Barriers to a trial of atherosclerosis prevention in systemic lupus erythematosus

Authors


Abstract

Objective

The effectiveness of aggressive management of traditional risk factors for accelerated atherosclerosis in systemic lupus erythematosus (SLE) has been advocated but not proven. We conducted a pilot, randomized, controlled trial of known prevention medications (pravastatin, ramipril, aspirin, and a combination B vitamin) plus individualized cardiovascular prevention education. We describe our experience in recruiting and retaining patients with SLE in this trial.

Methods

Patients with SLE by American College of Rheumatology criteria who lived within 1 hour of the hospital and had visits within the past 3 years were screened. All eligible patients were contacted by the principal investigator who was not their physician. The reasons for nonparticipation were elicited in a nonjudgmental manner.

Results

A total of 662 patients met the selection criteria for the study. Of these, 295 patients (45%) with contraindications to study medications were excluded. Ninety-seven (40%) of 244 eligible patients refused to participate. More than 40% of those phoned were unwilling to participate and, among those, 19% felt they were too sick, too well, or taking too many medications already. A total of 41 patients were enrolled in the trial, and 22 dropped out within 4 months.

Conclusion

SLE is a chronic disease, and the development and testing of interventions aimed at the prevention of long-term sequelae are of paramount importance. Prevention trials in SLE face serious challenges, including the recruitment and retention of participants. Our experience provides insights into the barriers to participation in randomized prevention trials in SLE.

INTRODUCTION

Systemic lupus erythematosus (SLE) is an inflammatory rheumatic disease of immunologic origin characterized by autoantibody production, polyarthritis, and protean clinical manifestations. SLE has now become a chronic disease with 5-year survival rates of 90% or better (1–3). Patients who survive the early years are at risk for accelerated cardiovascular disease (CVD) (3–8). The pathogenesis of CVD in patients with SLE appears to be multifactorial (9–13). Traditional cardiac risk factors, including hyperlipidemia, hypertension, and sedentary lifestyle, which are all prevalent in patients with SLE, cannot fully account for the magnitude of this increased risk; the duration and activity of SLE itself confer excess risk of CVD (14–16). The conventional wisdom in the field is that improved recognition and aggressive treatment of cardiac risk factors are necessary in SLE, although there are no data to support that this would be effective (17–21).

We conducted a pilot, proof-of-concept, double-blind, randomized controlled trial (RCT) of prevention strategies for atherosclerosis in SLE to assess the feasibility of a larger definitive trial (NIH AR47782). Unfortunately, we encountered barriers to patient recruitment and retention, some foreseen and others unforeseen. After 10 months, it became obvious that the recruitment rate was insufficient to support the larger trial and the study was discontinued. We report our experience with patient recruitment and retention in this pilot trial, and review the barriers to primary prevention trials in chronic disease.

PATIENTS AND METHODS

Study design.

The Prevention of Accelerated Atherosclerosis in SLE Study (PASS) was a pilot, double-blind, placebo-controlled RCT of 6 strategies with potential to decrease cardiac risk in SLE (Table 1). The cardiovascular risk model of the Framingham study (22, 23) was used as a surrogate endpoint for cardiovascular disease. The goal of PASS was to assess the feasibility of a definitive RCT using clinically-relevant endpoints, estimated to require 10,000– 12,000 patients. Each arm of the study incorporated medications proven to be effective and a novel, individualized, telephone risk factor management system, manned by experienced nurse practitioners. The medications used in the trial included pravastatin, ramipril, and aspirin, all agents shown to be effective in preventing CVD in the general population and in at-risk populations (24–27) but never studied in individuals with SLE. Patients at low cardiovascular risk, defined as a 10-year risk of coronary heart disease (CHD) <10% as calculated by the Framingham risk score, were randomized to 1 of 6 prevention strategies (28). Patients with a 10-year CHD risk ≥10% were not assigned to placebo and were randomized to 1 of 5 prevention strategies (Table 1). The trial was targeted to enroll 150 patients to be followed for 2 years and was approved by a Data Safety Monitoring committee and the hospital Institutional Review Board.

