal hypothesis test is two-sided allowing for chlorthalidone to be either more or less effective 
than hydrochlorothiazide.  A significant difference showing that the intervention chlorthalidone 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             34 
compared to the control hydrochlorothiazide decreases (or increases) the hazard of a major 
cardiovascular event will be regarded a positive result. The results for the primary outcome measure will 
be analyzed by means of the two-sided log-rank test to detect either a hazard ratio that exceeds 1.22 or 
is less than 0.82.  The test will have a two-sided 4.9% type I error.  The test has 90% power to detect a 
hazard ratio of 1.22 or larger or 0.82 or less with a total of 1,055 primary outcome events.   The 
remaining Type I error of 0.1% is used for the interim analysis.   
If the annual event rate is 2.5% (rather than the posited 3%), then the study has 84% power; if 2%, it has 
75% power.   
D. Primary Data Analysis 
The primary outcome hypothesis will be a time-to-event analysis with the use of a two-sided log-rank 
test based on intention-to-treat principles.  The model will not include any covariates.  Analytic reports 
will include hazard rates, their ratio, and the 95% confidence interval about the ratio.   
This will be followed by further refined covariate-adjusted exploratory analyses, using Cox proportional 
hazards regression modeling, controlling for baseline factors.  Covariates will include demographic 
factors (e.g., age, sex, smoking status, education) and clinical factors (e.g., blood pressure, medications, 
comorbidities, history of disease, and BMI).  We will test the proportional hazards assumption by 
including a time-treatment interaction term in the model.    
E. Interim Analysis 
We will perform one interim analysis when the 500th event occurs, approximately 3.5 years after 
initiation of enrollment.  Assuming a uniform rate of enrollment over time, the first patient entered will 
potentially have 3.5 years of follow-up and the last patient entered will potentially have 0.5 years of 
follow-up.  Thus, we will have an average follow-up time of approximately 2 years on 13,500 subjects. 
Using the O-Brien Fleming procedure, this interim analysis will have a type I error of 0.1%, which 
negligibly decreases the overall type I error and has virtually no effect on the power to show that 
chlorthalidone is different from hydrochlorothiazide.  The sample size of 13,532 accounts for the interim 
analysis with a corresponding inflation factor, for increase in sample size of 1.001, resulting in14 more 
subjects per arm (102).  We will confer with the Data Monitoring Committee (DMC) members and the 
program leadership for potential stopping guidelines based on findings from the interim analysis. 
F. Secondary Data Analysis 
1. Treatment Effect in Subgroups 
The Cox regression and competing risks modeling will explore the possibilities of treatment 
variation across pre-specified subgroups based on status at time of enrollment including: 
a) gender, 
b) age (dichotomized at median), 
c) baseline SBP (dichotomized at median), 
d) history of MI or stroke, 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             35 
e) black race vs. not, 
f) diabetes vs. not,  
g) eGFR < 60, and  
h) good compliance (medication possession ratio ≥ 80%) with hydrochlorothiazide over the 
year before randomization. 
 
2. Individual Components of Primary Outcome 
In addition to the subgroup analyses listed above, each component of the composite primary 
outcome measure (stroke, myocardial infarction, urgent coronary revascularization, 
hospitalization for acute congestive heart failure, and non-cancer death) will be separately 
analyzed using log-rank, Cox proportional hazards, and competing risks models to compare 
chlorthalidone and hydrochlorothiazide.  The adjusted analyses will include the covariates 
considered in the primary data analysis. 
3. Additional Outcomes of Interest (Analysis of Secondary and Tertiary Objectives) 
In addition we will run time-to-event analyses comparing the treatment effect on:  
a) all-cause mortality, 
b) the composite outcome substituting all deaths for non-cancer deaths, 
c) vascular deaths defined as all deaths caused by diabetes, vascular diseases, external causes, 
and unknown causes, 
d) the composite outcome substituting vascular deaths for non-cancer deaths, 
e) any revascularization of an artery, 
f) hospitalization for primary diagnosis of hypokalemia, hyponatremia, or renal failure, 
g) other hypokalemia (< 3.5 meq/L), hyponatremia (< 130 meq/L), or renal failure, 
h) new diabetes, requiring medications, defined as first use of medication for diabetes, 
i) 
acute gout episode, 
j) 
erectile dysfunction (ED), defined as first prescription for PDE5 inhibitor or referral for ED, 
and 
k) new allergic reaction to thiazide-like diuretic, defined as new flag warning in EHR 
This may include characterizing healthcare utilization associated with these outcomes, 
evaluation of incidence of the conditions, and defining these conditions with algorithms using 
administrative healthcare data. 
 
4. Primary Care Provider Metrics of Interest. 
a) percent of patients approved 
b) percent of approved patients for whom order signed 
c) reasons order not signed 
d) rate of discontinuation of both drugs 
e) reasons for discontinuation of both drugs 
 
5. Medication Compliance 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             36 
We will compare treatments with respect to overall compliance (adherence) to the randomly 
assigned medication, indirectly measured by the medication possession ratio (MPR) and average 
daily dose (ADD).  The comparison will be made using a GEE analysis to account for varying 
periods of follow-up.  The potential period ends if the subject dies, has an outcome event, or 
changes medication.  Subjects categorized as medication compliant will make up the per-
protocol subgroup of the study cohort. 
6. Non-acute Outcomes 
The repeated measures of systolic blood pressure during the disease-free intervals (free of 
component events) will be compared by treatment.   We will use a mixed effects repeated 
measures model allowing for irregular time intervals, the spatial power law extension of AR(1) 
covariance option where r(t1,t2) =  𝑟(𝑡1, 𝑡2) = exp⁡(|𝑡1 −𝑡2|). In each model we will assume 
linear growth over time. A random effect will be included for both intercept and linear time. The 
hypotheses will test if SBP increases/decreases over time for subjects receiving chlorthalidone, if 
SBP increases/decreases over time for subjects receiving hydrochlorothiazide, and if both have 
non-zero slopes, a test of whether they differ or are equal. 
We will conduct a time-to-event analysis comparing treatments for the outcome of time to first 
discontinuation of assigned diuretic (defined as no prescription for ≥ 3 months at last 
observation during study period) and time to first protocol deviation from assigned diuretic.  
G. Exploratory Objectives 
1. Per-protocol analysis 
The primary intent to treat analyses of randomly assigned treatments takes no account of post-
baseline changes such as protocol deviations and treatment switches from  chlorthalidone  to  
hydrochlorothiazide (and vice versa). Thus, exploratory analyses will model such changes to 
assess robustness of conclusions. 
The per-protocol analysis will determine if chlorthalidone and hydrochlorothiazide differ among 
the subset of protocol compliant subjects.  We will run other analyses that include all subjects 
and attempt to model the time-dependent effects of protocol deviations such as medication 
changes and levels of compliance.  Frailty analyses will assess center effects.  We will explore 
censoring patterns such as models that assume not missing-at-random censoring (103). 
A change in medication may alter the subsequent risk of a cardiovascular event.   First, we will 
add time-dependent covariates to a Cox model, such as binary indicators of a switch from 
chlorthalidone to hydrochlorothiazide, switch from hydrochlorothiazide to chlorthalidone, and 
the start of new medication that interacts with chlorthalidone or hydrochlorothiazide.   To 
directly estimate subsequent risk, we will use a multistage model (MSM) to assess the hazard 
rate of a major cardiovascular event after a switch (104).  MSM models extend the time-to-first-
event models to second, third, and more events.   This extension of the Cox model allows direct 
estimation of the hazard rate associated with any transition adjusted for previous history and 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             37 
baseline characteristics.  Within MSM we will carry out a competing risks analysis to assess the 
effect of cancer deaths. 
2. COVID-19 
COVID-19 is understood to more severely impact older patients with pre-existing conditions.  
There is also evidence from the Centers for Disease Control and Prevention that many patients 
with major medical events are not seeking the care they require during the COVID-19 pandemic. 
 
The DCP patient population is 65 or older with known baseline cardiovascular diseae, and many 
overweight with diabetes.  With a primary outcome consisting of components that often require 
immediate medical attention, there is a possibility that the observed rate of the study’s primary 
outcome will be impacted by the pandemic.  We will characterize event rates throughout the 
study to assess the impact of COVID-19.  We will also assess primary outcome event rates in 
COVID-positive patients and in geographic locations with particularly high rates of infection.  
H. Randomization 
To control for potential imbalance in randomization, both stratification and blocking will be employed.  
The randomization scheme will be stratified by participating site to account for possible regional 
differences in clinical practice.  Participants will be randomized to either hydrochlorothiazide or 
chlorthalidone within blocks of size 6. 
Enrollment and randomization of subjects will occur in accordance with Section IX. Study Procedures 
and Appendix C. Recruitment Flowchart. 
 
