The usefulness of information on HDL-cholesterol: potential pitfalls of conventional assumptions

Treatment decisions related to disease prevention are often based on two conventional and related assumptions. First, an intervention-induced change in a surrogate marker (such as high-density lipoprotein [HDL]-cholesterol) in the desired direction translates into health benefits (such as reduction in coronary events). Second, it is unimportant which interventions are used to alter surrogate markers, since an intervention benefit is independent of the means by which it is achieved. The scientific foundation for these assumptions has been questioned. In this commentary, the appropriateness of relying on low levels of HDL-cholesterol for treatment decisions is reviewed. The Veterans Affairs - HDL-Cholesterol Intervention Trial (VA-HIT) investigators recently reported that only 23% of the gemfibrozil-induced relative reduction in risk of coronary events observed in the trial could be explained by changes in HDL-cholesterol between baseline and the 1-year visit. Thus, 77% of the health benefit to the participants was unexplained. Other possible explanations are that gemfibrozil has multiple mechanisms of action, disease manifestations are multifactorial, and laboratory measurements of HDL-cholesterol are imprecise. The wisdom of relying on levels and changes in surrogate markers such as HDL-cholesterol to make decisions about treatment choices should questioned. It seems better to rely on direct evidence of health benefits and to prescribe specific interventions that have been shown to reduce mortality and morbidity. Since extrapolations based on surrogate markers may not be in patients' best interest, the practice of medicine ought to be evidence-based

Decisions by regulatory agencies: are they evidence-based?

Contradictory statements about the non-steroidal anti-inflammatory drugs from the European Medicines Agency and the United States Food and Drug Administration have raised questions about whether regulatory decisions are evidence-based. For the selective COX-2 inhibitors, there are clear contraindications and warnings in Europe, but only a vaguely worded Black Box warning in the United States. All the non-selective agents are given an almost "clean bill of health" in Europe, while all of them are judged to have a similar risk-benefit ratio as celecoxib in the United States. The regulatory agencies have failed to recognize the clinical trial evidence that the risk of cardiovascular events varies substantially among the non-selective agents, with diclofenac carrying the highest risk of harm

Withdrawal of cerivastatin from the world market

Cerivastatin was recently withdrawn from the market because of 52 deaths attributed to drug-related rhabdomyolysis that lead to kidney failure. The risk was found to be higher among patients who received the full dose (0.8 mg/day) and those who received gemfibrozil concomitantly. Rhabdomyolysis was 10 times more common with cerivastatin than the other five approved statins. We address three important questions raised by this withdrawal. Should we continue to approve drugs on surrogate efficacy? Are all statins interchangeable? Do the benefits outweigh the risks of statins? We conclude that decisions regarding the use of drugs should be based on direct evidence from long-term clinical outcome trials

Relations of Change in Plasma Levels of LDL‐C, Non‐HDL‐C and apoB With Risk Reduction From Statin Therapy: A Meta‐Analysis of Randomized Trials

Background: Identifying the best markers to judge the adequacy of lipid‐lowering treatment is increasingly important for coronary heart disease (CHD) prevention given that several novel, potent lipid‐lowering therapies are in development. Reductions in LDL‐C, non‐HDL‐C, or apoB can all be used but which most closely relates to benefit, as defined by the reduction in events on statin treatment, is not established. Methods and Results: We performed a random‐effects frequentist and Bayesian meta‐analysis of 7 placebo‐controlled statin trials in which LDL‐C, non‐HDL‐C, and apoB values were available at baseline and at 1‐year follow‐up. Summary level data for change in LDL‐C, non‐HDL‐C, and apoB were related to the relative risk reduction from statin therapy in each trial. In frequentist meta‐analyses, the mean CHD risk reduction (95% CI) per standard deviation decrease in each marker across these 7 trials were 20.1% (15.6%, 24.3%) for LDL‐C; 20.0% (15.2%, 24.7%) for non‐HDL‐C; and 24.4% (19.2%, 29.2%) for apoB. Compared within each trial, risk reduction per change in apoB averaged 21.6% (12.0%, 31.2%) greater than changes in LDL‐C (P<0.001) and 24.3% (22.4%, 26.2%) greater than changes in non‐HDL‐C (P<0.001). Similarly, in Bayesian meta‐analyses using various prior distributions, Bayes factors (BFs) favored reduction in apoB as more closely related to risk reduction from statins compared with LDL‐C or non‐HDL‐C (BFs ranging from 484 to 2380). Conclusions: Using both a frequentist and Bayesian approach, relative risk reduction across 7 major placebo‐controlled statin trials was more closely related to reductions in apoB than to reductions in either non‐HDL‐C or LDL‐C

Thanks to all those who reviewed for Trials in 2015.