Table 1. Randomization scheme*
Group 1Group 2Group 3Group 4Group 5Group 6
  • *

    ASA = acetylsalicylic acid.

  • Home blood pressure machine if history of hypertension.

Usual care Risk factor InformationUsual care Risk factor Information Pravastatin (40 mg/day)Usual care Risk factor Information Pravastatin (40 mg/day) ASA (81 mg/day)Usual care Risk factor Information Pravastatin (40 mg/day) Ramipril (10 mg day)Usual care Risk factor Information Pravastatin (40 mg/day) ASA (81 mg/day) Ramipril (10 mg/day)Usual care Risk factor Information Pravastatin (40 mg/day) ASA (81 mg/day) Ramipril (10 mg/day) Individualized education Vitamin B12 (1 mg/day) B6 (50 mg/day) Folate (3 mg/day)

Subject identification.

Potential participants were identified from a registry of patients with SLE followed at the Brigham and Women's Hospital who met the American College of Rheumatology criteria for SLE (29, 30). In addition, potential participants were required to live within 1 hour's drive of the hospital, and to have a minimum of 1 visit to the Brigham and Women's Hospital Arthritis Clinic in the last 3 years. Insufficient access to foreign language translators precluded the inclusion of non-English speakers from this trial, which required a large amount of telephone contact. Exclusion criteria included contraindications to pravastatin, ramipril, and aspirin (Table 2). The computerized medical record was reviewed to identify exclusion criteria and medications.

Table 2. Exclusion criteria*
  • *

    CPK = creatine phosphokinase; ACE = angiotensin-converting enzyme.

Contraindication to pravastatin
 Pregnancy, nursing, or unwillingness to use acceptable contraception
 History of muscle disease or baseline CPK >500 units/liter or 2× upper limit of normal
 Taking cyclosporine
 Taking lithium
 Taking cholestyramine, niacin, or erythromycin
 Abnormal liver function tests (>2× upper limit of normal)
Contraindication to ramipril
 Pregnancy, nursing, or unwillingness to use acceptable contraception
 Taking an ACE-inhibitor or an angiotensin receptor blocker
 History of allergy or sensitivity to an ACE-inhibitor or angiotensin receptor blocker
 Creatinine >2.0 mg/dl
 Renal artery stenosis
 Taking potassium supplements, or a potassium sparing diuretic
Contraindication to aspirin
 History of an intracranial bleed or brain tumor
 Bleeding diathesis or taking blood thinner (coumadin or heparin)
 Uncontrolled high blood pressure (180 mm Hg/110 mm Hg)
 Peptic ulcer disease in last 6 months
Inability to give informed consent in English

The trial was presented on 2 occasions at rheumatology staff meetings and at rheumatology grand rounds. E-mail updates were sent to rheumatologists and announcements were posted in the rheumatology clinic. Lists of potential patients with SLE and the exclusion criteria were sent to individual rheumatologists for their permission to contact the patients under their care. When a rheumatologist gave permission, he or she signed a letter about the study, which was also signed by the study principal investigator (MHL) and it was then mailed to the patient with an opt-out preaddressed and stamped reply card.

All potential participants who did not return the opt-out card were contacted by telephone within 2 weeks. The principal investigator (MHL) made all the recruitment phone calls during the morning, afternoon, and evening. None of his own patients were contacted. The phone calls followed a script. If the patient was not interested, the principal investigator asked in a nonjudgmental way for the patient's reasons. If the patient expressed interest in the study, the study was explained and the exclusion criteria were reviewed. An enrollment visit was then scheduled at the patient's convenience, although in the morning to obtain fasting lipid levels.