XII. 
Feasibility and Recruitment Plan 
A.  Feasibility 
In 2012, 69 VA medical centers prescribed single-agent hydrochlorothiazide 25 mg or 50 mg to at least 
2000 patients over age 65 (Appendix E.1). In VISN1, 80% of these had SBP ≥120 mm Hg at last 
measurement with no SBP measurement below 120 mm Hg in the previous 90 days (Appendix E.2). 
Applying these regional SBP data to the national medical center data, in 2012 there would have been 76 
VA medical centers with ≥1500 eligible patients and 104 centers with ≥1000 eligible patients.  
Based on experience with the CONFIRM study (CSP #577) and the Million Veteran Program and other 
sources, we estimate that: 15% of PCPs will opt out; PCPs who don’t opt out will exclude 5% of their 
patients; 5% of patients mailed the initial letter will opt out; we will reach 65% of patients we attempt to 
call; 60% of those we reach by phone will agree to be randomized; 2% of those who agree by phone will 
opt out or be removed by their PCP before randomization. Combining these rates: 
(.85)(.95)(.95)(.65)(.6)(.98) = .29, suggesting we should expect to enroll about 30% of eligible patients 
identified. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             38 
Based on these considerations, randomization of 13,700 patients (270 per site at 50 sites) should be 
feasible. We anticipate that this process will take 3 years, a duration that could be adjusted by the level 
of staffing of the central call center. If recruitment falls short of our expectations, our primary strategy 
will be to add additional sites as needed. 
B.  Recruitment Plans 
As previously described the primary recruitment plan will be to enroll patients who have been identified 
through the VA Corporate Data Warehouse as being eligible and cleared by their PCP through the direct 
mailing of an information letter followed by telephone based consent.  Enrollment will be initiated in 3 
VISNs at the start of the study. This will allow the DCP team to learn about the feasibility of recruitment, 
to identify issues with provider participation and EHR use, and to refine the primary recruitment plans 
based on the experience from the vanguard sites. Patients will also be allowed to self-refer to the study 
call center as well. In this regard, the DCP will allow all patients fitting the eligibility criteria to be 
enrolled regardless of how they were identified.  
In addition, we will initiate 20% more sites (i.e., 10 additional sites) than what is needed for successful 
enrollment into the study. As sites fail at recruitment or as the potential patient pool decreases at the 
vanguard sites, enrollment into the DCP will be started at the 10 additional sites.  
XIII. 
Data Collection and Data Sources  
Data for this study will be obtained from the medical and administrative data that are collected and 
maintained by the United States Department of Veterans Affairs (VA) Corporate Data Warehouse 
(CDW).  This database covers the entire veteran population that utilizes the VA and contains individual 
information on demographic factors, medical history, key laboratory values, procedure codes, and 
diagnoses (inpatient and outpatient) coded with the ICD-9-CM and ICD-10 classification systems. 
Healthcare encounters outside of the VA system will be captured using Medicare data that will be 
obtained from VIReC for this project. Data from the various VA databases (including COVID-19 data from 
the COVID-19 Shared Data Resource) will be linked together using a unique veteran identification 
number that is assigned to each veteran at entry into the system. 
Vital status will be ascertained from the VA Vital Status File. This file allows for complete ascertainment 
of death as it pulls data from multiple sources, including: the Beneficiary Identification and Records 
Locator Subsystem database; the Death Master File from the Social Security Administration; and the 
National Patient Care Database.  Ascertainment of death with this method has demonstrated 98% 
sensitivity and 98% agreement with the National Death Index. Cause of death will be collected from the 
National Death Index, as the VA Vital Status File does not aggregate cause of death across the 
aforementioned data sources.  
We will monitor for discontinuation or expiration of the assigned diuretic, detection of which will 
prompt queries to the PCP asking the reason. No effort will be made by the study to influence blood 
pressure goals or the prescribing of other drugs. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             39 
XIV. 
Data Management and Data Security Plans 
The Boston CSPCC will create and maintain an electronic study database to manage the trial data.  All 
study data will be collected electronically from EHR and a study-specific web application by the 
Coordinating Center throughout the duration of the study.  There will be limited paper-based study 
documents. 
Study data is housed on secure VA servers, encrypted and protected in accordance with VA policies 
compliant with FDA requirements, Federal Information Security Management Act and the HIPAA Privacy 
and Security rules.  Data for this study will be stored in two locations: 1) on a VINCI-hosted server and 2) 
on a Boston CSPCC-hosted server.  Boston CSPCC personnel manage the data access request process for 
the electronic systems to ensure that data access is appropriate for each individual and the level of the 
individual access.  Study project management will manage the Data Access Request Tracker (DART) 
activities associated with granting VINCI access to study databases.  VA’s Office of Information & 
Technology (OI&T) is responsible for managing other VA system access and ensuring the security and 
integrity of VA information systems, including the databases and servers housing study data.  In 
accordance with VA Handbooks and Directives, OI&T is responsible for ensuring that appropriate 
firewalls and data security is implemented and maintained, that data backups are performed and that 
data may be restored in the event of a system malfunction. 
Data security incidents will be reported according to 1058.01. All Boston CSPCC staff will be expected to 
report data security incidents to the responsible authority as they become aware of the breach. 
Whenever possible, the reporting of data security incidents will be handled by the Boston CSPCC 
Associate Center Director for Quality Assurance (ACDQA). This will be done to facilitate communication 
between the center and the oversight bodies. In the event that an incident must be reported by a staff 
member other than the ACDQA, all communication after the initial report will be handled by the Boston 
CSPCC Center Director, the Boston CSPCC ACDPOC, or the Boston CSPCC ACDQA. [Note: all new and 
current Boston CSPCC personnel will be trained on reporting data security incidents.]   
All local data security incidents will be reported in accordance with VA policy within one hour of 
discovering the incident to: 
1. The Boston Information Security Officer (ISO)  
2. The Boston Privacy Officer (PO)  
3. The Boston ACOS for Research  
4. The Boston CSPCC Quality Assurance department 
Data security incidents will be treated as unanticipated problems by the Boston CSPCC and reported to 
the VA Central IRB according to the procedure detailed below for unanticipated problems (Section 
XVII.C.3). 
Study data will be coded and stored using a unique study identifier for each participant. Identifiable 
information will be collected for patient tracking and safety purposes, and kept in an encrypted, 
password protected file to which a small number of people will have access. Access to the cross-walk file 
linking the participant's identifiers and their study data will be restricted to the approved personnel at 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             40 
the CSP coordinating center. At the end of the study, study data will be stored according to CSP 
guidelines and procedures. Retention of data will be conducted according to CSP operating procedures 
and federal and local VA regulations. This file will be destroyed according to CSP policy well after the 
close of the study. 
Access to the study data is restricted to individuals with CSP approval. Study team members must be 
properly credentialed research staff and must be compliant with VA security trainings (e.g. HIPAA, Rules 
of Behavior, and Good Clinical Practices). Once formal training is completed, user accounts for a study-
specific web application utilizing a URL specific to the study to access and use the system and enter 
patient data will be activated for project management, study nursing staff, and call center staff. 
Accounts will be password protected and unique to each user. The account permissions will correspond 
with the users' functional study group.  Furthermore, the permissions of the electronic systems are 
heavily restricted. The site Liaisons will not have access to study data. Only properly approved 
Coordinating Center personnel will have the ability to copy and export data. These individuals have 
received training on the local standard operating procedure (SOP) governing their permissions. Access to 
protected health information (PHI) will be restricted to individuals approved by CSP to have access to 
the data, including the study’s mailing vendor. 
At the Boston CSPCC the following staff will have access to all forms of PHI: 
1. Center Director 
2. Study Director 
3. Project Management 
4. Study Nurses  
5. Data Management 
6. Biostatisticians 
7. Quality Assurance Officer 
8. SAS/Database Programmer 
9. Research Assistant 
10. Clinical Applications Coordinator 
11. Informatics Team 
Periodic access control assessments will be made by Coordinating Center Quality Assurance personnel 
to verify that access is controlled and appropriate for personnel. In addition, the CSPCC QA group will 
provide continuing education on good clinical practices compliance and will evaluate clinical site 
operations for violations of VA policies including VA data security policies and GCP. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             41 
At the end of the study, the data for DCP will remain property of the Cooperative Studies Program and 
be stored and shared according to CSP guidelines and procedures. Retention and destruction of data will 
be conducted according to CSP operating procedures and federal and local VA regulations. This will 
include electronic data stored at the Boston CSPCC, and at the VA facility housing our servers. 
Identifiable data will be kept according to CSP policy as outlined in the "CSP Guidelines for the Planning 
and Conduct of Cooperative Studies”. 
XV. 
Human Subjects 
A. Waiver of HIPAA authorization  
A waiver of HIPAA authorization to use VA data to determine eligibility will be requested because the 
research could not practicably be conducted without access to and use of this information.  In order to 
conduct the study, it is necessary to first be able to identify eligible patients so that the recruitment 
letter can be mailed to them. 
We will also request IRB approval for a waiver of HIPAA authorization to collect data prospectively. 
Unlike traditional randomized clinical trials, a feature of the POC methodology is that data collection is 
performed by passive data capture. All data elements will be collected electronically from EHR/VISTA 
using both the Veteran’s Information and Computing Infrastructure (VINCI), a collaborative effort 
between the VA Office of Information Technology and the VA Office of Research and Development, and 
the Office of Information Technology’s Corporate Data Warehouse (CDW). Healthcare encounters 
outside of the VA will be captured using Medicare data. Data from the various VA databases will be 
linked together and maintained using a unique veteran identification number (not SSN).  Access to the 
cross-walk file linking the participant’s identifiers and their study data will be restricted to approved 
personnel at the CSP coordinating center. 
Because data abstraction is done electronically and not by staff perusing the electronic medical record 
we believe that a waiver of HIPAA authorization is justified and involves no more than minimal risk to 
the privacy of individuals. All protected health information, except participant address and treatment 
assignment, will remain within the VA. The information will only be shared with the mailing contractor 
using secure methods in alignment with VA policies. Moreover, it would be impractical to obtain a 
signed authorization from patients in this study for use of their health information. The PCP’s cannot 
obtain a written HIPAA authorization for research purposes from patients who are subjects in this study 
because they will not see the patient until weeks or months after the patient has been on the 
randomized treatment.  The PCPs are not study team members. We plan to identify and disclose to 
participants in our information statement the health information to be collected and the specific 
databases from which it will be obtained. 
In both instances, the patient eligibility screening and the prospective collection of patient data, the use 
of the requested information involves no more than minimal risk to the privacy of individuals based on 
the security measures used by the Boston CSPCC to protect the identifiers from improper use and 
disclosure, and to destroy the identifiers at the earliest opportunity consistent with conduct of the 
research. The requested information will not be reused or disclosed to any other person or entity, 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             42 
except as required by law, for authorized oversight of the research study, or for other research for which 
the use or disclosure of the requested information would be permitted by the Privacy Rule. 
B. Basis for Waiver of Documentation of Informed Consent  
Though we are not planning to obtain written informed consent, multiple measures are in place to 
ensure that all subjects are given all of the information they need in a manner that is understandable 
before they consent and throughout the study. Primary care providers will receive information through 
site liaisons as well as an introductory letter that is both mailed and emailed to their VA addresses prior 
to receiving the initial testpatient order in EHR. The initial testpatient order will be sent together with a 
progress note containing the Provider Information Sheet and by signing the testpatient order, the 
providers are consenting to participate. Provider participation is completely voluntary and minimal risk, 
facts that will be reiterated throughout this process. 
Patients are sent a transcript of the consent and an explanatory letter with study contact information 
before the first phone call, full consent is obtained on the call, and they are informed of the randomized 
group after the call. 
In this study, the relevant risks involved are those of changing therapy of half of the patients from 
hydrochlorothiazide to the equivalent dose of chlorthalidone, a very similar drug with the same 
indications and metabolic effects, plus the theoretical risk to confidentiality from compiling individual 
data.  
Regarding the former, both drugs have been in use for more than 50 years, have long been available as 
generics, and are included in the VA national formulary in the same drug class: USP code CV 701, 
thiazide-type diuretics. The VA frequently selects one member of such a class to make available “on 
formulary” based on cost or other considerations, and VA Pharmacy and Therapeutics Committees will 
direct VA pharmacies to substitute drugs within a class when one drug becomes unavailable, so it is not 
uncommon that VA physicians and patients have limited choice within a class. 
While thiazide-type diuretics affect some blood chemical levels as discussed above, these effects have 
not demonstrated adverse clinical impact that would affect their being the preferred treatment for 
hypertension. Furthermore, our plan to substitute an equivalent dose of chlorthalidone for the current 
dose of hydrochlorothiazide, i.e. half the number of milligrams, would be expected to have an effect on 
blood pressure and on blood chemical levels, small enough to be virtually indistinguishable from the 
variation in these parameters that would ensue with remaining on the prescribed hydrochlorothiazide 
(see Background and Rationale, parts F and I). We therefore propose that the study intervention 
qualifies as minimal risk. Because the two drugs are used interchangeably, and the choice between them 
is not influenced by any patient factors, but only by physician preference, randomization does not 
reduce individualization of patient care. Care remains personalized after randomization because the PCP 
manages the diuretic as usual. The patient’s needs are thus not subordinated to the needs of the trial. 
Furthermore, because hypertension is a chronic condition, randomized patients will themselves be 
among those expected to benefit from the information gained from this study. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             43 
In their article “Randomized, controlled trials as minimal risk: an ethical analysis”, Morris and Nelson 
(106) conclude that “A randomized, controlled trial poses no more than minimal risk only when all of the 
following five criteria are met: 1) genuine clinical equipoise exists; 2) all of the treatment options 
included in the research study fall within the current standard of care; 3) there is no currently available 
treatment with a more favorable risk-benefit profile than the treatments included in the research study; 
4) the nontherapeutic components of the research are safely under the minimal risk threshold; and 5) 
the research protocol provides sufficient latitude for treating physicians to individualize care when 
appropriate.” We have designed this study to meet all of these criteria. 
We believe that the Waiver of Documentation of Informed Consent that we are requesting is necessary 
to the successful completion of our study because obtaining the required sample size within the VA is 
only feasible if recruitment is maximally efficient, as described in the Feasibility section (XII.A). Published 
evidence demonstrates that requiring that written consent be returned by mail is likely to result in the 
loss of the great majority of patients who intend to consent (107-111). If requirement of returned 
written consent caused loss of most willing patients from our study, it is unlikely that it could be 
completed within the VA system. 
Based on these considerations, we will request IRB approval of a Waiver of Documentation of Informed 
Consent. Under the terms we are requesting for the Waiver, patients would be recruited by mail, and 
the elements of consent obtained over the phone, a written summary of the consent will be sent to the 
patient, but a signed returned document would not be required.  
Enrolled patients will be given study contact information for questions or withdrawal. 
C. Engagement in Research  
For this study, we consider the Site Liaison and the PCP’s to be not engaged in research. The Site Liaison 
(sometimes called a “Champion” in other studies) serves to provide information to local site personnel 
about the study and relays information and questions back to the coordinating center, but in our view 
takes no action that qualifies as research. The PCPs facilitate implementation of the intervention (after 
patients provide consent and are randomized by study personnel) by signing an order sent to them by 
study personnel. The PCPs are themselves research subjects in whom we are studying the 
implementation of the protocol.  
XVI. 
Quality Control Procedures 
Data that is extracted for the DCP will be cleaned and managed according to a rigorous data 
management plan that will be written in conjunction with the statistical analysis plan and the study 
operations manual (for chairs office and CSPCC personnel).  However, the data will also be subject to 
quality control procedures.  As a first line effort to ensure the validity of the data, 100% of the data 
elements collected from the first 10 individuals from each medical center will be subject to source 
verification and validation through chart review that will be done by an experienced clinician and clinical 
applications coordinator. In addition, chart review done through the creation of the algorithms to 
identify outcomes for the DCP will also be used to perform QC procedures on the data.  In brief, a 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             44 
sample of the data will be verified periodically by the data management and clinical operations teams. If 
errors are identified they will be referred to the data management teams at the Boston CSPCC or at 
VINCI for resolution.  
In addition, the quality management system (QMS) in place at the CSPCC will ensure further quality 
control for the DCP. The Quality Assurance Department of the CSPCC will subject the study to risk based 
audits according to internal SOPs for conducting risk based monitoring and auditing.    These audits will 
evaluate the studys’ compliance with QMS processes and procedures. If deviations or non-
conformances are identified they will be remedied through the internal corrective action/preventive 
action system of the QMS. 
 
