CSP #597 - Diuretic Comparison Project
Phase: PHASE3
Conditions: Hypertension
Sponsor: VA Office of Research and Development

 
 
 
 
 
 
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 
 
 
 
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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 
 
 
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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.  
 
 
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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 
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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 
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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 
 
 
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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 
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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 
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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 
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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 
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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 
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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). 
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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 
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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 
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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.  
 
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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 
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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.  
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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 
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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). 
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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 
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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  
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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. 
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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.  
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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 
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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).  
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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 
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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 
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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 
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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. 
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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 
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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, 
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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 
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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 
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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, 
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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 
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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 
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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. 
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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. 
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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 
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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. 
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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, 
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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. 
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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 
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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 
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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: 
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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  
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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 
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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 
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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 
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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. 
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