Prematurely Terminated Clinical Trials and Their Application to Cardiovascular Medicine
Abstract
Controlled clinical trials in cardiovascular disease remain the cornerstone of field-specific therapeutic advances. Since the introduction of the concept of controlled clinical trials, there has been considerable fine-tuning of the design, conduct, and analysis of such studies. A growing awareness of ethical issues emerging from such trials has led to increased public and investigator scrutiny and the routine requirement for both interim data analysis and full conflict-of-interest disclosure. A be stopped if the observed findings warrant early termination. For example, highly positive findings, as were noted in the HOPE Study (Heart Outcomes Prevention Evaluation), led to its closure after 4.5 years of treatment, which was 1 year earlier than anticipated. Also, the doxazosin treatment limb of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) and the amlodipine treatment limb of AASK (African American Study of Kidney Disease and Hypertension)were stopped early, because of negative findings in one of their treatment limbs. Finally, economic considerations can enter into the decision to close a study early, as was the case in the CONVINCE (Controlled-Onset Verapamil Investigation of Cardiovascular Endpoints)trial. Most such decisions rely heavily on information obtained from independent data and safety monitoring boards. Such boards ensure patient safety by providing an unbiased, ongoing review of data, which would otherwise be unavailable until a study's completion. Early termination of a clinical trial can have important clinical and economic implications and, in particular, can substantially redirect the pattern of clinical practice.
It is an important option in a clinical trial that, if necessary, it can be prematurely stopped. Several factors can influence the decision to terminate an ongoing clinical trial, including ethical concerns, changes in accepted clinical practice that make the continuation of a clinical trial unwise, and/or attainment of a positive or negative statistical end point earlier than was anticipated (Table). The discontinuation of a clinical trial can be prompted by either the investigator(s) and/or the study sponsor, with or without the input of an independent data and safety monitoring board.1 Investigator-specific considerations are generally applicable only to single-center trials (Table) but may occasionally influence multi center trials if the site in question has been a heavy enroller.2
| • Serious adverse reactions, including abnormalities in laboratory analyses, vital signs, or outcomes |
| • Inability to enroll an adequate number of patients |
| • Financial considerations |
| • Impractical or unworkable protocol |
| • Loss of interest by investigator(s) |
| • Problems relating to the medicine's stability or manufacture |
| • New toxicologic findings affecting the benefit-torisk ratio |
| • Failure of the investigator and/or staff to follow either good clinical practice standards or to adhere to protocol requirements |
| • Termination of the test medicine's development by the sponsor |
| • Unacceptable change in personnel or facilities at the investigative site |
| • Determination that no statistically significant result can be obtained |
There are a number of positive reasons for discontinuing a trial prematurely. For example, an unexpected benefit on the cardiovascular disease (CVD) event rate in the recently terminated Heart Outcomes Prevention Evaluation (HOPE) trial3 prompted a recommendation for early termination in order to extend the benefit of these observations to a large group of patients as quickly as possible. Although not specifically stated as such, it can be inferred that withholding the findings of the HOPE study until its planned date of conclusion would have been unethical. Another example of trial discontinuation for proper reasons was the collaborative Beta Blocker Heart Attack Trial.4,5 This was a randomized, double-blind, controlled trial comparing propranolol with placebo in 3837 patients with a recent myocardial infarction (MI). The trial was terminated 9 months before the scheduled closing date on the recommendation of the policy and data monitoring board. At the time of the decision, the propranolol treatment group had a 26% lower mortality. Several issues were considered in this decision, including the magnitude and consistency of the overall results, including causes of death and completeness of followup, across all subgroups and clinical centers.