XVII. 
Study Monitoring Plan 
A. Introduction 
The safety issues related to hydrochlorothiazide and chlorthalidone are well established in the medical 
literature and both diuretics are accepted first-line treatments for hypertension. Based on this 
information the study poses minimal risks to participants beyond the expected adverse events (AE) 
associated with the administration of either drug as part of “usual” care.  
Monitoring side effects and adverse events in the traditional manner of usual clinical trials is not feasible 
for Point of Care studies since there are no site personnel and all data is captured passively through the 
EMR.  In addition, real-time monitoring will neither provide new information regarding the safety of 
these two treatments nor assure adequate (or timely) safety of human subjects beyond that already 
done by the medical staff as part of routine medical care.  Accordingly, we propose an alternative safety 
reporting plan for the DCP study that ensures protection of the participants and that complies with VHA 
Policy (i.e., VHA Handbooks 1200.05 and 1058.01). In brief, health providers will identify, monitor, and 
treat (as necessary) adverse events that occur during the course of the study. The CSPCC will identify 
expected adverse events (as described below) through the EMR and report them to the monitoring 
committees for the trial. The sections that follow describe in more detail the proposed safety monitoring 
and reporting plan for this trial.   
B. Safety Monitoring Plan  
The participant’s physicians, nurses, and other health providers will continue their usual monitoring of 
the subject throughout the course of his/her treatment. If any treatments are indicated, they will be 
provided by health providers as a part of the participant’s routine medical care. The CSPCC staff will 
collect safety data from the medical record from the time of consent through the end of the study 
period.  The safety data will then be aggregated and classified according to ICD-10 codes.  
Aggregated safety data will be reported to the Data Monitoring Committee, the study Executive 
Committee, and the VA Central IRB using the processes described in Section C. Please refer to Section 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             45 
XVIII Study Organization and Administration for a more detailed description of the oversight committees 
for the trial. 
In addition to data culled from the EMR, the trial will allow for spontaneous reporting of events by study 
participants. The informed consent script and information sheet will include the contact information for 
the study call center should the participant wish to communicate safety concerns with the study team.   
C. Safety Reporting 
1. Adverse Events 
Adverse events will be collected using the 21 CFR 312.32, International Conference on Harmonisation 
(ICH) for Clinical Safety Data Management (ICH-E2A), and CSP Global SOP 3.6 definitions.  Adverse 
events (AEs) are defined by the 21 CFR 312.32 as "any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related." 
According to ICH-E2A,”an AE, therefore, can be any unfavorable or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the study interventions.” 
Expected adverse events of interest related to diuretics will be culled from the EMR as part of the 
outcome ascertainment activities of this protocol. The expected AEs of interest will be: 
1. Hospitalization for primary diagnosis of hypokalemia, hyponatremia, or renal failure 
2. Renal failure (dialysis or renal transplant) 
3. Other recorded hypokalemia (< 3.1 mEq/L), or hyponatremia (< 130 mEq/L)  
4. New diabetes, defined as first use of an outpatient medication for diabetes 
5. Acute gout episodes   
6. New allergic reaction to thiazide-type diuretic to be found in EMR allergy data 
These safety events are monitored and treated as part of routine medical care. These events will be 
identified by the CSPCC through the electronic medical record (EMR).  Informatics staff at the Boston 
CSPCC will extract medical record data on all subjects and identify adverse events through ICD-10 codes, 
laboratory values, and medication files.  Expected adverse events will be reported to the DMC in semi-
annual reports. The DMC also reserves the right to request reporting on additional safety data not 
specified above, as relevant to the study.  Data will be in the form of aggregated data tables detailing 
the frequencies of these events by blinded treatment group.  These events will be reported to the 
Central IRB in blinded aggregate form at the time of continuing review. 
Adverse events which develop into Serious Adverse Events, as defined below, will be reported as such. 
2. Expected Serious Adverse Events 
Serious adverse events (SAEs) are a subset of adverse events defined in 21 CFR 312.32(a) and VA 
Handbook 1058.01 paragraph 4(w), as follows: 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             46 
Definition of SAE from CFR 312.32 (a): Serious adverse event. An adverse event or suspected adverse 
reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in any of 
the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Definition of SAE according to VA Handbook 1058.01: An SAE is an AE in human research that results in 
death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent 
or significant disability or incapacity, congenital anomaly, or birth defect. An AE is also considered 
serious when medical, surgical, behavioral, social, or other intervention is needed to prevent such an 
outcome. 
The intervention in this study is the switch from hydrochlorothiazide to an equivalent dose of 
chlorthalidone, two widely-used diuretics with well-known risk profiles.  There are no safety events that 
are unanticipated in regard to these two drugs.  Thus, serious adverse events defined above that are 
feasibly identified through the medical record will be reported in aggregate to the DMC at 6 month 
intervals and to the Central IRB at continuing review. 
Expected serious adverse events will be reported to the IRB at the time of continuing review in 
aggregated data tables detailing the frequencies of these events. Study reports will also be circulated to 
appropriate members, including the study chairmen and DMC. 
This study will not use MedDRA coding of AE and SAE data.  The study team will define events using the 
data sources described above and categorize events by system organ class, major diagnostic category, or 
assessment type for reporting. 
3. Unanticipated Problems Involving Risks to Subjects and Others 
Any unanticipated problems involving risks to subjects or others (UPRs), but not qualifying as a serious 
adverse event by definition (such as errant distribution of study medication), will also be reported. 
Unanticipated problems related to the study design will be reported to the IRB in an expedited fashion 
(within 5 business days of identifying the problem).  Possible events include failure to distribute study 
drug, patient continuing previous prescription while taking study drug, or patient randomized without 
provider knowledge.  Informatics staff at the Boston CSPCC will extract medical record data on all 
subjects regularly allowing for the identification of UPRs at fixed intervals.  Study reports will be 
circulated to appropriate members, including the study chairmen. 
UPRs that result in an SAE, pursuant to the definition above, will be reported as an SAE to the VA Central 
IRB within 5 business days by the Boston CSP Coordinating Center after becoming aware of the event. 
XVIII. 
Study Organization and Administration  
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             47 
A. Administration 
The administrative structure of this study is similar to others in CSP and includes: 
The Cooperative Studies Program (VA Central Office) establishes overall policies and procedures that are 
applied to all VA cooperative studies through the Study Chair’s office and the CSPCC. 
The CSPCC and the Study Chair’s office jointly will perform the day-to-day scientific and administrative 
coordination of the study. These include developing and revising the study protocol; abstracting data 
from the national databases (CSPCC Only); ensuring the appropriate support for the participating 
centers; scheduling meetings and conference calls; answering questions about the protocol. The CSPCC 
will also prepare interim and final progress reports; and archive study data at the end of the study. 
Study progress reports will be produced every 6 months. Patient accrual, patient safety, and data quality 
will be monitored closely by the CSPCC, the study executive committee, and the DMC to ensure that the 
study is progressing satisfactorily. Further delineation of responsibilities will be documented in 
communications with the Study Chair’s office. 
The CSPCC will be responsible for monitoring and reporting the safety of trial participants through the 
review, assessment, and communication of adverse events and serious adverse events detected within 
the national data systems.  The CSPCC will document trends and analyze safety data to prepare reports 
for various committees including the DMC, VA Central IRB (CIRB), Executive Committee(s), and Study 
Group meetings.  
The CSPCC will work closely with the Minneapolis VAMC to track eligible participants as they move 
through the recruitment and enrollment workflow.  The primary responsibilities for the callers include 
contacting patients by telephone to obtain verbal informed consent and receiving incoming patient 
phone calls.  
The external mailing contractor will be primarily responsible for sending study communications to 
providers and patients. The mailing contractor will be sent regular mailing files compiled by the 
ProjectFlow application with participant name, address, and specific correspondence to be sent. PHI will 
be sent to the mailing contractor using secure methods in alignment with VA policies.  
The CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC) will provide advice and 
consultation about drug-related matters, review safety information, and serve as a regulatory affairs 
expert and liaison to the FDA for regulatory matters. 
 The Clinical Sciences Scientific Evaluation Committee (CSSEC) reviews the scientific merit of all new 
cooperative study proposals and all ongoing cooperative studies. The committee is composed of both 
VA and non-VA clinical research scientists, most of whom have had experience in managing their own 
cooperative studies. 
B. Monitoring 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             48 
The following groups monitor the various aspects of the study.  These committees will meet according 
to current Cooperative Studies Program guidelines.  
The Executive Committee is responsible for the operations of the study, including protocol amendments, 
and overall management of the study. It will be headed by the Study Chair and Study Director and 
consist of the study biostatistician, study project manager, CSP Center Director, selected VA experts, and 
outside consultants as needed. This committee will meet regularly to review blinded data (not broken 
down by treatment group), decide upon changes in the study, determine the fate of hospitals whose 
performance is substandard, initiate any subprotocols, and discuss publication of the study results.  This 
Committee must grant permission before any study data may be used for presentation or publication. 
The Technical Committee will advise the Executive Committee on informatics and database related 
issues pertaining to study operations.  This committee will serve as subject matter experts (SMEs) for 
the study database, web application, ETL procedures and primary data source, the Corporate Data 
Warehouse. It will consist of a VINCI representative, Boston CSPCC Director of Informatics, and other 
informaticians/SMEs as needed. 
The Data Monitoring Committee (DMC) will review the progress of the study and will monitor patient 
intake, outcomes, adverse events, and other issues related to patient safety. Interim, independent, and 
unbiased reviews of the study's ongoing progress will be provided. The DMC will consist of experts in the 
study’s subject matter field(s), clinical trials, biostatistics, and ethics. These individuals will not be 
participants in the trial and will not have participated in the planning of the protocol. The DMC will 
consider safety or other circumstances as grounds for early termination, including either compelling 
internal or external evidence of treatment differences or the unfeasibility of addressing the study 
hypothesis (e.g., poor patient intake, poor adherence to the protocol).  
At each of its meetings during the study period, the DMC will review the randomization rates and assess 
the difference between the actual and the projected rates, as well as the impact of these assessments 
on overall trial size. If the study enrollment is inadequate, the reasons for exclusion may be scrutinized 
and actions may be suggested. An assessment of whether the trial should be continued will be made 
followed by recommendations, as appropriate. All serious adverse events will be reported regularly to 
the DMC for review. Unexpected, related serious adverse events will be reported to the DMC as soon as 
they become known based upon the consensus of the Study Chair, the study biostatistician, the Study 
Director. The study biostatistician will provide the appropriate data to the DMC at specified intervals for 
this purpose. Conditional power estimates may be provided to the DMC to assist them in making their 
decisions and recommendations at their request. To help them make their assessment, the Study Chair 
and study biostatistician will furnish the Data Monitoring Committee with appropriate monitoring data 
before each meeting.  The DMC makes recommendations after each meeting to the Director of the 
Cooperative Studies Program (CSP)Service about whether the study should continue or be stopped.  
The VA Central IRB will be the IRB of record for all VA sites.  They will monitor the study’s serious 
adverse events on a continual basis.  They will conduct annual reviews of the study.  In addition, some 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             49 
study materials (such as subject correspondence and protocol changes) will have to be reviewed by the 
VA CIRB, and approved prior to implementation.  
The CSPCC Human Rights Committee (HRC) is composed primarily of lay people and is responsible for 
ensuring that patients' rights and safety are upheld prior to study initiation and during the conduct of 
the study. The committee reviews all new protocols, periodically makes site visits to participating 
centers to monitor firsthand the progress of the study, and may be asked to review any ethical and 
human rights issues that arise during the conduct of the study.   
XIX. 
Publications 
A. Publication policy 
It is the policy of the CSP that outcome data will not be revealed to the participating investigators until 
the data collection phase of the study is completed. This policy safeguards against possible biases 
affecting the data collection. All presentations and publications from this study will be done in 
accordance with current CSP Guidelines, including the Authorship Policy. The most current version of 
the Guidelines should be referenced when planning any study publication. 
The presentation or publication of any or all data collected by participating investigators on patients 
entered into the VA Cooperative Study is under the direct control of the study's Executive Committee. 
No individual participating investigator has any inherent right to perform analyses or interpretations or 
to make public presentations or seek publication of any or all of the data other than under the auspices 
and approval of the Executive Committee. 
The Executive Committee has the authority to establish one or more publication subgroups of   
investigators and members of the Executive Committee for producing scientific presentations and 
publications. Authors with VA appointments must list their VA affiliation first. The VA contributions to 
the research project should be acknowledged in all written and oral presentations of the research 
results, including scientific articles, news releases, news conferences, public lectures, and media 
interviews.   
All study reports and journal manuscripts must be reviewed and approved by the Boston CSPCC Director 
prior to submission for publication.  After approval for submission is granted by the Boston CSPCC 
Director, VA Central Office must be notified upon acceptance of any publications.  This includes minor 
publications such as abstracts and poster presentations.   
B.  Planned Publications 
A list of planned publications is below: 
I. 
Editorial: The first large clinically integrated VA trial  
II. 
Design of the DCP  
III. 
Ascertainment of urgent revascularization from administrative data 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             50 
IV. 
Ascertainment of acute heart failure episodes from administrative data 
V. 
Ascertainment of stroke episodes from administrative data 
VI. 
Use of and experiences with telephone informed consent 
VII. 
Challenges of embedding DCP into the electronic medical record 
VIII. 
Main outcomes paper 
IX. 
Blood pressure control and drug compliance in the DCP 
X. 
Blood chemistries in the DCP 
XX. 
Provider Experience Survey 
In order to improve the design of future point-of-care trials, a survey was designed to query providers 
that consented to participate in the CSP 597 study about their experience with the study (Appendix 21).  
The questions were designed to assess if education about the study was adequate and delivered in a 
convenient format, how interested providers are in the study question, time burden of study 
participation, and level of comfort with a pragmatic trial design.  Demographic information is also 
requested.  Survey results will be captured in a VA approved platform..  Completion of the survey is 
voluntary.  The study will be reviewed by CIRB and the Organizational Assessment Committee (OAC) 
before being distributed to consented CSP 597 providers.  Provider survey results will be made available 
through clinicaltrials.gov. Qualitative analysis will be performed for open text responses and sub-
questions.  Dichotomous responses and survey responses on a Likert scale will be analyzed using 
quantitative methods.     
An additional interview will be made available to consented providers at Minneapolis VAHCS (Appendix 
25). This interview will take place in person or via teleconference. Interview questions will focus on the 
providers individual experience throughout DCP and allow providers to give less structured feedback on 
the consent and randomization workflows. The aim is to further help structure future POC studies. All 
results will de-identified and made available on clinicaltrials.gov 
XXI. 
References 
1. 
http://www.cdc.gov/bloodpressure/hypertension_iom.htm 
2. 
http://www.webmd.com/news/20110420/the-10-most-prescribed-drugs 
3. 
http://www.healthquality.va.gov/hypertension/htn04_pdf1.pdf  
4. 
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on 
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 
2003;289:2560-72. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             51 
5. 
Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, Weiss NS. Health 
outcomes associated with various antihypertensive therapies used as first-line agents: a network 
meta-analysis. JAMA 2003;289:2534-44. 
6. 
Messerli FH, Bangalore S. Half a century of hydrochlorothiazide: facts, fads, fiction, and follies. Am 
J Med 2011;124:896-9. 
7. 
Ernst ME, Lund BC. Renewed interest in chlorthalidone: evidence from the Veterans Health 
Administration. J Clin Hypertens (Greenwich). 2010;12:927-34. 
8. 
Kaplan NM. Chlorthalidone versus hydrochlorothiazide: a tale of tortoises and a hare. 
Hypertension 2011;58:994-5. 
9. 
Mitka M. Experts argue not all diuretics the same. JAMA 2007;298:31. 
10. 
Kaplan NM. The case for low dose diuretic therapy. Am J Hypertens 1991;4:970-1. 
11. 
Materson BJ, Cushman WC, Goldstein G, Reda DJ, Freis ED, Ramirez EA, Talmers FN, White TJ, 
Nunn S, Chapman RH, et al. Treatment of hypertension in the elderly: I. Blood pressure and clinical 
changes. Results of a Department of Veterans Affairs Cooperative Study. Hypertension 
1990;15:348-60.  
12. 
Cushman WC, Khatri I, Materson BJ, Reda DJ, Freis ED, Goldstein G, Ramirez EA, Talmers FN, White 
TJ, Nunn S, et al. Treatment of hypertension in the elderly. III. Response of isolated systolic 
hypertension to various doses of hydrochlorothiazide: results of a Department of Veterans Affairs 
cooperative study. Department of Veterans Affairs Cooperative Study Group on Antihypertensive 
Agents. Arch Intern Med 1991;151:1954-60. 
13. 
Materson BJ, Oster JR, Michael UF, Bolton SM, Burton ZC, Stambaugh JE, Morledge J. Dose 
response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose. Clin 
Pharmacol Ther 1978;24:192-8. 
14.   Morledge JH, Ettinger B, Aranda J, McBarron F, Barra P, Gorwit J, Davidov M. Isolated systolic    
hypertension in the elderly. A placebo-controlled, dose-response evaluation of chlorthalidone. J Am 
Geriatr Soc 1986;34:199-206. 
15. 
Neff KM, Nawarskas JJ. Hydrochlorothiazide versus chlorthalidone in the management of 
hypertension. Cardiol Rev 2010;18:51-6.  
16. 
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high 
blood pressure in adults: report from the panel members appointed to the Eighth Joint National 
Committee (JNC 8). JAMA 2014;311:507-20. 
17. 
Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone reduces cardiovascular 
events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension 
2011;57:689-94.  
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             52 
18. 
Ernst ME, Neaton JD, Grimm RH Jr, Collins G, Thomas W, Soliman EZ, Prineas RJ; Multiple Risk 
Factor Intervention Trial Research Group. Long-term effects of chlorthalidone versus 
hydrochlorothiazide on electrocardiographic left ventricular hypertrophy in the multiple risk factor 
intervention trial. Hypertension 2011;58:1001-7. 
19. 
Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald 
GJ, Marley JE, Morgan TO, West MJ; Second Australian National Blood Pressure Study Group. A 
comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for 
hypertension in the elderly. N Engl J Med 2003;348:583-92. 
20. 
ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients 
randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: 
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 
2002;288:2981-97. 
 