At the enrollment visit, a physician reviewed the exclusion criteria and explained the consent form, which the patient and the coinvestigator both signed. A family member of the patient was often present and questions about the trial and participation were answered in detail. The most significant risks from the medications outlined in the consent form included cough, hypotension, or abnormal renal function due to ramipril; bleeding due to low-dose aspirin; and liver toxicity, myalgias, or increased muscle enzymes due to pravastatin. Height, weight, and blood pressure were recorded. A medical history including general medical and demographic questions, and cardiac risk assessment using the Framingham risk score (based on age, fasting total and high-density lipoprotein cholesterol, systolic blood pressure, and current cigarette smoking) were also obtained (28). Patients also completed the SLE Disease Activity Questionnaire (SLAQ) (31), the Cardiovascular Health Questionnaire (32), the Health Assessment Questionnaire (HAQ) (33), a measure of self-efficacy (34), and the Medical Outcomes Study Short Form 36 (SF-36) (35, 36). A fasting blood sample was obtained. Patients were offered reimbursement for their travel and parking expenses, but no other financial incentives were offered.

Depending on their Framingham risk score, patients were randomized by the hospital Investigational Drug Service, and a 4-month supply of medication and instructions was mailed to the patients' homes. Patients were asked to take either 2 or 3 capsules daily. Used pill packets were returned in prepaid envelopes to the investigators for pill counts to assess adherence. All patients were sent a summary letter with a brochure on cardiac risk factor modification. Those randomized to the individualized education group had monthly telephone conversations with the nurse practitioner to discuss cardiac risk factor modification strategies. At the patient's discretion, the rheumatologist was informed of laboratory test results. Any patient with a history of hypertension was provided a home blood pressure monitor.

Patients were asked to return 3 weeks after starting medications for a test of creatine phosphokinase (CPK), creatinine, alanine aminotransferase, and potassium levels, and a blood pressure measurement. Thereafter, patients were phoned every 4 months by the nurse practitioner to inquire about adherence to and side effects from the medications, cardiac risk behaviors, and interim illnesses and cardiovascular events. Patients were asked to fill out and return a SLAQ, HAQ, and SF-36 questionnaire once every 4 months. Patients were asked to return only once yearly for a longer visit that included height, weight, and blood pressure measurements and a fasting blood sample.

RESULTS

A total of 662 patients were identified in the SLE registry and met demographic criteria for inclusion in the trial (Figure 1). The mean ± SD age of eligible patients was 45.2 ± 13.4 years; 95.0% were women; and 68% were white, 17% were African American, 8% were Hispanic, and 7% were of another race. After initial medical record review, 214 patients were excluded. Of these, 136 were already taking an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, 13 had aspirin hypersensitivity, 59 were taking coumadin, 130 had an elevated creatinine level, 7 had an elevated CPK level, 2 were taking potassium supplements, 3 were taking lithium, 3 were taking cholestyramine, and 3 had abnormal liver function tests (not mutually exclusive). None reported an allergy or adverse reaction to statin medications.

Figure 1.

Recruitment flow. SLE = systemic lupus erythematosus; ACR = American College of Rheumatology.

Of the 448 patients not excluded by chart review, 204 were excluded by their rheumatologists, who excluded varying proportions of their patients from the trial. At the extremes, one provider gave permission to contact all of his patients and another excluded every patient on the list without explanation. Several physicians never responded. Reasons for not giving permission to contact patients with SLE included the exclusion criteria (n = 35), but also “moved or lives far away” (n = 10), “history of noncompliance or mental disorder” (n = 10), and “cancer or other serious comorbidity or frailty” (n = 7). Both “burnt-out/inactive SLE” (n = 6) and “very active/flaring SLE” (n = 5) were given as reasons to not contact the patient. Several rheumatologists expressed concern about randomizing patients to potential placebo and instead directly prescribed a statin medication for either hyperlipidemia or cardiac risk reduction, instead of encouraging participation in the study. Physicians were also concerned about potential medication interactions, in particular pravastatin with psychiatric medications and disease-modifying antirheumatic agents.

