Self-management of Blood Pressure Medication for Hypertensive Veterans
Phase: NA
Conditions: Hypertension
Sponsor: VA Office of Research and Development

Study Protocol and Statistical Analysis Plan 
Project Title: 
Self-Management of Blood pressure for Hypertensive Veterans 
NCT ID (NCT03224624) 
March 2, 2018 
 
 
 
 

MANUAL OF PROCEDURES 
 
Self-Management of Blood Pressure for 
Hypertensive Veterans (SMART) 
 
 
 
 
Table of Contents 
 
 
 
Chapter 1.  Background and motivation 
Chapter 2.  Complete Study Overview 
Chapter 3. Recruitment and Informed Consent 
Chapter 4. In Clinic Measurements and Administering Questionnaires 
Chapter 4.a Screening Visit Procedures 
Chapter 4.b Baseline/Randomization Visit Procedures 
Chapter 4.c Post Randomization Visit Procedures 6 mos and 12 mos 
Chapter 5. Retention, Adherence 
Chapter 6. Procedures for Inactive/Lost/Refused Participants and Missed Visits 
Chapter 7. Ascertainment and Documentation of Study Outcomes 
Chapter 8. Safety Monitoring and Reporting 
Chapter 9. Quality Control 
Chapter 10. Data Management and Security 
 
 
 
 
 

 
 
Chapter 1.  Background and motivation. 
1. Hypertension:  a chronic condition ready for patient-centered self-
management. Hypertension is the most common medical problem among US 
Veterans, with nearly 50% of the 5.5 million VA patients receiving health care 
services in 2006 having elevated blood pressure. Hypertension is the most common 
risk factor for stroke, cardiovascular disease, and kidney failure,1  and the leading 
modifiable contributor to global disease burden.2 The VA has been a leader in the 
study of hypertension and its outcomes for decades3 leading both landmark clinical 
trial and cohort studies demonstrating that hypertension is a clinically significant and 
treatable risk factor.4–7   Translating our knowledge into effective treatment demands 
that we reassess the decades-long status quo of physician-driven blood pressure 
management and consider other health delivery methods. 
  
2. Current standard-of-care blood pressure management is inadequate in 
reaching treatment goals. The long-time clinical practice standard for treatment of 
hypertension involves intermittent, office-based measurement of blood pressure and 
adjustment of blood pressure medications. This approach has been recognized as 
inadequate for several reasons. First, therapeutic inertia,8 or failure to initiate or 
increase medication despite poor control of blood pressure, is a major factor, 
exacerbated by infrequent office visits and reliance on in-clinic blood pressure 
measurements. Recent trials directed at reducing the behaviors associated with 
clinical inertia have not been successful in lowering BP.9 Second, in-office blood 
pressure readings are not always reflective of out-of-clinic blood pressures and may 
not be as trusted by patients or even providers. Third, initiation of and adherence to 
newly-prescribed blood pressure regimens are fraught with opportunities to delay or 
avoid treatment, and are affected by issues of cost,10 trust,11 denial, and perceived 
efficacy12 despite overwhelming evidence of the efficacy and cost-effectiveness of 
antihypertensive treatment.13  
  
3. Home blood pressure monitoring is increasingly recognized as critical and 
more predictive of events, but not routinely integrated into clinical practice. 
Blood pressure is a continuous, and continuously variable, physiological parameter. 
There has long been debate about how well clinically measured blood pressures 
reflect the underlying physiology in any given individual. In the 1940s Smirk14 
demonstrated the correlations of ‘basal’ (e.g. morning rest) BP and ‘casual’ (e.g. 
randomly measured BP) and described the substantial variability of the 
‘supplemental’ pressure – e.g. the amount of variability that could be expected 
surrounding a given basal pressure. Ambulatory blood pressure monitoring (ABPM) 
recordings – readings taken generally every 20 minutes throughout a day-night cycle 
– confirmed differences between in-clinic and out-of-clinic blood pressures and has 
also demonstrated that these various measures of blood pressure are not equal in 
terms of their implications for cardiac risk, with ABPM showing stronger relationships 
with cardiac risk than in-clinic blood pressure.15 
     In practice, however, while devices allowing self-measurement of blood pressure 
have been available for years, data from these devices has been slow to influence 
prescribing and treatment patterns despite guidelines.16 Concerns raised by 

physicians have included device inaccuracy, patient misuse or misreporting, and 
difficulties integrating data from home with clinic.17 
     Despite these concerns, multiple studies have demonstrated that patients are not 
only capable of home monitoring but that monitoring itself has a positive impact on 
hypertension care.18 Including a blood pressure monitor in a hypertension care plan 
improves self-efficacy, and in many circumstances improves blood pressure as well. 
At the VA, while blood pressure monitors are available and often issued to patients, 
the integration of data from these monitors is accomplished in a haphazard, clinic-
by-clinic fashion. To our knowledge, no formal VA study has attempted to allow 
patients to self-monitor and self-manage their blood pressure medications.  
  
4. Patient-centered care for chronic medical conditions is increasingly valued 
and accepted in other domains. Home-based measurements of blood pressure 
are clearly emerging as clinically relevant and necessary for appropriate treatment. 
From a health services standpoint, moving to self-monitoring and self-management 
of blood pressure medication would involve a paradigm shift in medical care for a 
condition traditionally considered the domain of physician-dominated prescribing and 
treatment. Per the Institute of Medicine (IOM), an essential component of quality 
medical care is patient-centeredness, a component that, until recently, has been 
both underappreciated and underutilized.19 The IOM issued ten rules for redesigning 
health care,20 with several specifically related to patient-centered care.  These 
included the patient as a source of control of that care; shared knowledge and the 
free flow of information; care based on a continuous healing relationship; and 
customization of care based on patient needs and values. Patient-centeredness 
includes both (a) the patient’s experience of, and contribution to, medical care, and 
(b) the presence of an effective partnership between clinician and patient (i.e., the 
clinician as a “collaborator”). 
     An effective plan for patients to self-manage their blood pressure must move 
toward patient-centered care without compromising safety. While medication 
management in diabetes, for example, has long been accomplished in collaborative 
fashion, with patients being empowered to use “sliding scales” for adjustment of 
different forms of insulin and different doses, the same is not true of hypertension, 
with conventional wisdom being that physician involvement would be required to 
adjust hypertension medications appropriately. However, acute hypo- or hyper-
glycemia is at least as dangerous as low or high BP, and glucose monitoring and 
insulin adjustment is far more complex than the single medication changes proposed 
here. 
  
5. Blood pressure self-monitoring and self-management in the TASMIN 
studies:  promising, but not yet ready for VA practice.  
     The two major trials in the UK were the Telemonitoring and Self-Management in 
Hypertension 2 (TASMINH2)21 trial and the Targets and Self-Management for the 
Control of Blood Pressure in Stroke and at Risk Groups (TASMIN-SR)22 trial. These 
targeted, respectively, a general population with hypertension in general practitioner 
practices in the National Health Service, and a more restricted population with at 
least one major risk factor (stroke or transient ischemic attack, diabetes, stage 3 
chronic kidney disease [CKD], past history of coronary bypass surgery, or history of 
myocardial infarction or angina). In each of these studies, participants in the 

intervention arm were instructed in the use of a self-monitoring device and told to 
self-monitor for at least a week each month.  If their BP was out of a pre-specified 
range, they were able to activate a step in a 2 or 3 step self-management plan. If BP 
was concerningly high or low, they were instructed to contact their general 
practitioner. The primary outcome was in-clinic BP change at 12 months. Each study 
found significant improvement in blood pressure in both groups, but more so in the 
intervention (self monitoring / self titration) group -- a between group difference of 
5.4 mm Hg, (95% CI 2.4-8.5) in TASMINH2, and 9.2 mm Hg (95% CI, 5.7-12.7) in 
the TASMIN-SR trial, in comparison to a group receiving usual, clinic-directed care, 
without an increase in serious adverse events (SAEs). These blood pressure 
differences are not only statistically significant, but also extremely clinically 
significant. Even very small BP changes on the order of 3-5 mm Hg averaged over 
populations have been demonstrated in large modeling studies to have dramatic 
effects on public health in terms of decreases in cardiovascular events and early 
mortality.23 Thus, the potential benefit of demonstrating that an intervention like this 
can be delivered through VA, even to a subset of its large hypertensive 
population, is tremendous.  
  