21. 
Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing 
cardiovascular events: systematic review and network meta-analyses. Hypertension 
2012;59:1110-7. 
22. 
Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting 
their interchangeability. Hypertension 2004;43:4-9. 
23. 
Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, Bergus GR. 
Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory 
and office blood pressure. Hypertension 2006;47:352-8. 
24. 
Kwon BJ, Jang SW, Choi KY, Kim DB, Cho EJ, Ihm SH, Youn HJ, Kim JH. Comparison of the efficacy 
between hydrochlorothiazide and chlorthalidone on central aortic pressure when added on to 
candesartan in treatment-naïve patients of hypertension. Hypertens Res. 2013;36:79-84. 
25. 
https://vaww.cmopnational.va.gov/cmop/PBM/Clinical Guidance/Archived Criteria, Guidelines 
and Reviews/Clinical Recommendations (Archive)/Thiazides in Hypertension, Review of Recent 
Evidence (Archived Dec 2014).doc  
26. 
Ernst ME, Carter BL, Zheng S, Grimm RH Jr. Meta-analysis of dose-response characteristics of 
hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium. Am J 
Hypertens 2010;23:440-6. 
27. 
Peterzan MA, Hardy R, Chaturvedi N, Hughes AD. Meta-analysis of dose-response relationships for 
hydrochlorothiazide, chlorthalidone, and bendroflumethiazide on blood pressure, serum 
potassium, and urate. Hypertension 2012;59:1104-9.  
28. 
Lund BC, Ernst ME. The comparative effectiveness of hydrochlorothiazide and chlorthalidone in an 
observational cohort of veterans. J Clin Hypertens (Greenwich). 2012 Sep;14(9):623-9. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             53 
29. 
Dhalla IA, Gomes T, Yao Z, Nagge J, Persaud N, Hellings C, Mamdani MM, Juurlink DN. 
Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: a 
population-based cohort study. Ann Intern Med 2013;158:447-55. 
30. 
Bakris GL, Sica D, White WB, Cushman WC, Weber MA, Handley A, Song E, Kupfer S. 
Antihypertensive efficacy of hydrochlorothiazide vs chlorthalidone combined with azilsartan 
medoxomil. Am J Med. 2012;125:1229.e1-1229.e10. 
31. 
Cushman WC, Bakris GL, White WB, Weber MA, Sica D, Roberts A, Lloyd E, Kupfer S. Azilsartan 
medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus 
hydrochlorothiazide in stage 2 systolic hypertension. Hypertension. 2012;60:310-8.  
32. 
Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009 Nov 
26;361(22):2153-64. 
33. 
Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den Hond E, McCormack P, Staessen JA, 
O'Brien E. Superiority of ambulatory over clinic blood pressure measurement in predicting 
mortality: the Dublin outcome study. Hypertension. 2005 Jul;46(1):156-61. 
34. 
Fagard RH, Celis H, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Daytime and 
nighttime blood pressure as predictors of death and cause-specific cardiovascular events in 
hypertension. Hypertension. 2008 Jan;51(1):55-61. 
35. 
Woodman R, Brown C, Lockette W. Chlorthalidone decreases platelet aggregation and vascular 
permeability and promotes angiogenesis. Hypertension. 2010 Sep;56(3):463-70. 
36. 
Kurtz TW. Chlorthalidone: don't call it "thiazide-like" anymore. Hypertension 2010;56:335-7. 
37. 
Rodenburg EM, Hoorn EJ, Ruiter R, Lous JJ, Hofman A, Uitterlinden AG, Stricker BH, Visser LE. 
Thiazide-Associated Hyponatremia: A Population-Based Study. Am J Kidney Dis. 2013 Apr 18. 
[Epub ahead of print]  
38. 
Alderman MH, Piller LB, Ford CE, et al; Antihypertensive and Lipid-Lowering Treatment to Prevent 
Heart Attack Trial Collaborative Research Group. Clinical significance of incident hypokalemia and 
hyperkalemia in treated hypertensive patients in the antihypertensive and lipid-lowering 
treatment to prevent heart attack trial. Hypertension. 2012;59(5):926-33. 
39. 
Barzilay JI, Davis BR, Cutler JA, Pressel SL, Whelton PK, Basile J, Margolis KL, Ong ST, Sadler LS, 
Summerson J; ALLHAT Collaborative Research Group. Fasting glucose levels and incident diabetes 
mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive 
treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart 
Attack Trial (ALLHAT). Arch Intern Med. 2006 Nov 13;166(20):2191-201.  
40. 
Barzilay JI, Davis BR, Pressel SL, Cutler JA, Einhorn PT, Black HR, Cushman WC, Ford CE, Margolis 
KL, Moloo J, Oparil S, Piller LB, Simmons DL, Sweeney ME, Whelton PK, Wong ND, Wright JT Jr; 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             54 
ALLHAT Collaborative Research Group. Long-term effects of incident diabetes mellitus on 
cardiovascular outcomes in people treated for hypertension: the ALLHAT Diabetes Extension 
Study. Circ Cardiovasc Qual Outcomes. 2012 Mar 1;5(2):153-62.  
41. 
McAdams DeMarco MA, Maynard JW, Baer AN, Gelber AC, Young JH, Alonso A, Coresh J. Diuretic 
use, increased serum urate levels, and risk of incident gout in a population-based study of adults 
with hypertension: the Atherosclerosis Risk in Communities cohort study. Arthritis Rheum. 2012 
Jan;64(1):121-9.  
42. 
Siegel D, Hulley SB, Black DM, Cheitlin MD, Sebastian A, Seeley DG, Hearst N, Fine R. Diuretics, 
serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men. JAMA 
1992;267:1083-9.  
 