If ethical considerations exist at the outset of a clinical trial, then carefully defined end points should be established, which, if reached, would prompt discontinuation of the trial. It should also be appreciated that discontinuation of a trial because of results that are either strongly positive or negative generally makes it difficult, if not impossible, to conduct a similar trial in the future. If the trial is to be terminated early, according to pre-established criteria he confirmatory data must be strong enough to convince the overwhelming majority of statisticians and clinicians of the validity of the conclusion; otherwise, positive findings of a trial may not be accepted or negative findings dismissed. For example, in the Beta Blocker Heart Attack Trial, two different statistical methods were used in determining that the overall mortality results were significant. The premature termination of a trial may also be financially prudent in that valuable resources can be reallocated. When an investigator terminates a clinical trial, careful consideration must also be given as to how to best phase patients back to their pretrial care and treatment.6 In many instances, this issue will be simple to address. In other cases, when patients have benefited greatly from participation in a trial, the weaning from frequent contact with the investigator and staff, plus the benefits of treatment, may prove challenging.
Appropriate Blood Pressure Control in Diabetes Study
The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial7 was a prospective, randomized study in patients with type 2 diabetes. It was designed to test the primary hypothesis that two modes of treatment—intensive vs. moderate blood pressure (BP) reduction—would either prevent cardiovascular events or slow the progression of nephropathy, neuropathy, and retinopathy. A secondary hypothesis of this study was that the long-acting dihydropyridine calcium channel blocker (CCB) nisoldipine and the angiotensin-converting enzyme (ACE) inhibitor enalapril would have equivalent effects on the rate at which diabetic complications progressed.
A total of 950 subjects with diabetes, both normotensive (n=480) and hypertensive (n=470), were randomly assigned to moderate (target diastolic BP, 80–89 mm Hg) or intensive (target diastolic BP, 75 mm Hg) antihypertensive treatment, administered in a double-blind fashion. In the hypertensive cohort, patients were randomly assigned to either nisoldipine or enalapril as a primary antihypertensive medication. Nisoldipine was started at 10 mg, with titration to 20, 40, or 60 mg/day as necessary; enalapril treatment began at 5 mg/day, with increases to 10, 20, or 40 mg/day, as warranted. If the study medication did not bring BP to goal, add-on therapy with open-label metoprolol or hydrochlorothiazide was permitted.
After 67 months, the data safety monitoring committee observed a significant difference in cardiovascular event rates between the two treatment groups in the hypertensive cohort; the nisoldipine-treated patients had a greater number of events. Nisoldipine therapy was terminated in the hypertensive cohort on July 14, 1997. In the enalapril treatment group, with both moderate and intensive treatment, there were fewer cardiovascular events than in the nisoldipine treatment cohort (25 fatal/nonfatal MIs for nisoldipine vs. five for enalapril). These data led to computation of an unadjusted risk ratio of 5.5 (95% confidence interval [CI], 2.1–14.6) and an adjusted risk ratio of 7.0 (95% CI, 2.3–21.4) for the combined end point of fatal and nonfatal MIs (nisoldipine:enalapril).
Because more than 50% of the subjects were not taking the original study medication by the end of the study, an additional analysis, according to actual drug exposure, was performed. This also yielded a significant difference in the rate of MIs between nisoldipine- and enalapril-treated patients. These findings suggest that patients taking nisoldipine were more apt to have an MI, and to experience it earlier, than enalapril-treated patients. Because of the presumed gravity of these findings, those in the hypertensive cohort randomized to nisoldipine were reassigned to treatment with enalapril.
Lesson: Do not prematurely report study results, particularly if the result is not prespecified a priori as an end point. The results of the ABCD trial require careful interpretation. The decisions to prematurely stop the study and to report only a secondary end point in the hypertensive subgroup are open to criticism. At the time of this study report, the treatment environment for the hypertensive diabetic was highly charged, which could have influenced the data and safety monitoring committee to act on an extreme result. This result was not prespecified a priori as an end point. Also, it was not subject to monitoring boundaries, which may have inflated the risk of a false-positive finding. Other confounding variables of this interim analysis included the facts that diuretic and β blocker add-on therapy was more common in the enalapril treatment group and that the study medication was discontinued more often in the nisoldipine treatment group. Because of these differences, overall cardiovascular protection may have been weighted in favor of the enalapril-treatment group.
