A Design for Testing Interventions to Improve Adherence Within a Hypertension Clinical Trial

Design Paper A Design for Testing Interventions to Improve Adherence Within a Hypertension Clinical Trial Brian F. Johnson, MD, Glenys Hamilton, DNSc, RN, Janis Fink, MSN, RN, Gail Lucey, MSN, RN, Nancy Bennet, MD, and Robert Lew, PhD Departments of Medicine, Nursing, and Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts

ABSTRACT: The Potassium Adherence Clinical Trial (PACT) incorporates one randomized clinical trial within another. A randomized trial of interventions to increase adherence to medication is nested within a second randomized clinical trial testing hypotensive effect of supplemental oral potassium. The trial aims principally to compare the effects of three intervention strategies: two sessions of individual patient counseling, two telephone contacts, or standard care. The trial aims secondarily to evaluate the effect of 60 mEq supplemental oral potassium daily on sitting systolic and diastolic blood pressure in hypertensive patients on established drug therapy. Therefore, it organizes the patients given potassium into three study groups for adherence interventions, and the patients assigned to placebo into a further three. We evaluate adherence primarily by means of the Medication Event Monitoring System (MEMS), an electronic system that records the date and time that the container of study medication is opened. Additional measurements, such as assessments of change in levels of urinary potassium, pill counts, appointment records, self-reporting by patients, and estimates by physician of adherence, are used and correlated with MEMS data. At a single center, the trial enrolled 107 participants between the ages of 26 and 80. This paper describes the background to this trial within a trial, details its design, documents the baseline characteristics of participants enrolled, and describes issues experienced during implementation of the trial. Control Clin Trials 2000;21:62–72  Elsevier Science Inc. 2000 KEY WORDS: Adherence (compliance), hypertension, oral potassium, supplementation, interventions

Funded by the National Center for Nursing Research, NIH, grant #NR03317. Address reprint requests to: Brian Johnson, Clinical Research Division, Pfizer, Inc., Eastern Point Road, Groton, CT 06340. Received March 24, 1998; revised January 27, 1999; accepted October 19, 1999. Controlled Clinical Trials 21:62–72 (2000)  Elsevier Science Inc. 2000 655 Avenue of the Americas, New York, NY 10010

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INTRODUCTION Although randomized clinical trials provide the main basis for formulating recommendations for treatment, we know relatively little of the extent to which outpatients vary in adherence to protocols for trial medications. This knowledge is important, however, because it could conceivably distort conclusions from trials. Further, there is a dearth of information about the effectiveness of methods aimed at improving adherence within trials. We designed our trial specifically to address an approach to controlling hypertension, as well as to provide the basis for measuring effects of interventions on adherence to prescribed medication. Rather than complicating an existing trial, we planned a more complex original design to facilitate determining effects of interventions aimed at improving adherence. We made this decision to avoid complex negotiation and delay, because we recognize the difficulties of coordinating the adherencerelated objectives within an existing ongoing trial. Hypertension is a major chronic health problem that calls for sustained adherence to drug regimens in order that the known major risks of stroke and cardiovascular and renal disease be reduced. Recruiting a sufficient number of patients to determine the effects of interventions often requires the collaborative efforts of a group of investigators. If, however, the study can avoid making major changes to individual treatment regimens, a much higher proportion of regular clinic patients can participate. With this rationale, we planned a single-center study of adherence interventions within a clinical trial to evaluate the effect of oral potassium supplementation on established control of blood pressure.

OBJECTIVES The Potassium Adherence Clinical Trial (PACT) aims to systematically assess the effects of two intervention strategies on adherence to prescribed medication within the setting of a clinical trial. A novel design integrates the testing of adherence-related strategies into a specifically designed clinical trial containing features specially relevant to adherence. We compare the effects of two sessions of individual patient counseling with a more modest strategy of telephone contacts, and with standard clinical trial care. An important but secondary aim is to evaluate the effects of 60 mEq daily supplemental oral potassium on measurements of blood pressure in hypertensive patients taking a variety of other drugs.