A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized. Although final decisions are always editorial, they are greatly facilitated by the deeper technical knowledge, scientific insights, understanding of social consequences, and passion that reviewers bring to our deliberations. For these reasons, the Editors-in-Chief and staff of Trials warmly thank the 854 reviewers whose comments helped to shape the journal, for their invaluable assistance with review of manuscripts in Volume 16 (2015)

Balancing commercial and public interests

A large number of randomized clinical trials with important health outcomes are completed each year. Those with favorable findings are typically reported and published rapidly, while the publication of those with unfavorable results is often delayed or given a positive "spin." This observation applies primarily to industry-sponsored trials. Our objectives are to discuss the responsibility of pharmaceutical firms to the public with respect to timely, complete, and unbiased information from all randomized clinical trials and to propose solutions for improvements. We believe that in addition to financial obligations to their shareholders, pharmaceutical companies have social responsibilities to the public and to health care providers. However, private markets do not reward or compel optimal disclosure of drug safety or inferiority information on a voluntary basis. A problem which has not previously been identified relates to non-comparability of drugs. A case report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) illustrates how public interests may be violated due to failure to inform about drug inferiority. The current system for dissemination of relevant medical information could be improved if all involved parties collaborated fully. However, full disclosure of trial results is unlikely when research results are unfavorable to the firm. We conclude that expanded government regulations will be required for a satisfactory solution to the problem

Time trends in the use of anti-hypertensive medications: Results from the Multi-Ethnic Study of Atherosclerosis

Background: Previous reports have suggested that new evidence of the comparative effectiveness of different medication classes from randomized controlled trials (RCTs) does not always alter treatment decisions for first-line anti-hypertensive therapy. Objectives: To evaluate the association of RCT evidence in December 2002 from the Anti-hypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) on use of anti-hypertensive medications in a multi-ethnic cohort. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) study, a prospective cohort study of 6814 adults from four ethnic groups, had four separate assessments of drug use. Users of anti-hypertensive medications at baseline were excluded. We evaluated temporal changes in the medication class reported by new users of anti-hypertensive medications. Results: After the exclusion of anti-hypertensive drug users at baseline, 32% of new users of anti-hypertensive drugs seen at exam 2 were prescribed a diuretic. The publication of ALLHATwas associated with a subsequent increase in the proportion of new users taking diuretics at exam 3 compared with exam 2 (relative risk (RR): 1.31; 95% confidence interval (CI): 1.09-1.59). After the report from ALLHAT, the proportion of users of diuretics seen at exam 3 rose to 44% (starting in 2004) and 39% in exam 4 (starting in 2005). This increase in the proportion of diuretic use among new users of anti-hypertensive medications declined slightly but could still be detected at exam 4 as compared to exam 2 (RR: 1.28; 95%CI: 1.04-1.57). Conclusions: The randomized trial evidence from the ALLHAT study was temporally associated with a moderate increase in diuretic use. Copyright © 2009 John Wiley & Sons, Ltd

Experience collecting interim data on mortality: an example from the RALES study

INTRODUCTION: The Randomized Aldactone Evaluation Study (RALES) randomized 822 patients to receive 25 mg spironolactone daily and 841 to receive placebo. The primary endpoint was death from all causes. Randomization began on March 24, 1995; recruitment was completed on December 31, 1996; follow-up was scheduled to continue through December 31, 1999. Evidence of a sizeable benefit on mortality emerged early in the RALES. The RALES data safety monitoring board (DSMB), which met semiannually throughout the trial, used a prespecified statistical guideline to recommend stopping for efficacy. At the DSMB's request, its meetings were preceded by an 'endpoint sweep', that is, a census of all participants to confirm their vital status. METHODS: We used computer simulation to evaluate the effect of the sweeps. RESULTS: The sweeps led to an estimated 5 to 8% increase in the number of reported deaths at the fourth and fifth interim analyses. The data crossed the statistical boundary at the fifth interim analysis. If investigators had reported all deaths within the protocol-required 24-h window, the DSMB might have recommended stopping after the fourth interim analysis. DISCUSSION: Although endpoint sweeps can cause practical problems at the clinical centers, sweeps are very useful if the intervals between patient visits or contact are long or if endpoints require adjudication by committee, reading center, or central laboratory. CONCLUSION: We recommend that trials with interim analyses institute active reporting of the primary endpoints and endpoint sweeps

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500