Recruitment letters were sent to 244 potential participants. Fourteen returned the opt-out post card and were not contacted. A total of 491 recruitment phone calls were made and 199 (87%) patients were reached. The most successful time for contacting an individual was 7:00–9:30 PM. An additional 40 (16%) patients were found to have medical contraindications to one or more study medication during this telephone call. Eighty-three (36%) patients refused to participate in the trial when contacted. Of these, 35 were not interested or gave no reason, 22 did not want to take more medications, and 7 were too busy. Nine patients felt that their SLE was in good control and did not want to upset that balance by adding another medication, and 7 felt that they were too ill or that their SLE was too active to participate in the trial. Three patients disliked the idea of being randomized.

Ultimately, 41 patients were enrolled in the trial over 10 months. All of these patients were women, their mean ± SD age was 44.3 ± 11.9 years, and the mean duration of their SLE was 12.9 ± 9.7 years. In general, it was a well-educated group of patients, with 46% having obtained more than a high school education. Eighty percent subscribed to private medical insurance and 20% received either Medicare or Medicaid. Seventy-six percent of the patients were white, a distribution representative of the population served by our center.

The patients enrolled in the study were the patients of 8 different rheumatologists. Six patients dropped out of the trial before taking any medications and another 16 dropped out during the first 4 months of the trial. Reasons for trial dropout included both probable adverse events (n = 5: 1 elevated CPK level, 2 cough, 1 hypotension, 1 nose bleed) and possible adverse events (n = 4: 1 lower extremity swelling, 1 migraine, 1 rash, 1 dizziness), as well as starting contraindicated medications (n = 2), too busy (n = 2), desire for pregnancy (n = 1), lupus flare (n = 1), and advised by another physician to stop (n = 1). The trial was halted at 10 months, with only 16 patients remaining enrolled, because it was clear that the question of the pilot was answered, and that a larger, multicenter RCT would not be feasible.

DISCUSSION

The main barriers that we encountered in recruiting patients with SLE, primarily women, to this long-term CVD prevention trial were lack of enthusiasm among the clinicians and patients alike; risk aversiveness; and misunderstanding of the importance of a prevention trial, of blinding, and of placebo. Forty-five percent of patients identified for this trial were not eligible due to one or more medical contraindications to a study drug, and 22% dropped out in the first 4 months due to a probable or possible side effect of one of the study drugs. This suggests that the widespread application of these preventive medications may be limited in SLE. Furthermore, >40% of patients with SLE who were contacted about the trial refused to participate, and of these, 19% felt they were too sick, too well, or taking too many medications already. Fifty-four percent of enrolled patients dropped out within the first 4 months.

Our experience in recruiting and retaining patients in this pilot, multifactorial risk intervention trial was similar to that reported in other SLE therapeutic trials (37). In particular, patient fears, protective attitudes of treating physicians, and lack of sustained momentum in the recruitment effort all contributed to underenrollment and selective enrollment, poor adherence, and attrition. Patients with SLE, many of whom have multiple organ system flares and remissions, see multiple providers, and take multiple medications, have unique concerns in not wanting to risk medication interactions or SLE flares. Both patients and rheumatologists involved in our trial believed that patients with active SLE or those taking multiple medications were not good candidates. Conversely, patients with “burnt-out” or inactive SLE were often not considered candidates, even though there is no data that they are at lower risk of CVD.

Several rheumatologists had a protective attitude, and the trial may have served as a reminder to them to address cardiac risk factors among their patients with SLE. Many patients were ineligible because they were already taking an aspirin or a statin for CVD prevention. Other rheumatologists expressed their beliefs that randomization was inappropriate for their patients with SLE at high cardiac risk, despite the fact that patients with a >10% 10-year cardiac risk would not receive placebo. With 6 arms, this prevention trial schema was complex and was difficult for both physicians and potential participants to grasp. Several treating physicians were concerned about not knowing which medication the patient might receive and about the potential for medication interactions.

Patients who had initial low levels of interest in the study may have had difficulty refusing the principal investigator on the telephone, and therefore feigned interest, only to not show up for the first visit, or to refuse consent at that point. All recruitment telephone calls and informed consent procedures were performed by physician coinvestigators other than the personal rheumatologists of the patients. Other SLE trials have reported higher rates of success in subject recruitment when the physician coinvestigator actively recruited his or her own patients (38–40). We believed this might be coercive, however, because participation in the trial could be interpreted as a physician recommendation.