VA HSR&D agreed and has funded us at VA San Diego to complete just such a 
study, in collaboration with VA SF, addressing the question of self-management in 
400 US Veterans. 
  
  
1.            Furmaga EM, Cunningham FE, Cushman WC, et al. National Utilization of 
Antihypertensive Medications From 2000 to 2006 in the Veterans Health Administration: 
Focus on Thiazide Diuretics. J Clin Hypertens. 2008;10(10):770-778. doi:10.1111/j.1751-
7176.2008.00019.x. 
2.            Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of 
disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-
2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 
2012;380(9859):2224-2260. doi:10.1016/S0140-6736(12)61766-8. 
3.            Fletcher RD, Amdur RL, Kolodner R, et al. Blood pressure control among US 
veterans: a large multiyear analysis of blood pressure data from the Veterans Administration 
health data repository. Circulation. 2012;125(20):2462-2468. 
doi:10.1161/CIRCULATIONAHA.111.029983. 
4.            Materson BJ, Reda DJ, Cushman WC, et al. Single-Drug Therapy for Hypertension 
in Men – A Comparison of Six Antihypertensive Agents with Placebo. N Engl J Med. 
1993;328(13):914-921. doi:10.1056/NEJM199304013281303. 
5.            Materson BJ, Reda DJ, Williams D. Lessons from combination therapy in Veterans 
Affairs Studies. Department of Veterans Affairs Cooperative Study Group on antihypertensive 
agents. Am J Hypertens. 1996;9(12 Pt 2):187S-191S. 
6.            Perry HM, Bingham S, Horney A, et al. Antihypertensive Efficacy of Treatment 
Regimens Used in Veterans Administration Hypertension Clinics. Hypertension. 
1998;31(3):771-779. doi:10.1161/01.HYP.31.3.771. 
7.            Effects of treatment on morbidity in hypertension. Results in patients with diastolic 
blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202(11):1028-1034. 
8.            Lebeau J-P, Cadwallader J-S, Aubin-Auger I, et al. The concept and definition of 
therapeutic inertia in hypertension in primary care: a qualitative systematic review. BMC Fam 
Pract. 2014;15:130. doi:10.1186/1471-2296-15-130. 
9.            Huebschmann AG, Mizrahi T, Soenksen A, Beaty BL, Denberg TD. Reducing 
clinical inertia in hypertension treatment: a pragmatic randomized controlled trial. J Clin 
Hypertens Greenwich Conn. 2012;14(5):322-329. doi:10.1111/j.1751-7176.2012.00607.x. 

10.          Li P, McElligott S, Bergquist H, Schwartz JS, Doshi JA. Effect of the Medicare Part 
D coverage gap on medication use among patients with hypertension and hyperlipidemia. 
Ann Intern Med. 2012;156(11):776-784, NaN-263, NaN-264, NaN-265, NaN-266, NaN-267, 
NaN-268, NaN-269. doi:10.7326/0003-4819-156-11-201206050-00004. 
11.          Logan AG, Dunai A, McIsaac WJ, Irvine MJ, Tisler A. Attitudes of primary care 
physicians and their patients about home blood pressure monitoring in Ontario. J Hypertens. 
2008;26(3):446-452. doi:10.1097/HJH.0b013e3282f2fdd4. 
12.          Morrison VL, Holmes EAF, Parveen S, et al. Predictors of self-reported adherence 
to antihypertensive medicines: a multinational, cross-sectional survey. Value Health J Int Soc 
Pharmacoeconomics Outcomes Res. 2015;18(2):206-216. doi:10.1016/j.jval.2014.12.013. 
13.          Moran AE, Odden MC, Thanataveerat A, et al. Cost-effectiveness of hypertension 
therapy according to 2014 guidelines. N Engl J Med. 2015;372(5):447-455. 
doi:10.1056/NEJMsa1406751. 
14.          Smirk FH. CASUAL AND BASAL BLOOD PRESSURES IV. THEIR 
RELATIONSHIP TO THE SUPPLEMENTAL PRESSURE WITH A NOTE ON STATISTICAL 
IMPLICATIONS. Br Heart J. 1944;6(4):176-182. 
15.          Pickering TG. What is the true blood pressure? Smirk revisited. J Clin Hypertens 
Greenwich Conn. 2005;7(7):421-424. 
16.          Pickering TG, Miller NH, Ogedegbe G, et al. Call to action on use and 
reimbursement for home blood pressure monitoring: a joint scientific statement from the 
American Heart Association, American Society Of Hypertension, and Preventive 
Cardiovascular Nurses Association. Hypertension. 2008;52(1):10-29. 
doi:10.1161/HYPERTENSIONAHA.107.189010. 
17.          Logan AG, Dunai A, McIsaac WJ, Irvine MJ, Tisler A. Attitudes of primary care 
physicians and their patients about home blood pressure monitoring in Ontario. J Hypertens. 
2008;26(3):446-452. doi:10.1097/HJH.0b013e3282f2fdd4. 
18.          Uhlig K, Patel K, Ip S, Kitsios GD, Balk EM. Self-measured blood pressure 
monitoring in the management of hypertension: a systematic review and meta-analysis. Ann 
Intern Med. 2013;159(3):185-194. doi:10.7326/0003-4819-159-3-201308060-00008. 
19.          Davis K, Schoenbaum SC, Audet A-M. A 2020 Vision of Patient-Centered Primary 
Care. J Gen Intern Med. 2005;20(10):953-957. doi:10.1111/j.1525-1497.2005.0178.x. 
20.          Institue of Medicine. Crossing the Quality Chasm: A New Health System for the 
21st Century.; 2001. 
21.          McManus RJ, Mant J, Bray EP, et al. Telemonitoring and self-management in the 
control of hypertension (TASMINH2): a randomised controlled trial. Lancet. 
2010;376(9736):163-172. doi:10.1016/S0140-6736(10)60964-6. 
22.          McManus RJ, Mant J, Haque M, et al. Effect of self-monitoring and medication self-
titration on systolic blood pressure in hypertensive patients at high risk of cardiovascular 
disease: The tasmin-sr randomized clinical trial. JAMA. 2014;312(8):799-808. 
doi:10.1001/jama.2014.10057. 
23.          Bibbins-Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt 
reductions on future cardiovascular disease. N Engl J Med. 2010;362(7):590-599. 
doi:10.1056/NEJMoa0907355.

Chapter 2.  Study overview. 
1. Study design overview. We plan a 400 participant, randomized, controlled, non-blinded, 
two-center study of patient-initiated self-management of blood pressure medication vs. usual 
care over a one-year study period, with planned post-study cohort follow-up via medical records. 
The primary outcome is the absolute change in in-clinic systolic blood pressure after 1 year. 
 
The design of this study is informed by that of the published TASMIN trials of self-management, 
to capitalize on the foundational work of those investigators, while adding critical modifications 
to the intervention to best serve the VA system and allow a full assessment of this delivery 
mechanism in clinics at a VA hospital and CBOCs.  Approximately 350 patients will enroll at VA 
San Diego; this value includes attrition. 30% of consented subjects are estimated to fail the 
screening process, therefore approximately 250 participants are expected to enter the follow-up 
period at this location.  At VA San Francisco, approximately 200 patients will enroll and 150 will 
follow the full course of the study. 
  
2. Description of the study population, sampling frame, and inclusion/exclusion criteria. 
We plan to enroll Veterans receiving healthcare through either (a) one of the VA San Diego 
Healthcare System's primary care clinics or area CBOCs (Chula Vista, Mission Valley, El 
Centro, Imperial Valley, Oceanside, covering an area from the Mexican border north to Orange 
County, and east to the rural desert and mountain communities) or (b) the VA San Francisco's 
primary care clinic who have a clinical diagnosis of hypertension and who are not currently at 
their in-clinic goal blood pressure, able to provide independent informed consent and expected 
to be in the area for at least 12 months. The figure gives an overview. 
 