The ABCD trial served to galvanize those inclined to the belief that CCB use carries a substantial cardiovascular risk. Its findings provided significant momentum to the drive to relegate CCBs to a secondary position in the treatment of hypertension, particularly when these findings were combined with the presumably negative findings of the Fosinopril Versus Amlodipine Cardiovascular Events Randomised Trial (FACET).8 Unfortunately, the ABCD data, as presented originally, were not completely accurate. During the remaining year of the study, a private detective identified six additional nonfatal MIs, which were confirmed by the blinded end point committee. Thus, since the publication of the original report, the number of patients in the nisoldipine group with fatal or nonfatal MIs has increased from 25 to 27, and the number in the enalapril group has increased from five to nine. Hence, the unadjusted risk ratio is now 3.3 (95% CI, 1.5–7.1; p=0.029) rather than 5.5, and the adjusted risk ratio is now 4.2 (95% CI, 1.8–10.1; p=0.001) rather than 7.0.9
One can only speculate on the degree to which CCB prescription use was adversely influenced by this reporting error. As the issue has unfolded over the past 3 years, a series of studies now suggest that CCB therapy is not deleterious per se,10,11 an observation also supported by a recent overview of antihypertensive therapy.12 This overview provided strong support for the benefits of ACE inhibitor and CCB therapy, and weaker evidence of differences between treatment regimens based on different drug classes. These more recent data support the original belief that the ABCD study could not determine if the differences between the rates of MI were because of a beneficial effect of enalapril or because the CCB was specifically harmful.
CONVINCE
CONVINCE13 (Controlled-Onset Verapamil Investigation of Cardiovascular Endpoints), was an international clinical trial that compared outcomes in hypertensive patients randomized to initial treatment with either controlled-onset, extended-release verapamil or the investigator's choice of either atenolol or hydrochlorothiazide. This study was uniquely successful in achieving goal systolic and diastolic Bps. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16,602 subjects After medication titration, with use of a transtelephonic computer that recommended an increase in the dose or number of antihypertensive medications whenever the BP was ≤140/90 mm Hg, 84.8% of the subjects attained the goal BP. During the 2 years of treatment, systolic BP control was maintained in ≅70% of the subjects (<140 mm Hg) and diastolic BP in ≅90% of the subjects (<90 mm Hg).14 These data, like those of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)15 and the Losartan Intervention for Endpoints (LIFE)16 studies, suggest that it is more difficult to control systolic than diastolic BP.
The CONVINCE trial was intended to provide insight into the influence of a controlled-onset, extended-release form of verapamil (COER-verapamil) on the incidence of fatal or nonfatal MIs, fatal or nonfatal stroke, and CVD-related death in comparison to the incidence with standard therapy employing either a diuretic or a β blocker. Since the verapamil form used in this study was given at bedtime and its major antihypertensive effect occurred 6–12 hours after administration, it was anticipated that the question of how this particular form of verapamil influenced the circadian pattern of end events might be answered.17
Lesson: It is imprudent, if not unethical, to prematurely terminate a clinical trial poised to answer an important clinical question, particularly if it is near completion. There was considerable disappointment when the CONVINCE study was prematurely closed. This trial was completely enrolled and approximately 4 years into follow-up. Only 1 year of additional follow-up was necessary to collect the prespecified number of events required to reach statistically sound conclusions. A loss of power typically results from stopping a study short of its planned date of completion. It is poorly appreciated that the power of a study increases dramatically as the follow-up lengthens. Moreover, verapamil use will be impacted adversely by the decision to close this study prematurely. Verapamil use in hypertension has been held back for some time by the lack of outcome data, despite the favorable experience with its use in coronary heart disease. As a result, verapamil is currently not included in any of the hypertension guidelines in most countries. This study was poised to answer the aforementioned question with some finality, which unfortunately will not occur as originally planned.