BACKGROUND Hypertension and Adherence Hypertension affects between 55 and 60 million persons in the United States, accounting for 24 million visits to physicians’ offices annually [1]. Adherence to hypertensive regimens remains erratic, however. In various studies, 50–60% of hypertensive patients have discontinued their treatments within the first few years of care [2–4]. We decided to compare the impact of educational and behavioral patient-centered counseling on adherence with a more modest

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intervention, and with standard clinical trial care. Accumulating evidence indicates that planned behavioral and health education strategies increase adherence to regimens in chronic diseases such as hypertension [5–14]. Studies have shown that counseling patients with beliefs not congruent with adherence can change their behavior. Beliefs that have been found to consistently produce significant relationships with adherence to prescribed regimens have been components of the health belief model, negotiation, elements of the client-provider relationship and amount of support [7, 15]. Although not abundant, intervention studies using these theoretical frameworks have continued to support their efficacy in increasing adherence to prescribed regimens. The major intervention selected for the proposed study is a patientcentered program of educational and behavioral counseling founded on the theoretical base of the health-belief model. Developed in an attempt to understand behavior related to the prevention and detection of disease, this model tested specifically how a person perceived a state of wellness or illness and its relation to behavior. It tested perceived susceptibility to complications from the condition, perceived severity of the condition, perceived benefit of following the regimen, perceived barriers to taking action, and general motivation to health. Choice of Trial Medication A number of placebo-controlled clinical studies have demonstrated that potassium supplements given to otherwise untreated hypertensive patients may cause small but useful reductions in blood pressure [16–20]. The doses of potassium have ranged between 6 and 200 mmol/d, and mean reduction in systolic blood pressure has ranged from 2–14 mm Hg, with the least effect seen in patients taking a sodium-depleted diet. In two studies of hypertensive patients in whom diuretics had induced hypokalemia, improvements of serum levels by oral potassium caused further reduction in blood pressure [21, 22]. Similarly, the antihypertensive effect of a slow-release metoprolol preparation was enhanced by replacement of table salt by a dietary salt substitute with high potassium content [23, 24]. By contrast, in a group of 287 men, administration of 96 mmol of potassium chloride daily for 12 weeks had no additional effect compared to existing diuretic or betablocker treatment [25]. It is important to note that these subjects were all prescribed a sodium-restricted diet. Hence, the lack of an additive effect in this study seems compatible with the reported failure of oral potassium to affect blood pressure substantially in sodium-depleted but otherwise untreated hypertensive patients. STUDY DESIGN General Design Features PACT assigns each subject randomly to receive either oral potassium or a matching placebo administered in double-blind fashion. Within each of these groups, we randomize subjects to take part in one of three programs relating to improved adherence.

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Figure 1 illustrates the general study design, according to which randomization takes place during the third clinic visit at the end of baseline period. We indicate the three possible adherence programs. Each enrolled patient maintains his or her regular antihypertensive drug therapy for the entire duration of the study, so that we can determine any supplemental effect of oral potassium on the control of blood pressure. Each patient attends the Hypertension Clinic on five occasions during the total 20-week period of the study. To be eligible a patient must demonstrate a history of established essential hypertension (initial untreated diastolic blood pressure above 94 mm Hg) for at least 2 years, with a requirement for continuing drug treatment as determined by his or her recorded response to medication. Exclusions are serum creatinine above 2 mg/dL, history of serum potassium above 5 mEq/L, treatment with potassiumsparing diuretics, active peptic ulcer, and other unstable concurrent disease. Baseline Phase The record of each patient who attends a Hypertension or Primary Care Clinic regularly is reviewed by the clinical trial coordinator on the basis of established criteria for selection and exclusion. Each suitable patient receives a letter from his or her primary care physician. At the first visit, after hearing a general description of the trial’s objectives and the interventions that he or she could receive, each patient is individually interviewed by the coordinator and is able to ask any questions. During visit 1 the patient signs the informed consent form. The three visits in the baseline phase occur at 4-week intervals, when the suitability of patients to progress into the intervention phase of the program is established. At each clinic visit, body weight is determined, and blood pressure and heart rate are recorded in the sitting position. Randomization requires that the patient has no change in the dosage of any antihypertensive drug, has not added any additional drug treatment that could affect blood pressure, and neither systolic or diastolic pressure can have changed by more than 5 mm Hg between visits 2 and 3. At visit 1, each patient is provided with a container, along with detailed oral and written instructions concerning how to collect urine over the 24 hours immediately preceding the date of visit 2. At visit 2, blood is collected to determine baseline serum potassium. Results of these evaluations are available at visit 3. Only patients whose diastolic blood pressure readings at visit 3 range between 80 and 105 mm Hg, and whose systolic blood pressure levels range between 120 and 180 mm Hg are eligible for randomization. Treatment Phase At visit 3 each patient is assigned a number in order of accrual to the study, and is randomized to adherence intervention group and the trial medication. Separate randomization lists are used to balance treatments within the strata of diuretic or nondiuretic takers, because oral potassium may have greater effect on blood pressure in patients taking diuretics, which reduce serum potassium concentrations. Patients are given either potassium supplement or a matching placebo with instructions to take two capsules three times daily with meals for a total of six