Enrollment and retention in clinical trials are not challenges unique to SLE (41). In one survey, 17 of 41 RCTs in the US recruited <75% of their targeted number (41). However, as a prevention study with little immediate benefit to the patients involved, patient altruism was all the more crucial. It was difficult to convince patients with a chronic disease to take additional and unknown medications, and to make more medical visits per year, with a goal of contributing to knowledge concerning the prevention of potential SLE complications. The study was designed to minimize time commitment from the patients, allowing telephone followup and limiting the number of visits and blood samples. We did not, however, offer a monetary compensation, and this may have affected recruitment. Because the medications involved in this RCT were not investigational drugs, several patients, sensitized to the issue of increased cardiovascular risk in SLE, asked their physicians to check fasting lipids and prescribe medications, preferring side effect monitoring by their personal physicians.

Personal attitudes toward risk and preferences probably contributed to choices concerning trial involvement. In 65 premenopausal women with SLE, Fraenkel and colleagues found that only 28% were “risk-seeking” in both their gambling strategies and the amount of potential medication toxicity they would accept in the treatment of lupus nephritis (42). In a related study, 28 of 91 patients with SLE were unwilling to accept potential toxicity associated with cyclophosphamide, even for improved long-term renal survival (43). The patients in these studies were similar to ours: mainly white, middle-aged women with SLE. Rosen and colleagues studied risk attitudes across sex, race, and age and found that female sex, white race, and lower education were all significant predictors of increasing risk aversion in medical treatment choices (44).

Fear of being a “guinea pig” and not knowing which medication they would be taking was expressed by many potential patients. Pope and colleagues surveyed participants in rheumatology, ophthalmology, and cardiology RCTs, and found that among respondents, trial concepts, including blinding and the use of placebo, were misunderstood or misinterpreted, regardless of self-assessed level of understanding or level of education (45). According to these authors, there is “a paucity of research on understanding (and patients' perceptions) of the consent process in clinical trials involving patients suffering from chronic diseases” (45).

Patients with SLE are at increased risk for accelerated atherosclerosis. In practice, traditional cardiovascular risk factor management appears to be substandard with respect to the magnitude of the problem, despite the recommendations of numerous authorities (18–21, 32, 46–48). Whether aggressive cardiac risk factor management can reduce the high rates of cardiovascular disease in SLE is not known and deserves study. It is an enormous challenge to develop an effective prevention program for this group in which so many patients are overwhelmed by their disease or medication regimen. Lack of motivation of both patients and physicians was a significant obstacle to the recruitment of patients with SLE for this trial of preventive strategies. The complex trial design, which was difficult for patients and physicians to understand, and the decision not to involve treating physicians in the enrollment of their own patients so as to avoid potential patient coercion, may have significantly impaired recruitment and retention. Our experience provides insight into the challenges of recruiting patients with SLE for prevention trials and raises questions about the feasibility of recruitment of sufficiently large groups of patients with SLE for definitive studies. This issue is especially relevant because studies suggest that even if all the known traditional risk factors were controlled, lupus and/or its treatment confer additional risk of CVD (14, 16). Focus groups and prospective preference assessment may suggest strategies for surmounting these barriers. Recruitment and retention of participants in RCTs are vital to the development of treatments and prevention of long-term sequelae of SLE and more research is required.

Acknowledgements

We are indebted to Ms. Angela Strickland and Ms. Danielle Blanch for assistance with manuscript preparation, and acknowledge the participation of Ms. Linda Baier, NP, the Investigational Drug Service at Brigham and Women's Hospital, and Karl Weinrich and staff at Longwood Pharmaceutical Research for the formulation of the study medicines. In addition, we would like to thank the members of our Data Safety Monitoring Board for their time and effort on behalf of this study: Barbara White, MD (Amgen), Dalene Stangl, PhD (Duke University), and Jean Rouleau, MD (University of Montreal).

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