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

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

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

Prescription Drugs Associated with Reports of Violence Towards Others

CONTEXT: Violence towards others is a seldom-studied adverse drug event and an atypical one because the risk of injury extends to others. OBJECTIVE: To identify the primary suspects in adverse drug event reports describing thoughts or acts of violence towards others, and assess the strength of the association. METHODOLOGY: From the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we extracted all serious adverse event reports for drugs with 200 or more cases received from 2004 through September 2009. We identified any case report indicating homicide, homicidal ideation, physical assault, physical abuse or violence related symptoms. MAIN OUTCOME MEASURES: Disproportionality in reporting was defined as a) 5 or more violence case reports, b) at least twice the number of reports expected given the volume of overall reports for that drug, c) a χ2 statistic indicating the violence cases were unlikely to have occurred by chance (p<0.01). RESULTS: We identified 1527 cases of violence disproportionally reported for 31 drugs. Primary suspect drugs included varenicline (an aid to smoking cessation), 11 antidepressants, 6 sedative/hypnotics and 3 drugs for attention deficit hyperactivity disorder. The evidence of an association was weaker and mixed for antipsychotic drugs and absent for all but 1 anticonvulsant/mood stabilizer. Two or fewer violence cases were reported for 435/484 (84.7%) of all evaluable drugs suggesting that an association with this adverse event is unlikely for these drugs. CONCLUSIONS: Acts of violence towards others are a genuine and serious adverse drug event associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and antidepressants with serotonergic effects were the most strongly and consistently implicated drugs. Prospective studies to evaluate systematically this side effect are needed to establish the incidence, confirm differences among drugs and identify additional common features

The causal exposure model of vascular disease

Primary prevention of cardiovascular disease is governed at present by the risk factor model for cardiovascular events, a model which is widely accepted by physicians and professional associations, but which has important limitations: most critically, that effective treatment to reduce arterial damage is often delayed until the age at which cardiovascular events become common. This delay means that many of the early victims of vascular disease will not be identified in time. This delay also allows atherosclerosis to develop and progress unchecked within the arterial tree with the result that the absolute effectiveness of preventive therapy is limited by the time it is eventually initiated. The causal exposure model of vascular disease is an alternative to the risk factor model for cardiovascular events. Whereas the risk factor model aims to identify and treat those at markedly increased risk of vascular events within the next decade, the causal exposure model of vascular disease aims to prevent events by treating the causes of the disease when they are identified. In the risk factor model, age is an independent non-modifiable risk factor and the predictive power of age far outweighs that of the other risk factors. In the causal exposure model, age is the duration of time the arterial wall is exposed to the causes of atherosclerosis: apoB (apolipoprotein B) lipoproteins, hypertension, diabetes and smoking. Preventing the development of advanced atherosclerotic lesions by treating the causes of vascular disease is the simplest, surest and most effective way to prevent clinical events

A Polypill for primary prevention of cardiovascular disease: A feasibility study of the World Health Organization

<p>Abstract</p> <p>Background</p> <p>The feasibility of conducting a large-scale Polypill clinical trial in developing countries remains unclear. More information is needed regarding the efficacy in reducing the risk factors of cardiovascular disease (CVD), side effects, improvement in adherence and physician/patient "acceptability" of the Polypill.</p> <p>Methods</p> <p>We conducted an open-label, parallel-group, randomized clinical trial involving three sites in Sri Lanka that enrolled a total of 216 patients without established CVD. The trial compared a Polypill (75 mg aspirin, 20 mg simvastatin, 10 mg lisinopril and 12.5 mg hydrochlorothiazide) to Standard Practice. After randomization, patients were followed monthly for three months. Pre-specified primary outcomes included reduction in systolic blood pressure, total cholesterol and estimated 10-year CVD risk. We also evaluated the recruitment process and acceptability of the Polypill by both physicians and patients.</p> <p>Results</p> <p>Patients were recruited in a six-month period as planned. Two hundred three patients (94.0%) completed the treatment program and returned for their three-month follow-up visits. No safety concerns were reported. These findings suggest a high rate of patient acceptability, a finding that is bolstered by the majority of patients completing the trial (90%) indicating that they would take the Polypill "for life" if proven to be effective in reducing CVD risk. Approximately 86% of the physicians surveyed agreed with and supported use of the Polypill for primary prevention and 93% for secondary prevention of CVD. Both the Polypill and Standard Practice resulted in marked reductions in systolic blood pressure, total cholesterol and 10-year risk of CVD. However, the differences between the treatment groups were not statistically significant.</p> <p>Conclusions</p> <p>We successfully completed a Polypill feasibility trial in Sri Lanka. We were able to document high acceptability of the Polypill to patients and physicians. We were unable to estimate the risk factor reductions on the Polypill because the control group received similar treatment with individual drugs. The Polypill was however simpler and achieved comparable risk factor reductions, highlighting its potential usefulness in the prevention of CVD.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/NCT00567307">NCT00567307</a></p