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Figure 1 General study design, indicating details of study sample formation, randomization, and intervention.

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capsules daily. Capsules are provided in vials with Medication Event Monitoring System (MEMS) lid monitors, which maintain an electronic record of the time of each vial opening. After 4 weeks, patients return for visit 4. They are instructed to return any unused capsules and the vials with the MEMS monitors. At this visit the clinical trial coordinator downloads the MEMS monitor, counts returned medication, and dispenses a 2-month supply of the study medication to the patient. A serum potassium level is determined. At each of the two visits in the study phase, staff record body weight, sitting systolic blood pressure, diastolic blood pressure, and heart rate. At the completion of the study on visit 5, staff obtain a 24-hour urine sample, and a further serum potassium. The coordinator again downloads the MEMS monitor and counts returned capsules for comparison with numbers provided to the patient. On discharge, the patient is advised to continue the established antihypertensive medication and to follow-up with his or her primary care physician. Blood Pressure The clinic staff measure blood pressure using a standard Baum sphygmomanometer, after the patient has sat quietly for at least 5 minutes. The staff applies to the left arm a cuff size in accordance with the American Heart Association’s recommendations and uses the same selected cuff size for the patient during all study visits. The staff records systolic blood pressure as the highest pressure at which sounds are heard for at least three consecutive heart beats, and records diastolic blood pressure at Korotkov phase 5, that is, when all sounds become inaudible. Staff obtain a minimum of three readings routinely, recording the final blood pressure as the lowest level determined at which consecutive readings are consistent within 2 mm Hg. The study blinds the physicians to the randomization of subjects and makes every effort to prevent clinic staff and follow-up procedures from revealing group assignment. The interviews and telephone calls occur in separate locations. All requests by subjects, adverse events, and so on go through the clinical trials coordinator to maintain blinding. In case of emergency, the subject has the telephone number of the study physician. The subjects know that the study is focused on their taking their medications as agreed upon. They are not given any feedback from the questionnaires, the MEMS, pill count or laboratory values unless action or referral is required, e.g., low potassium values, or high score on the depression instrument requiring referral. INTERVENTIONS Medication The intervention medications are oral potassium supplementation and matching placebo. The potassium consists of an immediately disbursing, extended-release oral dosage form of potassium chloride containing 750 mg of microencapsulated potassium chloride equivalent to 10 mmol of potassium in each capsule. The matching placebo appears identical to the oral potassium but contains only filler material without potassium. Staff counsel patients to take the medications with meals to reduce the risk of dyspepsia. Any patient