43. 
Mount DB, et al. Clinical manifestations and treatment of hypokalemia. UpToDate. Accessed July 
2013. 
 
44. 
Roush GC, Buddharaju V, Ernst ME, Holford TR. Chlorthalidone: Mechanisms of Action and Effect 
on Cardiovascular Events. Curr Hypertens Rep. 2013 Jul 10. [Epub ahead of print] 
45. 
Rahman M, Pressel S, Davis BR, et al. Renal outcomes in high-risk hypertensive patients treated 
with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a 
report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial 
(ALLHAT). Arch Intern Med. 2005 Apr 25;165(8):936-46.  
46. 
Rahman M, Ford CE, Cutler JA, et al; ALLHAT Collaborative Research Group. Long-term renal and 
cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart 
Attack Trial (ALLHAT) participants by baseline estimated GFR. Clin J Am Soc Nephrol. 2012 
Jun;7(6):989-1002. 
47. 
Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic 
hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP 
Cooperative Research Group. JAMA 1991;265:3255-64. 
48. 
Hueskes BA, Roovers EA, Mantel-Teeuwisse AK, Janssens HJ, van de Lisdonk EH, Janssen M. Use of 
diuretics and the risk of gouty arthritis: a systematic review. Semin Arthritis Rheum. 2012 
Jun;41(6):879-89.  
49. 
Mortality findings for stepped-care and referred-care participants in the hypertension detection 
and follow-up program, stratified by other risk factors. The Hypertension Detection and Follow-up 
Program Cooperative Research Group. Prev Med 1985;14:312-35. 
 
50. 
Wilson L, Nair KV, Saseen JJ. Comparison of New-Onset Gout in Adults Prescribed Chlorthalidone 
vs Hydrochlorothiazide for Hypertension. J Clin Hypertens. 2014 Sep 25. doi: 10.1111/jch.12413. 
[Epub ahead of print] 
 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             55 
51. 
Khosla N, Chua DY, Elliott WJ, Bakris GL. Are chlorthalidone and hydrochlorothiazide equivalent 
blood-pressure-lowering medications? J Clin Hypertens 2005;7:354-6. 
 
52. 
Matthews KA, Brenner MJ, Brenner AC. Evaluation of the Efficacy and Safety of a 
Hydrochlorothiazide to Chlorthalidone Medication Change in Veterans With Hypertension. Clin 
Ther. 2013 Aug 28.[Epub ahead of print] 
 
53. 
van Blijderveen JC, Straus SM, Rodenburg EM, Zietse R, Stricker BH, Sturkenboom MC, Verhamme 
KM. Risk of hyponatremia with diuretics: chlorthalidone versus hydrochlorothiazide. Am J Med 
2014;127:763-71. 
54. 
Roush GC, Buddharaju V, Ernst ME. Is chlorthalidone better than hydrochlorothiazide in reducing 
cardiovascular events in hypertensives? Curr Opin Cardiol 2013;28:426-32. 
55. 
Dhalla IA, Mamdani MM, Juurlink DN. Chlorthalidone versus hydrochlorothiazide. Ann Intern Med. 
2013;158:923-4. 
56. 
Einhorn PT, Cushman WC, Whelton PK; ALLHAT Collaborative Research Group. Chlorthalidone 
versus hydrochlorothiazide. Ann Intern Med 2013;158:922-3. 
57. 
Asche C, Yang J, Yu S, Hagan M. A profiling of hypertension patients treated with chlorthalidone or 
hydrochlorothiazide. Value Health. 2013 May;16(3):A295. 
58. 
Krause T, Lovibond K, Caulfield M, McCormack T, Williams B; Guideline Development Group. 
Management of hypertension: summary of NICE guidance. BMJ 2011;343:d4891. 
59. 
Mancia G, Fagard R, Narkiewicz K, et al; Task Force Members. 2013 ESH/ESC Guidelines for the 
management of arterial hypertension: the Task Force for the management of arterial hypertension 
of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J 
Hypertens 2013;31:1281-357.  
60. 
Floyd JS, Psaty BM. Observational Comparative Effectiveness Studies of Drug Therapies: High-
Quality Answers or Important Clinical Questions? Comment on "Comparative Effectiveness of 2 β-
Blockers in Hypertensive Patients". Arch Intern Med 2012:172:1412-4. 
61. 
Lauer MS, D'Agostino RB. The randomized registry trial — the next disruptive technology in clinical 
research? N Engl J Med 2013; 369:1579-1581.  
62. 
Jansen JP, Fleurence R, Devine B, Itzler R, Barrett A, Hawkins N, Lee K, Boersma C, Annemans L, 
Cappelleri JC. Interpreting indirect treatment comparisons and network meta-analysis for health-
care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good 
Research Practices: part 1. Value Health 2011;14:417-28. 
63. 
Pletcher MJ, Lo B, Grady D. Informed consent in randomized quality improvement trials: a critical 
barrier for learning health systems. JAMA Intern Med 2014;174:668-70. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             56 
64. 
Peto R, Collins R, Gray R. Large-scale randomized evidence: large, simple trials and overviews of 
trials. J Clin Epidemiol. 1995 Jan;48(1):23-40. 
65. 
Vickers AJ, Scardino PT. The clinically-integrated randomized trial: proposed novel method for 
conducting large trials at low cost. Trials. 2009;10:14.  
66. 
van Staa TP, Goldacre B, Gulliford M, Cassell J, Pirmohamed M, Taweel A, Delaney B, Smeeth L. 
Pragmatic randomised trials using routine electronic health records: putting them to the test. BMJ. 
2012 Feb 7;344:e55. 
67. 
Fiore LD, Brophy M, Ferguson RE, D'Avolio L, Hermos JA, Lew RA, Doros G, Conrad CH, O'Neil JA Jr, 
Sabin TP, Kaufman J, Swartz SL, Lawler E, Liang MH, Gaziano JM, Lavori PW. A point-of-care clinical 
trial comparing insulin administered using a sliding scale versus a weight-based regimen. Clin 
Trials. 2011;8:183-95.  
68. 
D'Avolio L, Ferguson R, Goryachev S, Woods P, Sabin T, O'Neil J, Conrad C, Gillon J, Escalera J, 
Brophy M, Lavori P, Fiore L. Implementation of the Department of Veterans Affairs' first point-of-
care clinical trial. J Am Med Inform Assoc. 2012 Jun 1;19(e1):e170-e176. Epub 2012 Feb 24. 
69. 
IOM Roundtable on Evidence-Based Medicine. Appendix A. Learning what works best: the nation's 
need for evidence on comparative effectiveness in health care: an issue overview. In: Learning 
What Works: Infrastructure Required for Comparative Effectiveness Research: Workshop 
Summary. Institute of Medicine (US) Roundtable on Value & Science-Driven Health Care. 
Washington (DC): National Academies Press (US); 2011. 
http://www.ncbi.nlm.nih.gov/books/NBK64784/ 
70. 
Eapen ZJ, Lauer MS, Temple RJ. The imperative of overcoming barriers to the conduct of large, 
simple trials. JAMA 2014;311:1397-8. 
71. 
Smith DH, Neutel JM, Lacourcière Y, Kempthorne-Rawson J. Prospective, randomized, open-label, 
blinded-endpoint (PROBE) designed trials yield the same results as double-blind, placebo-
controlled trials with respect to ABPM measurements. J Hypertens. 2003 Jul;21(7):1291-8. 
72. 
Kerr EA, Lucatorto MA, Holleman R, Hogan MM, Klamerus ML, Hofer TP; VA Diabetes Quality 
Enhancement Research Initiative (QUERI) Workgroup on Clinical Action Measures. Monitoring 
performance for blood pressure management among patients with diabetes mellitus: too much of 
a good thing? Arch Intern Med. 2012;172:938-45. 
73. 
Berry SD, Kiel DP. Treating hypertension in the elderly: should the risk of falls be part of the 
equation? JAMA Intern Med 2014;174:596-7. 
74. 
Nord J, Stults B, Rose R, Underwood AE, Williams T, West G, Huhtala T, Milne CK. Optimizing office 
blood pressure measurement at a VAMC. Fed Pract 2012;29(5):35-39. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             57 
75.  Kim JW, Bosworth HB, Voils CI, Olsen M, Dudley T, Gribbin M, Adams M, Oddone EZ. How well do 
clinic-based blood pressure measurements agree with the mercury standard? J Gen Intern Med 
2005;20:647-9. 
76. 
Freeman MK, White W, Iranikhah M. Tablet splitting: a review of the clinical and economic 
outcomes and patient acceptance. Consult Pharm 2012;27:421-30. 
77.    Kalsbeek WD, Botman SL, Massey JT, Liu PW. Cost-Efficiency and the Number of Allowable Call 
Attempts in the National Health Interview Survey. Journal of Official Statistics 1994;10(2): 133–52 
78.    Hörngren J, Lundquist P, Westling S. Effects of number of call attempts on nonresponse rates and 
nonresponse bias – result from some case studies at Statistics Sweden. Statistics Canada’s 
International Symposium Series: Proceedings, 2009. http://www.statcan.gc.ca/pub/11-522-
x/2008000/article/10999-eng.pdf 
79. 
Fowler FJ, Jr., Gallagher PM, Stringfellow VL, Zaslavsky AM, Thompson JW, Cleary PD. Using 
telephone interviews to reduce nonresponse bias to mail surveys of health plan members. Med 
Care. 2002;40:190-200.  
80. 
Fu SS, van Ryn M, Burgess DJ, Nelson D, Clothier B, Thomas JL, Nyman JA, Joseph AM. Proactive 
tobacco treatment for low income smokers: study protocol of a randomized controlled trial. BMC 
Public Health 2014;14:337.  
81. 
Koepsell T, McGuire V, Longstreth W, Nelson L, Belle G. Randomized trial of leaving messages on 
telephone answering machines for control recruitment in an epidemiologic study. Am J Epidemiol. 
1996;144:704-706. 
82. 
Andrade SE, Kahler KH, Frech F, Chan KA. Methods for evaluation of medication adherence and 
persistence using automated databases. Pharmacoepidemiol Drug Saf. 2006;15:565-74. 
83. 
Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, Elkind MSV, George MG, 
Hamdan AD, Higashida RT, Hoh BL, Janis LS, Kase CS, Kleindorfer DO, Lee J-M, Moseley ME, 
Peterson ED, Turan TN, Valderrama AL, Vinters HV. An updated definition of stroke for the 21st 
century: a statement for healthcare professionals from the American Heart Association/American 
Stroke Association. Stroke. 2013; 44:2064-2089.  
84.  Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; Joint ESC/ACCF/AHA/WHF 
Task Force for the Universal Definition of Myocardial Infarction, et al. Third universal definition of 
myocardial infarction. Circulation. 2012;126:2020-35. 
85. 
Braunwald E, Domanski MJ, Fowler SE, et al; PEACE Trial Investigators. Angiotensin-converting-
enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-68. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             58 
86. 
Morrow DA, Braunwald E, Bonaca MP, et al; TRA 2P–TIMI 50 Steering Committee and 
Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 
2012;366:1404-13. 
87. 
Tricoci P, Huang Z, Held C, et al; TRACER Investigators. Thrombin-receptor antagonist vorapaxar in 
acute coronary syndromes. N Engl J Med 2012;366:20-33. 
88. 
White WB, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC, et al. EXamination of 
cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes 
mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl 
peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am 
Heart J 2011;162:620-6. 
89. 
Einhorn PT, Davis BR, Massie BM, Cushman WC, Piller LB, Simpson LM, Levy D, Nwachuku CE, 
Black HR; ALLHAT Collaborative Research Group. The Antihypertensive and Lipid Lowering 
Treatment to Prevent Heart Attack Trial (ALLHAT) Heart Failure Validation Study: diagnosis and 
prognosis. Am Heart J. 2007 Jan;153(1):42-53. 
90. 
Go AS, Mozaffarian D, Roger VL, et al; AHA Statistics Committee and Stroke Statistics 
Subcommittee. Heart disease and stroke statistics--2013 update: a report from the American 
Heart Association. Circulation 2013;127:e6-e245. 
91. 
Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA 
1996;275:1571-6. 
92. 
Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J, Yawn BP, Jacobsen SJ. Trends 
in heart failure incidence and survival in a community based population. JAMA 2004;292:344-50. 
93. 
Hicks KA, Hung HMJ, Mahaffey KW, et al. Standardized definitions for cardiovascular and stroke 
end point events in clinical trials. FDA draft report, 2012. 
94. 
Ron E, Carter R, Jablon S, Mabuchi K. Agreement between death certificate and autopsy diagnoses 
among atomic bomb survivors. Epidemiology. 1994 Jan;5(1):48-56. 
95. 
Sesso HD, Gaziano JM, Glynn RJ, Buring JE. Value of an Endpoints Committee versus the use of 
nosologists for validating cause of death. Contemp Clin Trials.2006 Aug;27(4):  333-9. 
96. 
German RR, Fink AK, Heron M, et al. The accuracy of cancer mortality statistics based on death 
certificates in the United States. Cancer epidemiology 2011;35(2):126-31. 
97. 
Prieto-Merino D, Smeeth L, Staa TP, Roberts I. Dangers of non-specific composite outcome 
measures in clinical trials. BMJ 2013;347:f6782.  
98. 
McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: 
the Framingham study. N Engl J Med. 1971;285:1441–6. 
VA Central IRB
Effective Date:
October 26, 2022