  
 

HIPAA Waiver and patient identification. 
In the same manner as we have used in the past to recruit from primary care clinics for the 
SPRINT study, we have a partial HIPAA waiver to access the Computerized Patient Record 
System (CPRS) to identify hypertensive patients in primary care clinics and CBOCs; patients 
can also be identified through review of weekly clinic lists with providers.  Specifically, we will 
use PHI to identify potential subjects in the VA San Diego Healthcare System (including the 
CBOCs) based on limited data in the medical record, including the Computerized Patient 
Record System (CPRS) concerning patients with hypertension meeting the basic criteria below 
(e.g. taking 1 or fewer antihypertensives and with blood pressure above clinical goal). The 
purpose of this is to enable the study team to identify patients in order to be able to tell 
appropriate patients about the study and obtain verbal permission from the patient so that study 
staff can be notified of the patient’s interest in the study. Additionally, study staff may approach 
patients during their clinic sessions and invite them to learn more about the study. Recruitment 
letters may also be used instead of verbal contact during the course of providing medical care. 
Following introduction, study staff will communicate with interested individuals and set up a 
screening visit. Once study staff has discussed the study with the interested patient they will 
consent the participant and obtain full authorization for enrollment. 
  
      Exclusion criteria are designed to limit serious comorbidities and complex cases of 
hypertension while still permitting a large fraction of those with hypertension to be included in 
this study. Therefore, it is important to thoroughly investigate the patient’s history and clearly 
document inclusion and exclusion criteria. Medical record review can be used for prescreening. 
Study staff should obtain Institutional Review Board’s approval for these activities, as mandated 
by local practices. Local laboratories will be used for lab tests to determine screening eligibility. 
The maximum time between lab tests and screening eligibility will be 90 days.  
 
Centers also need to keep a listing of why the participant who was told about the study decided 
not to participate. These reasons are recorded on “The Reasons Why Participants who are 
Approached and do not Consent” tally sheet. This evaluation of reasons for non-enrollment and 
chart-based outcomes of non-enrollees is key to planning for dissemination of this technique 
within diverse VA sites and populations. 
  
     Criteria for exclusion will include:  
 
Active prescriptions for > 1 antihypertensive agent (excluding chronic agents prescribed 
primarily for other purposes, such as alpha blockers for prostate disease or PTSD);  
 
Known allergies to 2 or more antihypertensive agents;  
 
Specific reasons for a blood pressure target different from in-clinic target of 130/80, or a 
corresponding home management goal of 120/80 
 
Currently not primarily in charge of his/her own medication administration (e.g. those 
living in institutions or with dementia or other limitations making self-medication care not 
possible);  
 
Life expectancy of < 12 months;  
 
Blood pressure at screening visit > 180 mm Hg systolic or > 110 diastolic, or < 130 
systolic; screening cognitive function (Montreal Assessment of Cognitive Function, 
MoCA)50 score less than 25;  
 
eGFR < 25 ml/min /1.73m2 or end-stage renal disease (ESRD);  
 
Inability to use a standard home blood pressure cuff; 
 
Known secondary cause of hypertension that causes concern regarding safety of the 
protocol, in the opinion of the site investigator;  
 
Cardiovascular event or hospitalization for unstable angina within last 3 months;  

 
Symptomatic heart failure within the past 6 months or left ventricular ejection fraction < 
35%;  
 
Pregnancy or planned pregnancy, or of child-bearing age not using birth control; 
 
Current participation in another clinical trial;  
 
Major factors judged to be likely to significantly limit comprehension of or adherence to 
interventions including dementia, psychiatric disease, or substance abuse.   
 
Cancer treatment within the last year 
 
Primary care physicians and study staff will be able to exclude participants based on their 
judgment of the patient's capability to undergo the intervention. 
 
Screening Procedures. The screening procedure involves blood pressure measurement at the 
time of a primary care clinic visit followed by review by study staff of other inclusion/exclusion 
criteria obtainable prior to consent.  Participants must then complete a MoCA test (commonly 
used in primary care to screen for cognitive dysfunction) after completing the consent procedure 
for the study. 
 
Table. Measures to be completed during the study 
Category
Measures
Screen Baseline
6 mo. 
12 mo.
Screening 
Cognitive screen (MoCA) 
X 
  
  
  
   
Blood pressure (primary care clinic) 
X 
  
  
  
  
Review for exclusion/inclusion 
X 
  
  
  
Clinical Data
  
  
  
  
  
  
Demographics/comorbidities 
X 
  
  
  
Study clinic BP  
  
X 
X 
X 
  
Ambulatory BP 
           X 
X 
X 
  
Home BP 
  
Per protocol 
  
Medications review 
X 
X 
X 
X 
  
Chemistry panel 
X 
  
-PRN- 
X 
  
Urine albumin/creatinine 
X 
  
X 
  
Unscheduled clinic visits/ER 
visits/admissions 
  
Ongoing review 
  
Serious adverse events 
  
Ongoing review 
Other data 
  
  
To complete 
once during 
 Screen OR 
Baseline Visit 
 
6 mo. 
 
12 mo.
 
Patient-centered Rapid assessment of health literacy -SF
X 
  
  
  
Patient-practitioner orientation scale 
  
X 
  
X 
  
Lifestyle change survey 
 
X 
  
X 
Medication 
related 
Morisky medication adherence scale 
  
X 
  
X 
  
Medication possession ratios (Chart 
Review) 
  
  
X 
X 
HRQOL 
European Quality of Life 5-D 
 
X 
  
  
Social-Cognitive Hypertension self-efficacy scale  
  
X 
  
X 

 
 
 
  
3.Description of the baseline intake visit. After screening, both groups will complete a series 
of intake questionnaires on general health, demographics, and questions related to 
hypertension chronic management including health literacy, health-related locus of control, 
adherence, and quality-of-life questionnaires (Table 2). We have chosen the Rapid Assessment 
of Health Literacy (REALM-SF), Patient-Practitioner Orientation Scale, the adherence metrics in 
the Morisky Medication Adherence Scale, and the European Quality of Life scale.  
 
In addition to these widely known measures, we have adapted two surveys (attached in 
appendix) to quantify patient self-efficacy and satisfaction and lifestyle modification in relation to 
hypertension.  
  
During the screening or baseline study visit, all participants will receive training to appropriately 
check blood pressure at home using study-issued home blood pressure monitors. A baseline 
chemistry panel and assessment of albuminuria will be ordered, if not completed clinically within 
3 months of the study visit.  
 
Both groups will complete an initial study visit with the study team and physician and complete a 
24-hour ABPM session.  The ABPM session can be done prior to training for the intervention 
participants. 
  
4. Random allocation and blinding. Randomization will be 1:1 intervention/control. 
Randomization will be done by a central system, stratified by degree of hypertension at initial 
visit (> 160 systolic or below) and block-randomized by clinical sites using the centralized 
randomization tool through the Health Services Research Center data servers. The study 
participants and personnel will be unblinded. The research assistant in charge of checking blood 
pressures at the initial, 6-month, and 12-month visits may be aware of treatment allocation but 
will use standard procedures and an automated Omron cuff, using the SPRINT study blood 
pressure measurement protocol (5 minutes of quiet rest followed by 3 automated blood 
pressures at one-minute intervals, averaging last 2 to determine in-clinic BP), to ascertain blood 
pressures to avoid digit preference and bias.  
  
5. Follow-up study visits:  Participants in both randomization arms will then return for 6-month 
and 12-month study visits at which times blood pressure will be checked by a research 
assistant, and participants will complete questionnaires similar to those obtained at baseline, 
blood and urine studies for kidney function and albuminuria (as part of routine clinical care) at 
12-month visit, and repeat ABPM at both 6 and 12-month visits. 
  
6. Usual care and intervention protocols. Both groups will be issued a home blood pressure 
cuff with data recording capabilities identical to that in the active arm of the study, (Microlife BP, 
Microlife USA Inc), will meet the study physician and have questions answered, and will be 
instructed to record and share results with their primary care physician at routine clinic 
visits.  The patient’s and provider’s willingness to titrate to a clinical goal of 130/80 (home goal 
of 120/75) will be confirmed.  
 