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who reports clinically unacceptable side effects is asked to reduce the dose from two to one capsule. Continued unacceptable symptoms warrant the patient being dropped from the study. Adherence Intervention At the time it randomizes patients to medication, the trial also randomly assigns them to one of three adherence intervention groups: standard care, telephone group, or patient counseling group. Standard care represents usual care within a clinical trial on which basis additional interventions take place in the other groups. Standard care includes the involvement of consistent clinical personnel for the duration of the study, repetition in written form of medications and investigations, written reminders of appointments, prompt follow-up for missed appointments, compensation for parking, and a small stipend at the end of the study. Patients assigned to the telephone intervention group participate in two telephone calls with the nurse-interventionist, the first within 48 hours of randomization and the second after 7–8 weeks of medication. Each call lasts approximately 5–10 minutes. Using a standard protocol, the interventionist answers any questions, solves any problems arising from the study, and helps the patient develop a specific plan for taking the medication as prescribed. The telephone group adds to standard care additional individual time, attention, and support, review of specifics on prescriptions, and negotiated development of a behavioral plan for taking medication. Patients in the counseling group meet privately with the nurse-interventionist twice, immediately after randomization for 25–30 minutes and at the next study visit 4 weeks later for 10–15 minutes. Using a standard protocol, the interventionist focuses on potentially problematic health beliefs about health identified from a screening questionnaire the patient completed at the first visit, and helps the patient develop a specific plan for taking the medication as prescribed. This group adds to standard care additional individual time, attention, and support in two direct contacts, problem-centered counseling and reinforcement of health beliefs reported as predicting adherence, review of specifics on prescriptions, and negotiated development of a behavioral plan for taking medication. MONITORING ADHERENCE We shall use the following methods to assess the relative adherence to oral potassium capsules (or the matching placebo) of patients within the specific trial groups: 1. Medication event monitoring system (MEMS). When the patient returns the trial medication to the clinic, the data from each MEMS vial lid is read using PC-RDP software (Aprex Corporation, Fremont, California) in conjunction with an IBM 360K personal computer, by means of a connection through a MEMS communicator attached to the computer’s serial port. This permits display and printing of the patient’s dosing record in a calendar plot, which lists the specific date and time when the

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lid was removed from the medication vial. We compare the total number of openings recorded with the ideal number that would be noted if adherence had been 100%. Each patient should open the bottle three times during the day and take two capsules each time. Our simplest index of adherence is the proportion of the days that he or she opened the bottle three or more times. A variant on this measure gives the patient partial credit, allowing 1/3 or 2/3 of a point on a day when the patient opened the bottle exactly one or two times. A more stringent criterion requires that the bottle openings be spaced at least 3 hours apart. Our simple stringent index is the proportion of days on which at least three openings were suitably spaced. The analogous variant index gives partial credit of 2/3 of a point if two openings were suitably spaced, but not three. Counts of capsules. At visits 3 and 4, staff record the number of capsules handed to the patient. At visits 4 and 5, respectively, the clinical trial coordinator counts the number of capsules in the recovered vials. We estimate as a difference the number of capsules presumed taken. We calculate adherence score as this value expressed as a percentage of the number that should have been taken, i.e., six times the number of days since the last clinic visit. Excretion of urinary potassium. Determination of the relative increase in urinary potassium excretion over 24 hours provides a measure of adherence in those patients (50% of the sample) randomized to receive oral potassium. We analyze for mean changes in the excretion of potassium between intervention groups. Additionally, we classify patients receiving oral potassium as showing excellent adherence if their excretion increased from baseline by 50–70 mmol, as showing fair adherence if their increases were between 30–49 mmol or greater than 70 mmol, and showing poor adherence if their increases were less than 29 mmol per 24-hour period. Levels of serum potassium. We determine levels of serum potassium mainly to detect any patient with unexpected elevation to excessive levels during oral potassium treatment. In those patients randomized to oral potassium who continue taking diuretic drugs as part of their antihypertensive regimens, however, we determine changes in serum potassium between visits 2 and 5 to permit comparison between the adherence groups. Interviews with patients. At visit 5, each patient records his or her perceived level of success in adhering to the prescribed regimen (self-report). Estimates by physicians of adherence. After interviewing each patient at visit 5, the study physician completes a report on a standardized form (collateral report).

BASELINE CHARACTERISTICS OF SUBJECTS By completion of randomization, 107 hypertensive subjects were enrolled in the study, ranging in age from 26–80 years (mean 6 SD 5 58.2 6 11.1). There were almost equal numbers of men (55) and women (52). Approximately 75% were married and living with their spouses. Fourteen percent of the subjects were separated or divorced, 6% were widowed, and 6% had never married. About 30% were living with at least one child or parent. Educational experience ranged from 12–24 years of full-time schooling, and there was a corresponding