Version 4.5 | 25OCT2022 
 
 
 
 
 
             59 
99. 
Sohn MW, Arnold N, Maynard C, Hynes DM. Accuracy and completeness of mortality data in the 
Department of Veterans Affairs. Popul Health Metr. 2006 Apr 10;4:2. 
100. Fletcher RD, Amdur RL, Kolodner R, McManus C, Jones R, Faselis C, Kokkinos P, Singh S, 
Papademetriou V. Blood pressure control among US veterans: a large multiyear analysis of blood 
pressure data from the Veterans Administration health data repository. Circulation 
2012;125:2462-8.  
101. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-
pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-85(+ online 
supplement). 
102.  Jennison, C and Turnbull, B. Group Sequential Methods with Applications to Clinical Trials. Boca 
Raton, Fl: Chapman & Hall/CRC Interdisciplinary Statistics, 2000. 
103.  Daniels MJ and Hogan JW.  Missing Data in Longitudinal Studies: Strategies for Bayesian Modeling 
and Sensitivity Analysis. Boca Raton, Fl: Chapman and Hall/CRC, 2008. 
104.  Beyersmann  J, Allignol  A, and Schumacher  M. Competing Risks and Multistate Models with R. 
New York, NY: Springer, 2012. 
105. http://answers.hhs.gov/ohrp/questions/7276  
106. Morris MC; Nelson RM. Randomized, controlled trials as minimal risk: An ethical analysis. Crit Care 
Med 2007; 35:940–4. 
107. Nelson K, Garcia RE, Brown J, Mangione CM, Louis TA, Keeler E, Cretin S. Do patient consent 
procedures affect participation rates in health services research? Med Care 2002;40:283-8. 
 
108. Cann CI, Rothman KJ. IRBs and epidemiologic research: how inappropriate restrictions hamper 
studies. IRB 1984;6(4):5-7. 
 
109. Armstrong D, Kline-Rogers E, Jani SM, Goldman EB, Fang J, Mukherjee D, Nallamothu BK, Eagle KA. 
Potential impact of the HIPAA privacy rule on data collection in a registry of patients with acute 
coronary syndrome. Arch Intern Med 2005;165:1125-9. 
 
110. Kaiser J. Patient privacy. Rule to protect records may doom long-term heart study. Science 
2006;311:1547-8. 
 
111. Ellickson PL, Hawes JA. An assessment of active versus passive methods for obtaining parental 
consent. Eval Rev 1989;13:45-55. 
 
VA Central IRB
Effective Date:
October 26, 2022

ICF_004.pdf: 
DCP Informed Consent Documentation 
 1 
^Wϱϵϳ͗ŝƵƌĞƚŝĐŽŵƉĂƌŝƐŽŶWƌŽũĞĐƚ;WͿ
/ŶĨŽƌŵĞĚŽŶƐĞŶƚŽĐƵŵĞŶƚĂƚŝŽŶ
&ĞďƌƵĂƌǇϭϵ͕ϮϬϮϭ
NCT02185417 
/ŶĨŽƌŵĞĚŽŶƐĞŶƚKǀĞƌǀŝĞǁ
01. Provider Informed Consent Information Sheet v2.5 October 25, 2018
02. Patient Informed Consent Information Sheet v2.6 June 6, 2019
03. Patient Informed Consent Script v3.3 February 19, 2021


Ishani A, Cushman W: CSP#597 “Diuretic Comparison Project (DCP)” 
Provider Information Sheet v2.5 
 1 
Appendix B.3 Provider Information Sheet 
To be included as a Progress Note accompanying the initial test patient order in CPRS. 
VA COOPERATIVE STUDY (CSP#597) 
DIURETIC COMPARISON PROJECT (DCP) 
PROVIDER INFORMATION NOTE 
CONTACT INFORMATION: 1-800-XXX-XXXX OR HYPERLINK 
Site Liaison: name    
STUDY OVERVIEW  
The Diuretic Comparison Project is the first national study to implement the VA Point of Care design 
which embeds clinical research into routine medical care to create a ‘learning healthcare system’.  
The purpose of the trial is to compare the effects of hydrochlorothiazide and chlorthalidone, on 
cardiovascular outcomes in older veterans with hypertension who are currently taking HCTZ.  
Patients will be randomized to continue on HCTZ or switched to Chlorthalidone. 
Primary Care Provider Participation: 
•
A ‘ZZTEST PATIENT’ Order will be sent to PCPs asking for their participation and approval to
contact potentially eligible patients in their panel.
•
PCPs, on average, will have 3-4 eligible patients. Enrollment is limited to 2 patients per week.
•
Randomization - For each eligible patient, two additional View Alert Orders will be sent: 1) to
approve randomizing an individual patient and 2) to sign the randomization assignment text
order and corresponding medication orders (chlorthalidone order and HCTZ discontinue order if
patient is switched).
•
Once randomized, all care is managed by the PCP.
WHAT IS THE PURPOSE OF THE RESEARCH STUDY? 
The DCP is a large randomized trial designed to compare the effects of two thiazide-type diuretics, 
hydrochlorothiazide and chlorthalidone, on cardiovascular outcomes in patients with hypertension. 
95% of current VA thiazide-type diuretic prescriptions are for hydrochlorothiazide. Indirect 
comparisons of randomized trial results have suggested that chlorthalidone may be more effective 
at reducing cardiovascular events (Roush et al. Hypertension 2012;59:1110-7), though a large 
observational study did not support this (Dhalla et al. Ann Int Med 2013;158:447-55). 
To determine whether chlorthalidone might be a better choice for our VA patients, we plan to 
enroll 13,500 veterans, over 65 years old, who are receiving 25 or 50 mg hydrochlorothiazide daily 
from VA pharmacies as a single-agent preparation. Participants will be randomly assigned to 
continue their hydrochlorothiazide or to have their prescription changed to chlorthalidone at a 


Ishani A, Cushman W: CSP#597 “Diuretic Comparison Project (DCP)” 
 
Provider Information Sheet v2.5 
 
 
 
      
       
 
            2 
suggested equipotent dose (12.5 or 25 mg respectively, where 12.5 mg requires cutting a pill in 
half). 
 
DCP employs a new Point of Care Clinical Trial design which integrates clinical research into routine 
medical care. Subject recruitment and enrollment will be accomplished by embedding processes 
using View Alerts within CPRS, the VA electronic medical record.   
 
Because the DCP is a new type of study, we are also studying providers to see how effectively the 
protocol is implemented. Thus, participants in this study include both patients and providers.  
Your decision to participate or not will be kept confidential. 
 