Process-
acceptance 
Program Evaluation Survey 
  
X 
X 
Chart follow-up Clinically available blood pressures   
  
  
X+1yr 
  
Clinically available events 
  
  
  
X+1yr 

Usual care:  For those in the usual care group, further hypertension care and laboratory 
monitoring will be assumed by the primary care physician at intervals chosen by that physician 
in terms of frequency of follow-up or testing, and patients in this study arm can be referred for 
any support plan that is part of usual care, including nurse visits, home telehealth, or pharmacist 
visits. Participants will return to the study visit at month 6 and 12 to complete the same study 
measures summarized above including ABPM measures. Blood pressure will be recorded at 
these visits but medication changes will not be part of these visits so as not to affect blood 
pressure treatment in the usual care group.  We will track medication changes in the usual care 
group via chart review. 
  
Intervention:  The intervention group will be issued a home blood pressure cuff with data 
recording capabilities, identical to that in the control group, and instructed in its use. As part of 
the initial study visit with the study physician and study nurse they will learn about and review 
the blood pressure action algorithm (see Figure) and its use. Goal blood pressures in the home 
action algorithm are lower than in-clinic targets; it has been consistently demonstrated that 
home SBP is on average 10 mm Hg lower than in-clinic BP in most patients, so if the primary 
care clinician's stated target for a given patient is 130/80, the home target corresponding to this 
is 120/75.  
  
The patients in the intervention group are provided with extensive training on how to write down 
their blood pressure readings, when to initiate a change, and how to track their medications 
using a Participant Training Standard Operation Procedure (attached in Appendix.) They are 
instructed to call their PCP with side effect issues, as would be done for normal medication 
changes. They are further instructed to call with issues related to self-monitored low or high 
blood pressure, per the color-coded charts provided.  A training reinforcement call will also be 
made by the study coordinator to each of the participants in the intervention group after the 
training visit to ensure that each participant is fully confident in carrying out all aspects of the 
study.  
Patient handouts and assessments: 
1. Training Exercises 
2. Patient Training Notes 
3. Action Sheet 
4. Contact Information Sheet 
5. Weekly Reading Logs 
6. Medication Change Details Forms 
7. Color Coding Chart for patients 
8. Final Training assessment 
  
After the training session for the intervention, each patient will be individually assessed by study 
staff, to satisfy the research team that they are capable of self-managing their blood 
pressure.  For those patients who do not successfully satisfy all areas of the assessment, an 
additional training session will be arranged after discussion with the study physician. 
  
If patients are unable to successfully learn to self-monitor their blood pressure, it will be 
explained to them that they will be unable to participate in the active arm of the study and that 
they will return to their usual routine care. The reason for their withdrawal from active self-
management will be recorded. They will be followed in an intention to treat fashion and will 
complete 6 and 12 month visits. 
  

Intervention safety checking:  The goal of the study is that the at-home group does not get 
routine in-person or telephone assessment prior to initiating a new medication. Indeed, if we did 
such assessments it would fundamentally negate the intervention. One training reinforcement 
phone call will be made to the participant after the baseline training session to answer any final 
questions the participant may have before beginning self-management protocol.  At the 6 month 
visit, we will have an opportunity to review patients' blood pressures in clinic and if they have 
changed their medications according to the protocol.    Participants' self-monitoring logs will be 
reviewed at the 6 month visit and graded according to whether they performed the self-titration 
procotol (a) correctly and (b) safely over the first 6 months.  However, we will not conduct in 
person or telephone reassessment of patients at the time of each patient-initiated medication 
change.  Protocol violations will be reviewed as they are reported and patients unable to 
continue with self-management will be withdrawn and returned to usual care, based on the 
judgement of the site investigator (with continued analysis by intention to treat).  Patients calling 
to review the protocol or with questions about self-management will be reassessed by phone 
and study staff and physician will note whether they are able to continue.   
 
     The study research staff will be responsible for teaching the participant randomized to the 
intervention arm on appropriate use of the home cuff and how to record readings.  Using 
standard techniques of adult learning theory, the team will assess the individual participant's 
understanding and readiness to learn; will gear the education to the participant's skills and 
knowledge; and will approach initial errors in a non-judgmental fashion. The study team and 
physician will assess whether the learning session has adequately prepared the participant to 
self-manage by using 5 pre-set scenarios that lead down each of the potential pathways (e.g. 
blood pressures too low, too high, appropriate, not enough data to make a change, see training 
appendix) and asking the patient to describe their actions based on those scenarios.  If there 
are concerns about the patient's readiness after a single session, an additional session will be 
scheduled to facilitate maximal comfort with the algorithm (maximum 2 sessions). The number 
of training sessions needed per participant will be noted in the study database. The participant 
will be provided with paper log books to track their self-monitoring and medication changes, as 
well as any symptoms or notes they wish to make.  The study team and physician will be 
available by phone for questions throughout the study period; these calls will be noted in the 
study database.  If a participant in the intervention group does not feel comfortable with the 
algorithm after 2 training sessions, he or she will be returned to usual care, but as the 
participant has been randomized, his or her data will be handled as though self-managing, to 
follow the intention-to-treat protocol.   
 
 
The default stepped medication self-management algorithm (Figure, similar to protocols 
used successfully at the Kaiser healthcare systems) will be reviewed and, if necessary, 
customized by the study physician, to include information about when laboratory tests should be 
done.  Unless there are compelling reasons to continue current medication, participants already 
taking one medication will be switched to the first step medication in the study protocol. If 
participants are not willing to change to the study medication, or have specific indications for 
their current medication (e.g. beta-blocker for atrial fibrillation, ACE inhibitor for diabetes) a 
personalized self-management plan including their current medication will be developed by the 
study physician.  Concerns such as medication allergies, specific indications or 
contraindications, will be discussed on an individual basis based on the initial study visit, the 
self-management plan will be modified as needed, and the final self-management plan will be 
shared with the primary care physician via co-signature-requiring notes in CPRS.  

 
All study prescriptions will be entered by the study physician in ‘suspended’ status at the 
initiation of the study.  The pharmacy system allows medications to be ordered in this status and 
then activated at an appropriate interval, as for for medications intended for a forthcoming 
procedure.  Prescriptions in this mode cannot be activated without the involvement of a 
physician or designated pharmacist.  The patient will be able to activate the steps in the protocol 
by calling the SMART study phone line, the study team will alert the study physician to activate 
the next medication.  The study physician, team pharmacist, or coordinator, in turn, will alert the 
primary care physician to changes via mandatory co-signature and approval on notes in the 
medical record.  This will alert the physician of an impending medication change.   The primary 
care physician will still be the first point of contact for any in-person visits related to 
hypertension; any interval calls to the study team regarding blood pressure symptoms will also 
be routed to the primary care physician.   
The primary care team will be able to stop, start, or alter the doses of medications based 
on new clinical information.  All study-related prescription fills and use of antihypertensive 
medications outside the scope of the study will be tracked.  Some safety issues will be 
monitored in this fashion as well:  If a patient (for example) attempts to activate 2 steps in the 
course of a week (which would violate the monitoring protocol, which specifies a longer interval 
of home monitoring prior to a new medication) that will be considered a potential safety violation 
related to the self-management protocol.  We note that we cannot capture via pharmacy records 
all instances of medication mismanagement or non-compliance by patients either in the self-
management or the usual care arm. 
  
Follow-up laboratory testing for electrolyte abnormalities (basic chemistry panel) will be 
triggered by any request by a patient for Step 3 or Step 4 medications.  The initial instruction 
manual for self-management will clearly indicate that laboratory tests must be done after adding 
a medication with electrolyte effects.  Participants will be reminded of the need for laboratory 
testing by specific labeling on the new medication bottle.  Those who do not report for the 
required laboratory test within a two week window will receive a phone call from study staff 
reminding them to do so.   These laboratory studies will be routed primarily to the study team, 
with additional mandatory notification to the primary care team; any action on abnormal labs 
will be primarily managed by primary care, with oversight by study physicians to ensure 
safety. Between-visit contact with the study will be limited to patient-triggered calls to issue 
blood pressure medication according to the algorithm. All other care will be handled by the 
primary care team. Patients who require all 4 steps of the algorithm and are not at blood 

pressure target will be considered to have exhausted the self-management algorithm and will 
then be treated at the discretion of their primary care physician. Follow up will continue by 
protocol to allow analysis of data by intent-to-treat.  
  