The site investigators were also told by the study sponsor that the study was being closed for “business reasons.” The early termination of this trial essentially wasted the resources that had been allocated to it. Patients were willing to assume risks in this study, and its cancellation eliminates all chance of balancing the risk-benefit ratio of patient participation in a clinical trial. The manner in which the investigator-patient relationship was terminated in this study will, no doubt, have implications for future randomized clinical trials. Future trials will require different assurances that funding will be available to complete a trial irrespective of shifts in business philosophy. Interestingly, some in the industry have suggested that the investigators in this study were being paid for their time; therefore, there was minimal harm in closing this study early. This is a shortsighted view, which, if it were to become pervasive, would seriously jeopardize investigator-industry relationships.
ALLHAT
A study involving high-risk hypertensive patients aged 55 years or older, ALLHAT was a large, simple trial, designed to closely mimic clinical practice as it occurs in high-risk patients. One of its goals was to determine whether the incidence of the primary outcome—a composite of fatal coronary heart disease and nonfatal MI—differed between treatment with a diuretic (chlorthalidone 12.5–25.0 mg/day) and treatment with each of three other antihypertensive drugs: the CCB amlodipine, the ACE inhibitor lisinopril, and the α-adrenergic blocker doxazosin. Secondary outcomes included all-cause mortality, stroke, and all major CVD events. If patients did not meet the BP goal with the maximum tolerated dose of the initial medication, an open-label step 2 agent (atenolol 25–100 mg/day, reserpine, 0.05–0.2 mg/day, or clonidine, 0.1–0.3 mg twice daily) or an open-label step 3 agent (hydralazine 25–100 mg twice daily) could be added. In addition, a number of ALLHAT participants (n=10,337) participated in a randomized, open-label trial designed to determine whether lowering low-density lipoprotein cholesterol with pravastatin reduced all-cause mortality compared to mortality in a control group receiving usual care. Patient enrollment in ALLHAT began in February, 1994 and active follow-up is scheduled to conclude in March, 2002.18
These data from the ALLHAT trial would have allowed, for the first time, direct comparison of doxazosin with the gold standard for hypertensive therapy—a thiazide diuretic—from an evidence-based medicine perspective.18–20 There was a sound rationale for the inclusion of a peripheral α-adrenergic antagonist, such as doxazosin, as one of the treatment limbs of the ALLHAT study. Doxazosin, as well as other α-adrenergic antagonists, had previously been shown to effectively reduce BP, with efficacy comparable to that of hydrochlorothiazide.21–23 In addition, it is well documented that these drugs favorably modify the insulin resistance and hyperlipidemia of the hypertensive metabolic syndrome;24–26 that they have beneficial effects on fibrinolysis,27 red blood cell deformability,28 and endothelial function;29,30 and that they inhibit the proliferation and migration of human vascular smooth muscle cells.31 A number of these findings became apparent even as the ALLHAT trial was in progress, and simply supported prior evidence. Thus, it was anticipated that doxazosin, beyond its ability to reduce BP, would confer additional cardiovascular benefit as a consequence of its favorable effects on metabolic risk factors known to increase the risk of coronary heart disease32
Thus, there was considerable surprise and disappointment when the National Heart, Lung, and Blood Institute (NHLBI) announced that doxazosin was to be withdrawn from the trial after an interim analysis showed a 25% higher rate of a secondary end point, combined cardiovascular disease, in patients on doxazosin than in those on chlorthalidone—a result largely driven by congestive heart failure.15 Also, there was no difference in the primary end point, fatal coronary heart disease and nonfatal MI, and calculations indicated that this was unlikely to change by the end of the trial. Following independent data reviews on January 6 and 21, 2000, the director of the NHLBI accepted a recommendation to discontinue the doxazosin treatment arm in the BP component of the trial. It was determined that participants assigned to the doxazosin group should be informed of their BP treatment assignment and that the major clinical findings regarding this treatment and its comparison agent, chlorthalidone, should be reported as soon as possible. The ALLHAT data and safety monitoring board specifically stressed the importance of continuing the rest of the BP and lipid-lowering trial.