WHO IS CONDUCTING THE STUDY?  
VA Cooperative Study (CSP#597) 
Study Chairman: Areef Ishani, M.D. Minneapolis VAMC 
Study Co-Chairman: William Cushman, M.D. Memphis VAMC 
 
WHAT WILL HAPPEN DURING THE STUDY? 
 
‘ZZTEST PATIENT’ ORDER - The first step is to obtain your approval for the study team to contact your 
potentially eligible patients. You are receiving a ‘ZZTEST PATIENT’ (imaginary) ORDER that would allow 
DCP investigators to contact your patients. If you do not wish us to contact your patients at this time, 
discontinue the order. We will give you a second opportunity to consider participating at a later time. 
We may send you one additional ‘ZZTESTPATIENT’ order to seek your participation in about 8 weeks. If 
you discontinue this second order and do not wish to participate, you will receive no further 
correspondence from the study. 
PATIENT INFORMED CONSENT - If you allow your patients to be contacted by signing the order, a 
letter will be sent to your potentially eligible patients, including those of your residents, informing 
them about the study. Patients who do not opt out by voicemail will then be contacted by phone to 
describe the study in more detail and to seek oral informed consent. An easily understood summary 
of the consent document will be mailed to patients prior to the phone call. 
 
APPROVE RANDOMIZATION - Once a patient’s eligibility has been confirmed and they have 
consented, a View Alert order will be sent to you, to approve (sign) or disapprove (discontinue) 
randomization. Reasons for disapproval include: 1) impaired decision-making capacity rendering the 
patient unable to provide informed consent (which we will also try to assess when the study team 
calls the patient), 2) life expectancy less than 6 months, 3) unlikely to comply with treatment, or 4) 
any other reasons you believe make participation in this study inappropriate for that particular 
patient. The study team will follow-up with you by email if you do not take action on the randomization 
View Alert order within 4 weeks.   
If you do not approve randomization the patient will receive a letter notifying him of your decision. 
 


Ishani A, Cushman W: CSP#597 “Diuretic Comparison Project (DCP)” 
 
Provider Information Sheet v2.5 
 
 
 
      
       
 
            3 
MEDICATION ORDERS - After you approve a patient’s randomization, a note confirming 
randomization will be entered by the study staff for your acknowledgment.  For patients assigned to 
chlorthalidone, a prescription order for the proposed dose will be sent to you as a View Alert, at 
which time you can make any dosage change and order any laboratory tests as you see fit. At that 
time you will also receive an alert to cancel the existing hydrochlorothiazide prescription. Patients 
randomized to chlorthalidone will be reimbursed for their co-pay for any discarded 
hydrochlorothiazide pills.  
 
Patients assigned to continue on hydrochlorothiazide will remain on their current prescription. No 
new orders for hydrochlorothiazide will be entered by the study team. 
 
We will try to enroll patients about a month or two before a planned appointment with you to 
facilitate your evaluation of diuretic treatment at the appointment. There will be no designated 
study visits for the patients.  
 
FOLLOW-UP CARE - All further management is directed by you in the usual way, including blood 
pressure and laboratory measurements, dose changes, drug discontinuation (which may prompt a 
query to you from the study team), and management of any other antihypertensive agents. All 
outcome measures, specifically major cardiovascular events, will be determined from the VA 
electronic medical record and associated Medicare databases. In some cases, we may ask for your 
assessment of these events.  
 
PATIENTS FOLLOWED BY RESIDENTS - As a participant you will receive View Alerts to sign study 
related orders; your resident will NOT be alerted to sign these orders. Notes entered by study staff 
describing the randomization assignment will be sent to both you and your resident for 
acknowledgment.  
 
The study team will collect data on diuretic management within the study and may contact you 
from time to time by phone or email to learn your reasons for declining a particular patient or 
discontinuing a new chlorthalidone order or an ongoing diuretic prescription. If it is necessary to 
include PHI in follow-up communication regarding patient orders, the email will be encrypted. 
 
RISKS AND BENEFITS 
There is minimal risk for your participation in the study.  Participation in the study will not affect 
your job performance evaluation and we will not inform your supervisors regarding your decision to 
participate. Your decision to participate or not will be kept confidential.  
There is no direct benefit to you from your participation; however it is hoped that the VA can learn 
which drug may have the most benefit in reducing cardiovascular events. 
 
INJURY 
Every reasonable safety measure will be used to protect your well-being. If you are injured as a 
result of taking part in this study, the VA will provide necessary medical treatment at no cost to you 
unless the injury was due to your not following the study procedures. 


Ishani A, Cushman W: CSP#597 “Diuretic Comparison Project (DCP)” 
 
Provider Information Sheet v2.5 
 
 
 
      
       
 
            4 
If you should have a medical concern as a result of taking part in this study, call the study PIs (Areef 
Ishani, MD and William Cushman, MD) at 612-467-4431 or 901-577-7357 
 
CONFIDENTIALITY 
Information collected about the diuretic management of your patients will be kept confidential in 
encrypted and protected files on secure VA servers. Only members of the study team that are 
properly research credentialed and are compliant with VA security trainings will have access to the 
data. The VA Central IRB; the VHA Office of Research Oversight, the Office of Human Research 
Protections and the Government Accountability Office may have access to the study’s research 
records. At the end of the study, the data for CSP#597 will remain property of the Cooperative 
Studies Program and be stored and shared according to CSP guidelines and procedures. Retention 
and destruction of data will be conducted according to CSP operating procedures and federal and 
local VA regulations. A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information 
that can identify you. At most, the Web site will include a summary of the results. You can search 
this Web site at any time.  
 
You can reach the VA Central IRB Toll Free at 1-877-254-3130 if you have any questions or concerns, 
or would like to verify that this is a valid VA approved study. 
 
 
 


Ishani A, Cushman W: CSP#597 “Diuretic Comparison Project (DCP) 
 
Patient Information Sheet v2.6 
 
 
 
      
 
       
            1 
Appendix B.2 Patient Information Sheet 
Informed Consent Information 
What is the purpose of the research study? The Diuretics Comparison Project is a nationwide VA 
research study examining two diuretics, or water pills, used to treat high blood pressure. The 
medications are called hydrochlorothiazide (which you are currently prescribed) and chlorthalidone. 
Both drugs are believed to be the best treatment for high blood pressure, are approved by the FDA, and 
have been prescribed by doctors for over 50 years.  
There is no specific reason for doctors to pick one medication over the other. Some doctors think that 
chlorthalidone may be better in preventing strokes and heart attacks; however, hydrochlorothiazide is 
the more commonly used of the two drugs. This study will compare the benefits of these two drugs in 
our Veteran population. 
Who is conducting the study? This is a VA study and the lead researchers are Dr. Areef Ishani of the 
Minneapolis VA and Dr. William Cushman of the Memphis VA. They are experts in the treatment of high 
blood pressure and in leading research studies.   
Who will be asked to participate? We hope to enroll more than 13,000 Veterans. 
What will happen during the study? There is very little to participate in this study. If you agree to take 
part, you will have a 50:50 chance (like the flip of a coin) of staying on hydrocholorothiazide (what you 
are currently taking) or being switched to chlorthalidone. 
If you are switched to chlorthalidone, you will receive the new drug in the mail with instructions. If you 
are assigned to hydrochlorothiazide you will continue to take it as you do now. 
Both you and your VA providerwill know which medication you are taking.Your doctor has given 
permission for their patients to participate and will continue to care for you as usual. This includes 
checking your blood pressure and blood tests and making any changes to your medicines as needed. If 
your provider decides that either of the drugs is not right for you, he or she can change your medicine at 
any time.  
You will not have any added tests, clinic visits, or forms to fill out because of the study. You will not be 
asked for any information. All of the information for the study will be collected from your health 
records.  
If you decide to participate, you agree to allow us to collect data from your electronic health records 
over the next 10 years. You will not be asked for any information. We will get data from your VA health 
record and other national databases, like Medicare. Specifically, we will collect demographic 
information, blood pressure readings, lab tests, and all medicines that you take. We will also collect data 
on medical conditions and any hospitalizations that may be due to high blood pressure.  
Are there risks, inconveniences or discomforts associated with my participation? For most people, the 
dose of chlorthalidone will be half of their current hydrochlorothiazide dose. This change may not be 
exact for everyone, so there may be some changes in your blood pressure (either higher or lower) and 
your lab tests (potassium and kidney function). Your provider will routinely check these results and treat 
them as needed. You may need to cut chlorthalidone tablets in half to receive the correct dose – if you 
do, you will be mailed a pill splitter. If you are assigned to chlorthalidone, you will need  to throw away 


Ishani A, Cushman W: CSP#597 “Diuretic Comparison Project (DCP) 
 
Patient Information Sheet v2.6 
 
 
 
      
 
       
            2 
your old hydrochlorothiazide pills. We will reimburse you for the cost of any co-pay you have made for 
the pills that are thrown away. 
The risks related to taking chlorthalidone are very similar to those of taking hydrochlorothiazide. The 
safety concerns for both drugs are very well understood and both drugs are believed to be the best 
treatment. Both medications often lower blood potassium levels and many people using these drugs are 
also treated with potassium supplements. New diabetes, new gout, and reduced kidney function (by 
25%) may occur in about 2% of people. Serious allergic reactions may occur in 1 in 1000 persons. There 
could be unforeseen risks of switching medications, so if you experience side effects from either drug, 
you should contact your doctor.  
Are there any benefits to me from participation? There is no direct benefit to you from being in this 
study. However, your participation may help other veterans and other people with high blood pressure 
in the future.   
What if I get injured? Every reasonable safety measure will be used to protect your well-being. If you 
are injured as a result of taking part in this study, the VA will provide necessary medical treatment at no 
cost to you unless injury was due to your not following the study procedures. If you require emergency 
medical attention, please contact your provider directly. If you should have a medical concern or get 
hurt of sick as a result of taking part in this study, call 1-800-863-1604. 
What if I decline to participate? If you decide not to participate, your provider will continue to treat you 
as they do now. You will continue to receive all the VA care to which you are entitled. Your participation 
in this study is completely voluntary. You have the right to refuse participation or leave the study at any 
time. Leaving the study will not result in any penalty or loss of benefits. The study has been approved by 
the VA Human Rights Committee in Boston and by the VA Central Institutional Review Board. 
Will my research results be kept confidential? Only members of the study team that have been trained 
on VA security will have access to the data. The researchers who collect this information will keep your 
health information confidential in encrypted and protected files on secure VA servers. We will only 
share data with approved researchers and officials who monitor VA research studies, including VHA 
Office of Research Oversite, Office of Human Research Protections, and the Government Accountability 
Office . You will not be personally identified in any papers, reports, or presentations from this study.  
If you agree to participate, you will be asked to state that agreement. After the phone call we will get 
final approval from your provider. You will receive a letter stating which medication you have been 
randomized to. If your medication is switched, we will send you your new prescription in the mail.  
Will I incur any costs or receive any compensation for participating in this study? If your prescription 
changes from hydrochlorothiazide to chlorthalidone we will reimburse your first co-pay. If your 
prescription does not change, we are unable to reimburse you. We are not able to compensate you for 
your normal doctor’s appointments.  
Where can I find additional information? A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This website will not include information that can 
identify you. At most, the website will include a summary of the results. You can search this website at 
any time.  


Ishani A, Cushman W: CSP#597 “Diuretic Comparison Project (DCP) 
 
Patient Information Sheet v2.6 
 
 
 
      
 
       
            3 
If you have questions about your rights as a study participant, you may contact the VA Central 
Institutional Review Board (IRB) toll free at 1-877-254-3130. For questions about the research or to 
withdraw from the study, call 1-800-865-3384 extension 44562. 
 


