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

Acceptance of a Polypill Approach to Prevent Cardiovascular Disease Among a Sample of U.S. Physicians

Objective—Toex amine US physicians’ self-reported knowledge about the Polypill, factors considered in deciding whether to prescribe it, and acceptance of prescribing it for cardiovascular disease (CVD)prevention. Methods—Numerical scales of 0 (lowest) to 5 (highest) were used to assess self-reported knowledge and importance of factors relevant to making a decision to prescribe a Polypill. Characteristics of physicians indicating they would prescribe a Polypill were compared. Results—Among 952 physicians surveyed February through March 2010, mean self-rated knowledge about the Polypill was 2.0±1.5. Importance of degree of CVD event reduction, cost, and side effects were rated with means of 4.4, 4.3, and 4.3, respectively. 83% of respondents indicated they would “definitely” or “probably” prescribe it for high-risk patients; 62% would do so for moderate risk patients. Physicians with self-rated knowledge at ≥75th percentile were more likely to indicate they would prescribe a Polypill for moderate risk ( adjusted OR 2.16; 95% CI 1.60–2.93) and high-risk (adjusted OR 1.57; 95% CI 1.07–2.32) patients. Conclusion—Among this sample of physicians, there is relatively high acceptance of prescribing a Polypill for CVD prevention despite relatively modest knowledge about it

802-6 The Cost-Effectiveness of Pravastatin in Secondary Prevention of Coronary Heart Disease

To determine the cost-effectiveness of pravastatin therapy in patients with coronary heart disease, a projected risk model was developed that used the results of the three-year, double blind, placebo controlled clinical trials: Pravastatin Limitation ofAtherosclerosis in the Coronary Arteries (PLAC I) and Pravastatin, Upids and Atherosclerosis in the Carotid Arteries (PLAC II). In addition to measuring atherosclerotic progression, the PLAC studies evaluated four outcome variables: coronary heart disease death, non-coronary heart disease death, fatal myocardial infarction, and non-fatal myocardial infarction in a patient population (mean age 60 years) with established coronary heart disease and moderate low-density-lipoprotein cholesterol levels, Pooled PLAC data analysis (n=559) revealed a statistically significant (p<0.05) difference in male non-fatal myocardial infarctions between the pravastatin and placebo groups. The projected risk model utilized Framingham data to project the risk of mortality 10 years post myocardial infarction. Markov Process was used to estimate the life-years saved and cost. All costs and benefits were discounted by 5%, Results are presented in the table below:Patient Risk ProfileCost per Life-Year SavedMale with CHD + 1Additional Risk Factor$19,082Male with CHD + 2 Additional Risk Factors$14,022Male with CHD + 3 Additional Risk Factors$10,630Based on this model, pravastatin monotherapy in secondary prevention of coronary heart disease has a cost-effectiveness ratio comparable to some of the widely accepted medical interventions such as breast cancer screening,$21,700, hydrochlorothiazide in the treatment of hypertension, $16,400, and pneumococcal vaccine,$12,000

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