Lesson: The discontinuation of the doxazosin treatment limb left open to speculation the role of doxazosin in the management of hypertension, either as first-step therapy or as add-on therapy, and confused physicians as to the safety of its use in the treatment of symptoms of benign prostatic hyperplasia. The issue of what represents an adequate demonstration of safety of a compound has been raised by the ALLHAT study. In the future, hard end point studies may become an important, if not mandatory, requirement for a new compound to reach the market.
ALLHAT was not a placebo-controlled, but rather an active-controlled trial; thus, the study did not permit an assessment of whether doxazosin is better than placebo. ALLHAT was not exactly a simple drug-todrug comparison of doxazosin to chlorthalidone, since additional drugs were permitted, as necessary, to achieve goal BP. Four years into the study, 40% and 47% of the chlorthalidone and the doxazosin treatment groups, respectively, were receiving step 2 and/or 3 medications. Furthermore, use of doxazosin as part of a multidrug regimen for treating hypertension or benign prostatic hypertrophy was not per se tested in this trial, and doxazosin should not be discontinued from such regimens solely on the basis of the ALLHAT results. However, an admonition is warranted: patients with recognizable cardiovascular risk factors who are treated with doxazosin should be carefully observed for any evidence of extracellular volume expansion and/or sympathetic activation, as might be inferred from persistent tachycardia. If either is observed, appropriate management steps should be taken, including either reduction of the doxazosin dose and/or correction of the volume-overload state with diuretics.
The Joint National Committee recommendations33 include doxazosin as appropriate first-step therapy in certain patients when β blockers or diuretics are not advisable, particularly for patients with dyslipidemia or benign prostatic hypertrophy. These recommendations, as well as those of the World Health Organization,34 the British Hypertension Society,35 the Canadian Medical Association,36 and the French Groupe de Travail,37 may need to be revised to the effect that doxazosin, or for that matter all peripheral α-adrenergic drugs, should no longer be considered for first-line antihypertensive therapy.
The approach of the Food and Drug Administration (FDA) to these data will ultimately prove more problematic. To date, this regulatory body has accepted equivalent BP reduction as a suitable surrogate marker for comparability of different antihypertensive classes.38 This position may need to be reconsidered when the final analysis of these interim ALLHAT findings becomes available sometime next year. Equivalent BP reduction by different antihypertensive medications seemed an economically prudent way to bring new drug classes to market quickly and thereby to provide new treatment options for physicians. The ALLHAT data would argue that hard end point trials—albeit more costly and timeconsuming undertakings—may need to become a component of the regulatory approval of an antihypertensive compound.
HOPE Study
The HOPE study3 was a large, simple, factorial-design, double-blind, placebo-controlled trial, conducted in 267 centers in 19 countries, that determined the risk of cardiovascular events in over 9500 patients. The patients were considered at high risk of future cardiovascular death or morbidity because of age, in that they were required to be older than 55 years, or because they had either diabetes, evidence of a prior vascular event, or existing vascular disease. Diabetics were required to have either known vascular disease or one other risk factor for cardiovascular disease, such as cigarette smoking, BP over 140/90 mm Hg, or elevated cholesterol (>5.2 mmol/L). Diabetics were included in this study because even without recognizable coronary artery disease, they have about the same risk for coronary events as nondiabetic patients with established coronary disease.39 Subjects with congestive heart failure or an ejection fraction below 40% were excluded, as were patients taking vitamin E and those for whom an ACE inhibitor was indicated, such as those with left ventricular dysfunction.