     After completion of the 12-month study, all patients will be followed in a cohort phase of the 
study which will involve chart review for further blood pressure measurements done as part of 
clinical care and for safety outcomes and events over the following 12 months, and then for 
long-term outcomes (e.g. blood pressure control, CVD events, mortality) over another 8 years. 
We will complete this cohort phase, which is a low-cost follow-up protocol, because of concerns 
about transience of study effect in prior clinical trials; this will allow us to evaluate whether any 
blood pressure differences we detect are long-lasting or transient, and allows us to conduct 
long-term outcomes based analyses. 
  
7. Outcome measures. 
Primary blood pressure outcome: in-clinic blood pressure change. The primary blood pressure 
outcome measure for the study will be between-group change in in-clinic systolic blood 
pressure, defined as difference between the averaged blood pressure at the baseline visits vs. 
the averaged blood pressure at the scheduled final study clinic visit. This outcome measure is 
the standard in BP treatment studies, optimizes power, and allows comparison between our 
results and those of other studies. Measurements will be made by an Omron automated blood 
pressure cuff 3 times 1 minute apart after 5 minutes of rest; the average of the 2nd and 3rd BP 
will be used to define primary outcome BP.  
Secondary blood pressure outcomes:  Secondary blood pressure outcome measures will 
include change in ABPM over the course of the study and percentage at goal blood pressure 
based on the in-clinic readings. 
  
     The ABPM gives multiple different 24-hour parameters to be examined. In our work we will 
focus on 24-hour average systolic and 24-hour average diastolic blood pressures, rather than 
examining diurnal patterns. The reason for this choice is that these 2 metrics essentially give 
more precise characterizations of two variables (systolic and diastolic blood pressure in clinic) at 
the 3 timepoints at which they are obtained than clinic blood pressures do. They also allow 
characterization of participants as having ‘white coat’ hypertension (higher in-clinic than ABPM) 
vs. ‘masked’ hypertension (higher ABPM average than in-clinic) vs ‘true’ normo- or hyper-
tension.  
 
8. Safety metrics. We will assess SAEs both by active chart surveillance for ER or 
unscheduled clinic visits for enrolled veterans as well as by interview at the study visits. The 
CPRS system allows automated notifications to study physicians and staff for all patients 
enrolled in the study, so that admissions and ER visits can be reviewed on an ongoing basis; we 
will compile these quarterly. Every time a new medication is requested, a chart review by study 
staff will be triggered to confirm that medications are not being requested too frequently 
(protocol violation) in the intervention arm.  Participants with significant safety violations in the 
intervention arm, identified either through interval contact or through log reviews at the 6 month 
visit, will be considered to have failed self-management and will be returned to usual 
care.  Participant-reported side effects and adverse events will be actively collected at the 6- 
and 12-month visits in both groups. 
  
     Potentially study-related SAEs and all hospitalizations and major events will be reviewed 
locally by the study physicians.  An un-blinded DSMB consisting of 3 experienced nephrologist-
epidemiologists and a general internist, all working in the VA system and assisted by the study 
statistician, will review SAEs and in clinic BP data in both groups at the point where 100 

participants reach the six-month time point, and every time an additional 100 participants reach 
six months. Any major interval SAEs or concerns will be communicated to the lead member of 
the DSMB who will have the option to ask for a full review. 
  
9. Patient oriented metrics.  
The Patient-Practitioner Orientation Scale has been used in prior hypertension studies at VA 
and assesses patients’ preferred role orientation (patient- vs. provider-centered) in their clinical 
encounters.   
Acceptability:  Acceptability of the intervention will be measured using research study retention 
rates, patient satisfaction questionnaires including both quantitative and qualitative ratings, and 
adherence measures described below. We will assess participant satisfaction using 10 
questions developed by the investigators. Similar questions have been used by Dr. Groessl in 
other studies. (See Appendix 1).  Clinicians with at least 2 intervention participants in the study 
will be surveyed with two simple Likert-scale questions regarding their opinion of the 
intervention and whether they would want future patients to use a similar plan. 
Adherence:  Adherence to the intervention protocol will be measured using data on patterns of 
use of the home blood pressure cuff in comparison with the recommended schedule of 
monitoring, and self-reported and pharmacy-confirmed medication requests in response to 
blood pressure results. We will issue medications for all participants enrolled in this study as 30-
day refills, to best estimate medication possession ratios over the 12 month study. The Morisky 
medication adherence scale will be used to assess participants' medication adherence behavior 
at each study visit. 
Self-efficacy:  Self-efficacy for hypertension self-care reflects levels of confidence in the ability to 
perform basic self-care activities crucial to the intervention as well as confidence that these 
activities can be performed and be beneficial as a whole. The wording of the items has been 
adapted to be specific to hypertension self-care (see Appendix). The measure consists of 6 
items, rated on a 10-point scale.  
Health-related quality of life (HRQOL): We will administer the EQ5D questionnaires to assess 
HRQOL at baseline, to assess the impact of baseline health status in this population. 
  
 
 
Chapter 3. Recruitment and Informed Consent 
 
3.1 Best Practices for Recruitment 
The different sites may require different approaches to recruitment.  In our prior clinical trials 
recruiting from VA populations, we have had success via HIPAA waivers and chart reviews 
combined with letters/phone calls to potential participants; we have also been successful in 
recruiting in-person in the clinic setting, reminding clinicians of inclusion/exclusion criteria, using 
notecard-size handouts with study phone contact, etc. 
 
Organizational approaches 
On a weekly basis, each actively recruiting site should track: 
* methods used to identify new participants 
* number identified 
* number of initial contacts 
* number of screening visits scheduled/planned 
 
Oversight 
The clinic PI and coordinators will meet regularly during recruitment to review the past week’s 
and month’s (and recruitment period to date) recruitment productivity 

(e.g., telephone screenings conducted, clinic screenings conducted, number of potential eligible, 
number randomized), the next week’s schedule for screening and randomization visits, and the 
next month’s schedule of recruitment activities (days on which practices or pharmacies will be 
visited, mailings will be disseminated, etc.)  
 
 
3.2 Participant Screening within the Clinical Practice 
Both sites should be recruiting from primary care practices (not hypertension specialty clinics, 
renal or cardiology clinics).   
 
1. Direct contact 
  Approach patients or doctors in the wards and clinics. Display posters and 
pamphlets in the clinics and wards. 
2. Clinic chart reviews 
  Performing a thorough clinic chart review can help to identify potential 
participants. Once potential participants are identified, a letter can be sent 
describing the study to the participant. 
  If the participant agrees to come in for a screening visit, send a letter describing 
what the visit will entail, as well as what they can expect to happen once 
randomized into the study. 
 
3.3 Informed consent. 
Obtaining Consent from Participants 
 
Consent must be obtained at a time and place when there is opportunity for: 
Giving a participant adequate information about the study; 
Providing adequate opportunity for the participant to consider all options; 
Responding to the participant's questions; 
Ensuring the participant has comprehended the information; 
Obtaining the participant's voluntary agreement to enter the study; 
Continuing to provide information as the participant or situation requires. 
 
 
 
Who can obtain consent from potential participants? 
 
The site PI and his or her designees can obtain consent.  Local site procedures such as 
providing the participant a copy of the consent form and local research informational brochures 
should be done at this point in time. 
 