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wide range of incomes. There were two black, one Hispanic, and one Asian patient, and the remaining 103 were white. Almost half (52) of the subjects were employed, 33 were retired, and 14 were unemployed. Almost all had some type of private medical insurance, with 26% being covered by Medicare and 2% by Medicaid. We may conclude that the results of the study will apply generally to a predominantly white, middle-class population of hypertensives. PROPOSED STATISTICAL ANALYSIS The analysis tests the effects of (a) behavioral/educational patient-centered interventions to increase adherence to medication and (b) a potassium supplement to lower blood pressure. The primary outcome measures of effect on adherence are the three continuous MEMS determinations. For each continuous outcome, a balanced two-way analysis of variance has main factors of potassium supplement, type of support, and their interaction. The study posits that the full intervention would increase adherence by at least 20% over the scores for standard care. With a two-sided type I error rate of 5%, a test of the difference in mean level of adherence has 80% power to detect a difference of 20% or more. This calculation assumes a comparison of 36 persons with intense counseling with 36 persons receiving no support. The study will have 99% power to detect a drop of at least 5 mm Hg in systolic pressure assuming a population standard deviation of 12 mm Hg for a simple t-test comparison of two groups of 53 or 54 persons, one receiving potassium supplement and the other not receiving any supplement. This assumes a dropout rate of 11%. By using an intent-to-treat analytic approach, the sample size for the power calculation is only reduced by the number of patients who drop out. In secondary analyses we will explore the relationship between patterns of adherence early in the follow-up period and the outcome of dropout [26]. PROBLEMS AND ISSUES Study personnel have recorded some problems during the study. •

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Working part-time in the study, staff members have to balance their responsibilities with other tasks. Hence, they have had to reschedule appointments with patients, occasionally causing patients inconvenience in the interest of maintaining consistency of protocol. Staff have expressed concern over the need to prepare all patients for counseling visits that only one-third will actually perform, and over the exceeding of protocol limits for telephone counseling for patients reached at home only after several calls. Some staff members have perceived the protocol’s constraints as occasionally conflicting with optimal care. A patient assigned to usual care who receives a telephone call about a missed appointment cannot receive any counseling. Staff have also felt some constraint in communicating to the study physicians information obtained during counseling, lest they inadvertently reveal the study assignment. Some have been unsure which of the study’s objectives was of primary importance.

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Patients too have experienced problems. The potassium capsules are large, and some patients have reported finding them difficult to swallow. The medication bottle required for the selected MEMS cap has also proven too large to fit in a shirt pocket or a small purse. Many patients have needed to discuss suitable and specific solutions that suit their work needs and other aspects of their lifestyles. Some patients have had to wait a long time for appointments when their study physicians were delayed by acute clinical situations. Those patients receiving counseling interviews have been more likely to have long waits, and staff members have sensed their anxiety to leave. Often, patients were obviously less relaxed during visits with the adherence specialist. Patients have, however, been at least as likely to make positive comments about the study as to complain. Those assigned to adherence interventions have appeared to welcome the opportunity to provide information and receive feedback. Many patients have expressed interest in the MEMS caps and the computer-chip technology, and many have expressed gratitude for the support and caring they have received at the study center. Another set of problems has arisen because the counseling protocol and the supplement protocol do not readily dovetail. Where one staff person might supervise two complementary medications, our trial requires a counseling supervisor and a separate medication supervisor. The added intervention complicates the rescheduling of patients’ visits within a busy clinic. Combining interventions may also affect the analysis. Complicated protocols might make nonrandom dropouts and nonrandom missing data more likely.

In general, only a minority of the problems experienced relate to the specific study design. Most of the experiences of patients and study personnel are probably similar to those reported by participants in clinical trials with other types of design. We discuss any problems shortly after they are first experienced and actions are taken to resolve them so as to ensure the study integrity. We see no reason to fear that the greater complexity of our study design increases problems substantially, nor that any of the issues experienced will prevent the trial achieving its objectives. REFERENCES 1. Binstock ML, Franklin KL. A comparison of compliance techniques on the control of high blood pressure. Am J Hypertens 1988;1(3 Pt 3):192S–194S. 2. Champion VL. Instrument development for health belief model constructs. Adv Nurs Sci 1984;4:73–85. 3. Champion VL. The relationship of breast self-examination to health belief model variables. Res Nurs Health 1987;10:375–382. 4. Gorkin L, Goldstein MG, Follick MJ, Lefebvre RC. Strategies for enhancing adherence in clinical trials. In: Schumaker SA, Schron EB, Ockene JK, eds. The Handbook of Health Behavior Change. New York: Springer; 1990. 5. Cramer JA. Overview of methods to measure and enhance patient compliance. In: Cramer JA, Spilker B, eds. Patient Compliance in Medical Practice and Clinical Trials. New York: Raven; 1991.

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