The HOPE protocol included a run-in period for tolerance. During this period, all 10,576 initially eligible patients received a 2.5-mg dose of ramipril for 7–10 days; thereafter, they received a matching placebo for 10–14 days. This approach was taken to identify those prone to early side effects and those who experienced an exclusionary change in serum electrolytes or creatinine. Approximately 10% of the population, or 1035 patients, were excluded for these reasons. The remaining 9541 subjects were randomized to ramipril or placebo, beginning with a titration phase of 2.5 mg/day for 1 week, followed by 5 mg/day for 3 weeks. Thereafter, patients received 10 mg/day until study completion. Follow-up was at 1 month and thereafter every 6 months. All patients received either vitamin E (400 IU) or matching placebo.40
The primary end point was defined as a combination of cardiovascular death, nonfatal MI, and nonfatal stroke. The trial was stopped about 1 year early, after 4.5 years of treatment, on the advice of the data and safety monitoring committee, since the weight of the available evidence strongly supported a more favorable outcome in the ramipril-treated group. During the study period, 17.8% of subjects in the placebo group reached the primary combined end point, compared with 14% in the ramipril-treated group. This difference represented a 22% reduction in relative risk. The individual components of the composite end point were also significantly reduced: by 32% for stroke, 26% for cardiovascular death, and 20% for MI. Ramipril also reduced the risk of several other clinical end points—congestive heart failure by 23% and revascularization procedures by 15%.
Lesson: Early discontinuation of a study is critical if the findings can be applied to the benefit of a broad sampling of patients who exhibit a similar risk profile. The HOPE study results show substantial benefits in mortality and morbidity from the use of ramipril in a large group of subjects at high risk of future cardiovascular events. These results were of sufficient importance to prompt the American Heart Association (AHA) to include this study in its “top ten list” of research advances for the year 1999. In addition, the FDA has allowed a labeling change for ramipril, to incorporate the findings of the HOPE study. Thus, if the sentiments of either the FDA or the AHA are in any way relevant to the significance of the HOPE study, it seems prudent to have stopped this study early.
The results of the HOPE study were achieved on top of current conventional treatment and are therefore broadly applicable to clinical practice. The implications for diabetic patients are particularly striking. These results should extend the use of ACE inhibitors to a wider group of patients. ACE inhibitor therapy has previously been shown to be of proven benefit to those with left ventricular dysfunction, hypertension, or diabetes with proteinuria. ACE inhibitor use can now be extended to a different patient group: those at risk for vascular events but without substantive evidence of left ventricular dysfunction, many of whom are receiving aspirin prophylaxis. Finally, the HOPE study findings provide the factual underpinnings for conducting additional studies employing differing pharmacologic approaches to interruption of the renin-angiotensin system in at-risk patients. The HOPE study was not designed to determine whether ACE inhibitors are the optimal agents for preventing cardiovascular events in high-risk hypertensive patients. This issue is being addressed in ALLHAT.15,18
Conclusion
Guidelines for early termination of a clinical trial should be established before any data review is undertaken. Interim data analyses, in conjunction with the totality of available evidence, provides the necessary framework from which data and safety monitoring boards can make informed and prudent recommendations. Controlled clinical trials should not be prematurely terminated for trivial reasons. They also should not be terminated prematurely on economic grounds, particularly if the information to be gained adds substantially to the knowledge base on the therapy of specific disease states. Such, for example, is the case with the early stoppage of the CONVINCE trial: the motives for its discontinuation were presumed to be fiduciary responsibility to the stockholders, since it was believed that the findings might not place the drug in the “blockbuster” category. Finally, continuation of a trial deemed to be futile is wasteful of resources and potentially unethical. This was the case in ALLHAT, wherein early termination of the doxazosin treatment limb was based on an unacceptably high rate of congestive heart failure when doxazosin-treated patients were compared to those receiving chlorthalidone. Similarly, there was an early termination of the amlodipine treatment limb of the AASK trial. When amlodipine-treated patients with clinical proteinuria were compared to those receiving the ACE inhibitor ramipril, there was a sufficient difference in the rate of renal functional decline to compel the data and safety monitoring board to prematurely terminate this treatment limb.