 
 
Chapter 4. In Clinic Measurements and Administering Questionnaires 
 
4.1 Inclusion and Exclusion Criteria 
 
Criteria for inclusion: 
Over 18 years of age 
Clinical diagnosis of hypertension 
Currently above clinical goal blood pressure (>130 or >80 in clinic)  

 
Criteria for exclusion: 
active prescriptions for > 1 antihypertensive agent;  
known allergies to 2 or more antihypertensive agents;  
currently not primarily in charge of his/her own medication administration (e.g. those living in 
institutions or with dementia or other limitations making self-medication care not possible at the 
discretion of site investigator);  
life expectancy of less than 12 months;  
blood pressure at screening visit > 180 mm Hg systolic or > 110 diastolic 
Specific reasons for a blood pressure target different from in-clinic target of 130/80, or a 
corresponding home management goal of 120/75 
Screening cognitive function (Montreal Assessment of Cognitive Function, MoCA)50 score less 
than 25;  
eGFR < 25 ml/min /1.73m2 or end-stage renal disease (ESRD);  
inability to use a standard home blood pressure cuff; 
 known secondary cause of hypertension that causes concern regarding safety of the protocol, 
in the opinion of the site investigator;  
cardiovascular event or hospitalization for unstable angina within last 3 months;  
symptomatic heart failure within the past 6 months or left ventricular ejection fraction < 35%;  
pregnancy or planned pregnancy, or of child-bearing age not using birth control; 
current participation in another clinical trial;  
or major factors judged to be likely to significantly limit comprehension of or adherence to 
interventions including dementia, psychiatric disease, or substance abuse.   
Cancer treatment within the last year.  
 
 
4.2 Visit Procedures 
 
Screening Visit procedure  
 
1. Verify participant's interest in study. 
2. Obtain in person study consent and HIPAA authorization for main trial prior to 
randomization (randomization can also occur at time of screening visit if time allows) 
3. Continue collection of screening information, including such items as contact 
information, additional eligibility information including BP measurement, concomitant 
medications, medical history, and MoCA. If time allows, questionnaires can be 
completed once at Screening or Baseline visit.  
Baseline visit (Randomization Visit) 
 
1. Reconfirmation that all inclusion/exclusion criteria were addressed at screening 
2. Verification of participant consent and HIPAA authorization. 
3. Verification of participant contact information 
4. Completion of the study randomization procedure and baseline data collection 
5. Issuance of home BP cuff (to all participants) and initial training session (for active self-
management). Issuance of home BP cuff can also be done at Screening visit, if time 
allows.  
 
 
4.3 Baseline/Randomization Visit Procedures 
 

Measures as described in the table below are completed at each visit: 
Table. Measures to be completed during the study 
Category
Measures
Screen Baseline
6 mo. 
12 mo.
Screening 
Cognitive screen (MoCA) 
X 
  
  
  
   
Blood pressure (primary care clinic) 
X 
  
  
  
  
Review for exclusion/inclusion 
X 
  
  
  
Clinical Data
  
  
  
  
  
  
Demographics/comorbidities 
X 
  
  
  
Study clinic BP  
  
X 
X 
X 
  
Ambulatory BP 
           X 
X 
X 
  
Home BP 
  
Per protocol 
  
Medications review 
X 
X 
X 
X 
  
Chemistry panel 
X 
  
-PRN- 
X 
  
Urine albumin/creatinine 
X 
  
X 
  
Unscheduled clinic visits/ER 
visits/admissions 
  
Ongoing review 
  
Serious adverse events 
  
Ongoing review 
Other data 
  
  
To complete 
once during 
 Screen OR 
Baseline Visit 
 
6 mo. 
 
12 mo.
 
Patient-centered Rapid assessment of health literacy -SF
X 
  
  
  
Patient-practitioner orientation scale 
  
X 
  
X 
  
Lifestyle change survey 
 
X 
  
X 
Medication 
related 
Morisky medication adherence scale 
  
X 
  
X 
  
Medication possession ratios (Chart 
Review) 
  
  
X 
X 
HRQOL 
European Quality of Life 5-D 
 
X 
  
  
Social-Cognitive Hypertension self-efficacy scale  
  
X 
  
X 
Process-
acceptance 
Program Evaluation Survey 
  
X 
X 
Chart follow-up Clinically available blood pressures   
  
  
X+1yr 
  
Clinically available events 
  
  
  
X+1yr 
 
 
 
At the baseline visit, entry of demographic data, contact information, review for common 
comorbidities and chart review for history of past medical history can be completed prior to the 
visit and confirmed with the participant. 
 
Participants should be instructed to bring all medications, prescription and nonprescription, to 
the baseline visit.  It is especially important that they bring prescriptions or supplements not 
provided by VA so that study physicians are aware of other medications and potential 
interactions. 

 
Participants should have a chemistry panel and urine testing ordered clinically, if not completed 
clinically within 3 months of the study visit, with agreement of the primary care physician. 
 
After consent, at either screening or baseline/randomization visit, the participant will also initiate 
24 hour blood pressure monitoring; they should be informed in advance of this and plan to wear 
a button-down shirt to facilitate placement of the monitor.  They may need to adjust evening 
plans to allow them to wear the monitor continuously for the next 24hours. 
 
Participants should also be advised that the training session for self-monitoring is potentially 
lengthy.  If they cannot stay for ~ 3 hours, they should be scheduled for a second appointment 
at the same time as the baseline visit appointment, in anticipation of being randomized to the 
active treatment arm. 
 
Training 
 
For those randomized to the self-management arm, the first step is to undergo training in self-
monitoring.  Refer to Patient Training SOP (attached in appendix). Once the participant can 
reliably use the self-monitoring device, training on recording and responding to blood pressures 
can begin.  If a single session is not satisfactory, an additional session should be scheduled 
before the participant makes any blood pressure adjustments on his or her own. Patients are 
also welcome to bring their spouse/partner along to the training sessions.  
 
Learning Objectives 
 
At the end of the training the patients will: 
 
 
Understand the justifications and requirements of the study 
 
Know who to contact and how, in case of questions, emergencies, queries and problems  
 
Demonstrate the correct assembly and use of the blood pressure monitor 
 
Know how often and when to measure their blood pressure 
 
Demonstrate how to record the readings correctly 
 
Understand the color coding system 
 
Correctly color code each day’s readings 
 
Correctly color code each overall week of readings 
 
Correctly choose the action required to be taken at the end of each week 
 
Understand when and how to adjust their own medications 
 
Feel confident to be able to carry out the requirements of the study 
 
The patients will then be asked to practice with the study staff.  
 
Assessment- Each participant in the self-management arm will be individually assessed to 
satisfy to the research team that they are capable of self-managing their blood pressure.  
 
The patient will be assessed on their ability to: 
 
Demonstrate accurate use of the blood pressure monitor and recording of results at 
home 
 
Demonstrate accurate use of the blood pressure monitor and recording of results in front 
of the assessor 
 
Demonstrate correct application of the color chart to readings 

 
Demonstrate good knowledge and application of the theory related to the required 
actions and medication changes  
 
The theoretical requirements will be assessed using paper-based exercises, as well as verbal 
questions and answers based around case scenarios. A training form that includes details of the 
assessment scores will be completed by the trainer to ensure the patient has successfully 
satisfied all areas of the assessment. For those patients who do not successfully satisfy all 
areas of the assessment, an additional training session will be arranged after discussion with 
the study physician.  
 
If participants are unable to self-monitor their blood pressure after 2 trainings, it will be explained 
to them that they will be unable to participate in self-management; they will continue in the 
study, in an intention to treat fashion, but will not self-manage. The reason for this will be 
recorded on the training form.  
 
Making Medication Changes 
 
Medication changes will only apply to blood pressure medication and will involve either: 
 
Increasing the dose of current medication, or  
 
Starting to take a new medication, usually in addition to the ones the patient already 
takes  
 
During the final step in training, the participant will meet with the study physician to learn when 
and how to adjust their medication by learning the self-titration algorithm. (See attached Patient 
Training SOP) 
 
 
Agents available for the self-titration algorithm 
 
The preferred titration scheme is: 
Amlodipine 5 mg 
Amlodipine 10 mg 
Amlodipine 10 mg plus HCTZ 12.5 mg/Lisinopril 10 mg (combination pill) 
Amlodipine 10 mg plus HCTZ 25 mg/Lisinopril 20 mg (combination pill) 
 
 
This 4 step plan was chosen for several reasons: 
1) It starts with an agent that does not require monitoring of chemistry panels 
2) It includes the 3 preferred classes of antihypertensive agents after step 2 
3) It includes only 2 different physical pills 
 
 
Although there is a preferred standard titration scheme, there will be participants for whom 
switching from current single medication to amlodipine is not feasible (or who are already taking 
larger doses of amlodipine); for whom prior history precludes use of one of these three agents 
(note that an ‘allergy’ is not the only reason to preclude use of a medication, e.g. chart must be 
reviewed for hyponatremia in setting of HCTZ in past); for whom there are reasonable 
expectations of drug interactions, etc. 
 