Ishani A,: CSP#597 “Diuretic Comparison Project (DCP) 
 
Version3.3 | 18FEB2021  
 
1 
 
Appendix B.1 Patient Telephone Informed Consent Script  
Hello, my name is <Caller’s Name> and I am calling from the Veterans Affairs.  May I speak to Mr. (Ms.) 
<Veteran’s Name>?   
I’m calling today to follow up on a letter we sent to you about a research study called the Diuretic 
Comparison Project. The letter was about your high blood pressure medication, hydrochlorothiazide. Do 
you recall if you received that letter from us?  
[Yes] Do you have any questions about the study I might answer for you? 
 
[Yes] *See FAQ* 
[No] Do you have a little time to go over the study? It should only take a few minutes of your 
time. 
[Yes] *Proceed to Page 2* 
[No] When would be a better time to call you back? 
Thank you for your time today <Veteran’s name>. I will be in touch with you at <the stated date 
and time>. 
[No] Okay. In order to improve our service to our Veterans, may I ask, is there any particular 
reason?  
Thank you for your time today and for your service.  
 May I confirm the current address we have on file for you?  We have: XX Street, City, State, Zip. Is that 
correct?  
 
[No] I will go ahead and update that in our study system. What is your current address? 
 
I have [read back new address given to confirm accuracy], is that correct? 
 
Please be aware that I can only update your address as it applies to this study.  
 
 
Would you like me to send you a new letter? 
[Yes] Okay. I will have that sent to you. Do you have time now to talk about the 
content of the letter? 
[Yes] *Proceed to page 2*  
[No] Okay I will send you the letter and we will be back in touch with 
you in about two weeks after you’ve had a chance to review it. Is this a 


Ishani A,: CSP#597 “Diuretic Comparison Project (DCP) 
 
Version3.3 | 18FEB2021  
 
2 
 
good time of day to reach you? Thank you for your time today and for 
your service.  
 
 
 
[No] Okay. I take it that you are not interested in this study?  
[Yes] Well thank you for your time today and for your service . Do you 
mind telling me why you are not willing to participate? This information 
will help us with future studies.. We will remove you from our system.  
The Diuretic Comparison Project is a nationwide VA research study comparing two diuretics, or water 
pills, to treat high blood pressure. The medications are called hydrochlorothiazide (which you are 
currently prescribed) and chlorthalidone. Both are believed to be the best treatment for high blood 
pressure, are approved by the FDA, and have been used for over 50 years.   
There is no specific reason for doctors to pick one medication over the other. Hydrochlorothiazide is the 
more commonly used of the two drugs, but some doctors think that chlorthalidone may be better in 
preventing strokes and heart attacks. This study will help us learn which drug is more effective in our 
Veteran population.  
We hope to enroll more than 13,000 Veterans. 
There is very little that you will need to do to participate in this study. If you agree to take part, you will 
have a 50:50 chance of staying on hydrochlorothiazide (what you are currently taking) or being switched 
to chlorthalidone.   
If you are switched to chlorthalidone, you will receive the new drug in the mail with instructions. There 
will also be the name and phone number of someone to call if you have any questions. If you are 
assigned to hydrochlorothiazide you will continue to take it as you do now.   
Both you and your VA provider will know which medication you will be taking. Your doctor has given 
permission for their patients to participate and will continue to care for you as usual regardless of your 
participation in this study.  If you or your provider decides that either of the drugs is not right for you, 
they can change your medicine at any time.   
You will not have any added tests, clinic visits, or forms to fill out because of the study. You will not be 
asked for any information. All of the information for the study will be collected from your health 
records.   
If you decide to participate, you agree to allow us to collect data from your electronic health records 
over the next 10 years. We will get data from your VA health record and other national databases, like 
Medicare. Specifically, we will collect demographic, blood pressure readings, lab tests results, and all 
medications that you take. We will also collect data on medical conditions and any hospitalizations that 
may be due to high blood pressure.   
For most people, the dose of chlorthalidone will be half of their current hydrochlorothiazide dose. This 
change may not be exact for everyone, so there may be some changes in your blood pressure (either 
higher or lower) and your lab tests (specifically potassium and kidney function). You may need to cut 


Ishani A,: CSP#597 “Diuretic Comparison Project (DCP) 
 
Version3.3 | 18FEB2021  
 
3 
 
chlorthalidone tablets in half to receive the correct dose – if you do, you will be mailed a pill splitter. If 
you are assigned to chlorthalidone, you will need to throw away your hydrochlorothiazide pills. We will 
reimburse you for the co-pay on the pills that are thrown away.  
The risks related to taking chlorthalidone are very similar to those of taking hydrochlorothiazide. The 
safety concerns for both drugs are very well understood. Both medications often lower blood potassium 
levels and many people using these drugs are also treated with potassium supplements. Other side 
effects, which may occur in about 2% of people, include: new diabetes, new gout, and reduced kidney 
function (by 25%). Serious allergic reactions may occur in 1 in 1000 persons. As with any change in 
medication there could be unforeseen risks, so if you experience side effects from either drug, you 
should contact your doctor.   
This study has been approved by the VA Human Rights Committee in Boston and the VA Central 
Institutional Review Board.  
Your health information will be kept confidential through physical and electronic security measures, 
such as encryption and protected files on secure VA servers. Only member of the study team trained on 
VA security, will have access to the data. We will only share data with approved researchers and officials 
who monitor VA research studies, including Veterans Health Administration (VHA) Office of Research 
Oversite, the Office for Human Research Protections, and the Government Accountability Office. If you 
have any questions about your rights as a study participant, you may contact the VA Central Institutional 
Review Board (IRB) toll free at 1-877-254-3130.   
As required by U.S. Law, a description of this clinical trial will be available on the internet at, 
www.ClinicalTrials.gov. This website will never include information that can identify you. You will not be 
personally identified in any papers, reports, or presentations from this study. At most, the website will 
include a summary of the results. You can search the website at any time.  
There is no direct benefit to you from being in this study. However, your participation may help other 
Veterans and other people with high blood pressure in the future.  
If you decide not to participate, your provider will continue to treat you as they do now. You will 
continue to receive all the VA care to which you are entitled. Your participation in this study is 
completely voluntary. You have the right to refuse participation or leave the study at any time. Leaving 
the study will not result in any penalty or loss of benefits.  
Every reasonable safety measure will be used to protect your well-being. If you are injured as a result of 
taking part in this study, the VA will provide necessary medical treatment at no cost to you unless the 
injury was due to your not following the study procedures. 
If you require emergency medical attention, please contact your provider directly. If you should have a 
medical concern or get hurt or sick as a result of taking part in this study, call 1-800-863-1604. 
If you do agree to participate, I will ask you to state that agreement to me. After the phone call we will 
get final approval from your provider.  You will then receive a letter stating which medication you have 
been randomized to or if you are determined to be ineligible. If your medication is switched, we will 
send you your new medication in the mail. This process can take a while. If you have any questions 


Ishani A,: CSP#597 “Diuretic Comparison Project (DCP) 
 
Version3.3 | 18FEB2021  
 
4 
 
about the status of your consent, please do not hesitate to call the study number. All letters sent to you 
will contain a phone number for you to call if you have any study related questions. All medical 
questions should be directed to your provider.  
For questions about the research or to withdraw from the study, call us at 1-800-863-1604.  
Do you understand everything that has been said?     
Do you have any further questions?   
Do you need more time to think about participating?  
Do you want to discuss participating with your family or doctor?   
Are you willing to participate?   
[Yes] Thank you so much for your time, willingness to participate, and your service. We will let your 
provider know your decision and as soon as we get final approval, we will send you a letter to let you 
know if you will continue on hydrochlorothiazide, switch to chlorthalidone, or are ineligible. For now, 
please continue to take your hydrochlorothiazide. If you have any questions or concerns in the future, 
feel free to contact us. Have a good day.  
[No] Thank you so much for your time. If you wish to participate in the future or have any questions 
about the study, feel free to contact us. Have a good day. 
Reaffirmation Script 
Hello, My name is <Caller’s Name> and I am calling from the Department of Veterans Affairs.  Is this Mr. 
(Ms.) <Veteran’s Name>?   
We are contacting you because you previously consented to participate in the Diuretic Comparison 
Project.  
You should have received a letter explaining that you were temporarily ineligible for our study and that 
we would contact you as soon as you were eligible.  
We have confirmed that you are now eligible.  
As a reminder, the purpose of this study is to compare the benefits of hydrochlorothiazide and 
chlorthalidone in our Veteran population.  
Both you and your VA Provider will know which medication you will be taking. If you or your provider 
decides that either of the drugs is not right for you, your Provider can change your medicine at any 
time.   


Ishani A,: CSP#597 “Diuretic Comparison Project (DCP) 
 
Version3.3 | 18FEB2021  
 
5 
 
Your participation in this study is completely voluntary. You have the right to leave the study at any 
time. Leaving the study will not result in any penalty or loss of benefits. After the phone call we will get 
final approval from your provider.  You will receive a letter stating to which medication you have been 
randomized. If your medication is switched, we will send you your new medication in the mail.  
Voicemail Message Script  
1-800-865-3384 extension 44562 
Thank you for calling the diuretic comparison project your call is important to us. If you have a question 
or would like to speak to a representative please leave your name and a detailed message. 
If you do not want to receive a call about the study and wish to Opt-out please leave your name, DOB, 
and last four of your social security number and state that you would like to opt-out of the study. Thank 
you and have a good day. 
1-800-863-1604 
During business hours: (0800 to 1600) 
Hello, thank you for calling the VA’s Diuretic Comparison Project.  
1. If you have questions or if you would like to participate, please press one. → ACD Queue 
a. If no one is logged in  → To Mailbox A  
2. If you do not wish to participate in the study please press two. → Mailbox B. 
After business hours: (16:30:01 to 07:59:59) 
Hello, thank you for calling the VA’s Diuretic Comparison Project. Our center is currently closed. You may 
leave us a message or call back between 8:00am and 4:30pm Central Time Monday-Friday. 
1. For questions you may have about the research study, or if you would like to participate, please 
press one and leave a message. →Mailbox A 
2. If you do not wish to participate in the study please press two.  → Mailbox B. 
 
Mailbox A Greeting: 
We are sorry we could not answer your call at this time; your call is important to us. Please leave 
your name, date of birth, and telephone number. We will return your call as soon as possible.  
 
 
Mailbox B Greeting:  


Ishani A,: CSP#597 “Diuretic Comparison Project (DCP) 
 
Version3.3 | 18FEB2021  
 
6 
 
If you do not wish to participate in the Diuretic Comparison project research study, please state your 
name, date of birth, the last four digits of your social security number, and that you wish to decline to 
participate. 
Voicemail Message Script once recruitment is reached 
Hello, thank you for calling the VA’s Diuretic Comparison Project. Our study is no longer recruiting new 
participants.  
1. If you are currently in the study and have questions or concerns for the study team, please press 
one. →Mailbox A 
2. If you no longer wish to participate in the study, please press two.  → Mailbox B. 
 
Mailbox A Greeting: 
We are sorry we could not answer your call at this time; your call is important to us. Please leave 
your name, date of birth, and telephone number. We will return your call as soon as possible.  
 
 
Mailbox B Greeting:  
If you do not wish to participate in the Diuretic Comparison project research study, please state your 
name, date of birth, the last four digits of your social security number, and that you wish to decline to 
participate.