For these participants, the study physicians at each site will choose a reasonable titration 
algorithm, also including two different drugs, and 4 titration steps as above. 

 
Preferred medications are any VA formulary medication, to include in order of general 
preference: 
 
• Sustained-release calcium channel blockers (CCBs) 
• Thiazide-type diuretics 
• Loop diuretics 
• Angiotensin converting enzyme (ACE)-inhibitors 
• Angiotension receptor blockers (ARBs) 
• Beta-blockers 
• Direct vasodilators 
• Potassium-sparing diuretics 
• Alpha1-receptor blockers 
• Adrenergic inhibitors 
 
To facilitate titration, combination pills are encouraged. 
 
 
 
Chapter 4.c Post Randomization Visit Procedures 6 mos and 12 mos 
 
These visits should be scheduled at the time of the baseline visits.  Participants should receive 
a reminder phone call 1-2 weeks prior to the visit to ensure that the date remains acceptable.  
Participants should bring all written logs of home blood pressure (both groups) for collection and 
copying (participants may return with their logs to home if they so desire). 
 
At the 6 and 12 month visits, procedures and surveys should be completed per the table above 
and blood pressure recorded in the study visit.  24-hour blood pressure monitors will again be 
used so participants should be reminded ahead of time to plan for this, and reminded at the visit 
to mail the device back promptly. 
 
 
At the 12 month visits, participants should be reminded to return the equipment issued for the 
study.  This includes blood pressure cuffs as well as logs and notebooks.  They should be seen 
by the study physician at this visit and reminded that their blood pressure care is fully managed 
by their primary care physician from this point forward. 
 
 
Chapter 5. Retention, Adherence 
 
Adherence and retention for a clinical trial are essential.  In this trial, we foresee several 
potential barriers and solutions: 
1) Disappointment with being in the ‘usual care’ arm leading to lack of follow-up for the 6 
and 12 month visits 
 
Approach: make sure randomization is not set up as a ‘win/lose’ situation 
Remind all participants that the financial incentives are for completion of 6 and 12 month 
visits 
 
2) Frustration/fear/anxiety about self-monitoring, leading to avoidance of the intervention 
protocol, repeated phone calls to study staff or PCP, etc 

 
Approach: up-front support and extra training visits as needed; but need to avoid ‘taking 
over’ from primary care and over-supporting during period of test of self-monitoring.  If 
participant calls frequently remind them about 6 and 12 month visits and alert their PCP, 
or alert study physician to contact PCP 
 
3) Primary care ‘burnout’ from study burdens – confusion about response to participants in 
a blood pressure study 
 
Approach: repeated and patient education, for both physicians and PACT team 
 
 
 
Chapter 6. Procedures for Inactive/Lost/Refused Participants and Missed Visits 
 
 During the course of the study, we may find that certain participants become disinterested or 
frustrated.  Participants in the active arm of the study may fail that arm (because of increasing 
meds above study titration plan, failure to follow protocol, etc) but should stay in the study for 
follow up purposes in intention to treat fashion. 
 
Potential status options for a participant are: 
 
 
Active status – a participant is considered to be active if following the assigned 
randomized treatment and in contact with the study. 
 
 
Inactive status – a participant is considered to be inactive if he or she is no longer self-
monitoring/self-managing for any reason (but is still in contact with study). 
 
 
Lost status – a participant is considered to be lost-to-follow-up if he/she has 
missed more than a follow-up visit, cannot be contacted by any ordinary 
means (e.g., home phone, cell phone, mail, email, fax, etc.), clinic staff do not know the 
participant’s whereabouts, and alternative contacts either do not know where the 
participant is or cannot be contacted themselves. 
 
 
Refused status – a participant is considered to be refused if he/she has 
withdrawn consent to participate in the study and refuses further contact for any reason. 
 
 
To the greatest extent possible, we will attempt to complete follow-up visits for participants who 
are either active or inactive and to contact lost participants. 
 
 
 
 
 
Chapter 7. Ascertainment of Study Outcomes 
 
Blood pressure will be measured in the primary care clinic at the start of the study.  We will use 
the clinically measured blood pressure as the blood pressure used for eligibility criteria, since 
primary care physicians may act on this blood pressure prior to the patient enrolling in the study.  

Study clinic blood pressure will also be used to verify primary care clinic measurements and 
ensure that blood pressure is at least 130 systolic at baseline.  
 
At the baseline, six-month, and twelve-month visits, the blood pressure will be measured 
by a research protocol (3 measurements with interval pauses as above).  The blood pressure 
from the research study visit on the day of randomization will serve as the baseline study visit 
for this trial.  The outcome blood pressure will be the similarly measured (research protocol) 
blood pressure at the 12 month study visit. 
 ABPM set-up will be done according to our previously used Spacelabs protocols from 
SPRINT study. 
 
All study instruments will be administered by research staff in-person with patients at the 
baseline, 6 and 12 month visits. 
 
Chapter 8. Safety Monitoring and Reporting 
 
The main clinical adverse events that will be monitored during this trial are those related to over- 
or under-treatment of blood pressure. These were not different from usual care during the two 
studies of similar interventions in the UK, and only 3% of those in the intervention group 
deviated from self-titration protocols in those studies. Nevertheless, we plan to actively monitor 
for these issues by scheduled chart review for clinical or ER visits, hospitalizations, and 
potentially study-related serious adverse events (e.g. syncope, hypertensive urgency, stroke, 
MI, death). Other adverse events potentially related to the study will also be collected (e.g. 
medication side effects, abnormal laboratory findings including sodium < 130 or potassium <3 
(for those on thiazide); potassium >6 for those on ACE; creatinine 50% higher than baseline). 
 
We have assembled a DSMB for this study given the potential risks of self-management of 
blood pressure. This will consist of experienced nephrologist-epidemiologists and a general 
internist, all working in the VA system. Assisted by the study statistician they will review AEs 
and BP data in both groups at the point where each group of 100 participants have reached the 
six-month time point.  
Real-time Safety Monitoring: The DSMB lead will be informed by formal written event reports 
and directly by teleconference within 24 hours of any serious adverse event (SAE) deemed by 
the investigators to be potentially study related. The chair will make preliminary 
recommendations and/or call a full ad hoc meeting of the DSMB. All other related AEs and 
unrelated SAEs will be reported to the chair at a frequency determined by him/her, and 
reviewed by the full DSMB at the mid-point meetings or earlier, at the discretion of the DSMB 
chair. Serious adverse events will be reported to VA IRB by the investigators as required. 
 
Data Safety Monitoring Board: The DSMB will include 3 physicians from VA institutions with 
statistical expertise and clinical knowledge of hypertension as well as trial experience. 
All lab tests in this protocol (renal function panel, urinalysis, urine protein, urine creatinine) are 
used in routine care and will be reported in CPRS to both the study team and primary care 
physician. 

 
 
Chapter 9. Data Management, Quality Control, and Statistical Considerations 
DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS. 
1. Data Management Overview. Data will be collected on paper forms and questionnaires. All 
forms will be coded to facilitate entry into quantitative computer database. The project 
coordinator and research assistant will monitor the quality of the data on a weekly basis so that 
prompt resolution of errors and omissions can be achieved. Coding and data entry will be done 
as data is collected.   All data will be entered in the secure online data base, using study ID 
numbers.  Links to identifiers will be saved internally at each site.  Paper data forms will be 
stored in locked cabinets in the study office space. 
  
2. Data analytic plan. Preliminary analyses will begin with an examination of the distribution of 
variables to assess their characteristics (means, standard deviations, medians, outliers), to 
provide descriptive statistics of the study population, and to allow assessment of 
randomization. Continuous measures will be tested for normality and non-normally distributed 
variables will be transformed to meet the normal distribution assumption for linear models. 
Randomization will be tested by performing a series of Wilcoxon rank sum test and Fisher’s 
exact test to compare the two study groups on demographic and initial clinical variables. 
Randomization will be stratified by BP level at entry (at 160 systolic), and block (of 10) 
randomization will be done for each clinical site.  We will pursue standard intention-to-treat 
analysis of the randomized group as a primary analysis, with the ANCOVA analyses as 
secondary approaches should randomization have failed on critical metrics.  Blinded 
randomization should assure that the distribution of risk factors will not confound the 
associations of interest, however inclusion as covariates may reduce error variance and may 
therefore improve statistical power.  In case of missing data, appropriate data analytic 
techniques will be used, which may include deletion, imputation, inclusion of an indicator of 
missing values, or pattern-mixture modeling. All analyses for the primary aims will use an 
intention-to-treat approach. Sensitivity analyses will consider the importance of missing data or 
loss-to-follow-up (last observation carried forward, vs. imputation of data from other sources 
such as clinic visits). Outcomes will be analyzed using open source statistical software R.65 
      For ambulatory blood pressure data, each individual 24-hour BP reading will be assessed 
for adequacy (defined as at least 14 daytime and 7 nighttime readings) and transformed into 
summary variables (e.g. 24-hour mean blood pressures). Home blood pressure data will be 
recorded in 2 ways: (1) the internal memory of the home BP device will be downloaded directly 
at the time of 6- and 12-month visits and (2) in the event of a memory failure, the participants’ 
log book records will be reviewed and values entered. Questionnaire data will be entered and 
encoded along appropriate scales and scores on these questionnaires will be examined in 
univariate analyses to determine response distributions and coding. 
  
Hypothesis 1a (primary hypothesis): Improvement in systolic blood pressure measured 
at clinic from baseline to 12 month will be greater in the intervention vs. the usual care 
group. The primary outcome is the absolute change of systolic blood pressure (SBP) measured 
in mmHg from the study clinic randomization visit to the  month 12 visit. The primary statistical 
test for comparison for continuous outcomes is a simple t-test across the two randomized 
groups.  As a secondary analysis, in case of issues with randomization for differences in 
baseline BP, an Analysis of Covariance (ANCOVA) model with intervention group as a main 
effect and baseline SBP as a covariate will be fitted to study the group difference in change of 
SBP from baseline to week 12. Baseline sociodemographic and other clinically important 
characteristics at baseline will be assessed for imbalance between the two study groups and 
their association with the outcome using a univariate analysis (Wilcoxon rank-sum test, Kruskal-

Wallis test, Spearman correlation coefficient or Fisher’s exact test). These variables will be 
included as covariates in the ANCOVA model if found to be moderately associated (p < 0.15) 
with the outcome or unbalanced (p < 0.10) between groups. Purposeful model selection 
method66 will be used to select the main effects in the final model, all covariates that are 
significant at p< 0.10 will be kept in the final model. To assess the difference in the effect of 
patient characteristics on the outcome between intervention and control group, we will study the 
interaction between treatment and patient characteristics in the final model, as appropriate. Pre-
specified interactions will include analyses of effects in, older vs. younger participants (< 65), , 
African-American vs. other races, and initial BP level (> 160 vs.  lower), and educational level 
(less than high school degree or more). We recognize the possibility of chance findings due to 
multiple comparisons by these strata, P-values for interaction will be evaluated conservatively, 
and data will be conservatively interpreted.  If numbers in any of these subgroups are too small 
to allow a reasonable investigation, the subgroup analysis will be dropped.  Forest plots will be 
constructed to assess whether subgroup effects are similar, in exploratory analyses. 
  
Hypothesis 1b: Improvement in systolic blood pressure measured by ABPM from 
baseline to 12 month will be greater in the intervention vs. the usual care group. For SBP 
measure by ABPM, we will take an average SBP over the 24 hour measurements as the 
outcome measure. The change in average SBP between baseline and month 12 will be 
compared between two intervention groups using similar analysis methods as we described for 
Hypothesis 1a.  
  
Hypothesis 1c: The proportion of blood pressure reaching the 130/80 goal at month 12 in 
intervention group will be greater in the intervention vs. the usual care group. The 
outcome is a binary variable which measures whether the blood pressure was at goal. The 
Fisher’s exact test will be used to compare the proportion of subjects with blood pressure 
reaching the individualized goal at month 12 between the intervention and the usual care arm. 
Multivariable logistic regression will be used to study the difference in outcome between two 
study groups with adjustment for baseline variables if randomization is unbalanced. Univariate 
analyses (Fisher’s exact test, Wilcoxon rank sum test) will be used to assess the association 
between the baseline characteristics and the outcome first, then those variables that are 
moderately associated (p < 0.15) with the outcome or unbalanced (p < 0.10) between study 
groups will be included as potential covariates in multivariable model. 
  
Hypothesis 2. Medication related SAEs and patient-reported outcomes will be similar in 
the two arms and there will be similar rates of ER visits and hospitalizations in the two 
arms. Descriptive statistics (mean, SD, median and range) will be used to summarize the 
number of medication related SAEs, patient-reported outcomes, number of unscheduled clinic 
visits, number of ER visits and hospitalizations over the 12-month study period. The difference 
in proportion of subjects with medication related SAEs, proportion of subjects unscheduled clinic 
visits, rates of patient-reported symptoms, proportion of subjects with ER visits and proportion of 
subjects with hospitalizations will be compared between two study groups using Fisher’s exact 
test.  
  
Hypothesis 3: End-of-study levels of acceptability of the self-management protocol will 
be high. Patient self-efficacy will be higher in the self-management arm relative to the 
usual care arm. End-of-study acceptability scores will be reported descriptively as 
percentages.  For self-efficacy scores and other scores measured at multiple time points, the 
change in outcome from baseline to month 12 will be compared between two study groups, and 
we will use similar analysis methods as those used for Hypothesis 1a.  
  

F4. Sample size and power. Power analyses were conducted for detecting the difference in 
mean change of SBP over 12 months between the subjects with intervention and subjects in 
control group (Hypothesis 1a) assuming a two-sided Type I error of 0.05 and an attrition rate of 
20% at month 12, with sample size estimation based on a 2 sample t-test. Based on prior 
literature in hypertension, we assumed a standard deviation of individual change in BP over 1 
year of 16 mm Hg (conservative estimate based on standard deviation of blood pressure 
measurement in multiple clinical studies,40,41 and similar to that seen in our pilot data in older 
CKD patients43) and considered a difference of 5 mm Hg to be a clinically significant difference, 
a smaller difference than was seen in the TASMIN studies (which found differences of 5.4 and 
9.2 mm Hg with similar sample sizes). With a 20% attrition rate, we need to recruit 200 
participants per arm, or 400 total participants (total of 320 participants completing the study) to 
have 80% power to detect a minimum of 5mmHg (Cohen’s effect size of 0.31) for the difference 
in mean change of SBP over 12 months between intervention and control groups.  
Data Safety Monitoring. We will, in addition to proactively collecting adverse events, 
hospitalizations, clinic visits and protocol violations, collect blood pressure data from participants 
at the six-month in-person visit as they self-monitor during the study. At the point where 100, 
200, and 300 participants cross the 6-month point, the DSMB will review the accumulated 
information both from the in-clinic blood pressure averages as well as the log reports from the 
home BP cuffs in both groups. Although TASMIN investigators reported a less than 3% rate of 
protocol violations in the self-management participants, we are interested in tracking this in our 
intervention arm as well at the midpoint of the study.  Inappropriate requests for study 
prescriptions will be tabulated.  DSMB members will be able to examine whether out-of-range 
readings led to appropriate participant behavior. If this rate is considered to be too high by the 
DSMB, they will have the option of halting the study due to safety concerns. They will also have 
the option of halting the study due to SAEs or other concerns.  
  
Chapter 10.  Data Security and database management 
 
The database for this project is being managed by UCSD's Health Services Clinical Research 
Center, with data security as per their prior work with VA contracts.  Forms will be completed on 
paper during visits and then entered into the data base using ID numbers only.  Full identifiers 
will be stored on local secure drives in master log files and paper backup copies of records will 
be stored locally.  Data integrity checks will be performed regularly by HSCRC and the study 
statistician.