Surrogate outcomes are frequently used in cardiovascular disease research. A concern is that changes in surrogate markers may not reflect changes in disease outcomes. Two recent clinical trials (Heart and Estrogen/Progestin Replacement Study [HERS], and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]) underscore this problem since their results contradicted what was expected based on the surrogate outcomes. The current regulatory policy to allow new therapies to be introduced onto the market based solely on surrogate outcomes may need to be reviewed.

In one of the biggest dilemmas facing cardiovascular clinical research, clinical trials are increasingly being required to show benefits on clinical end-points rather than surrogate end-points, while at the same time the incremental benefits of newer treatments are getting smaller. These two factors have a huge impact on sample size, which has led some investigators to design trials to show that the new treatment has an effect similar to that of the standard, rather than outright superiority. Recent examples of fibrinolytic trials that have demonstrated similar effects of two drugs are ASSENT (Assessment of the Safety and Efficacy of a New Thrombolytic)-2, GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-III, and COBALT (Continuous Infusion Versus Double-Bolus Administration of Alteplase) [1,2,3,4]. However, as discussed by several authors [5,6,7,8], there are issues with trials of this type that make them considerably less credible than superiority trials.

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.

The present review assesses the data on long-term outcome after coronary stenting. Histological, angiographical and intravascular imaging data have shown that the insertion of stents constitutes only a transient stimulus to lumen renarrowing, that this process is almost complete at 6 months and that a certain degree of neointima regression is also possible after this time. Clinical data have confirmed the sustained benefit of stenting in the long term. Careful selection of optimal stent designs and application of the recent advances in adjunctive pharmacological therapy are currently effective strategies to improve both short-and long-term results with coronary stenting. However, further efforts are needed and are ongoing to combat restenosis, a process that counters the excellent short-term results of stenting in the long term.

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is a prospective, randomized, multicenter clinical trial of carotid endarterectomy (CEA) versus carotid artery stenting (CAS) as prevention for stroke in patients with symptomatic stenosis greater than or equal to 50%. CREST is sponsored by the US National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (NIH), with additional support by a device manufacturer, and will provide data to the US Food and Drug Administration (FDA) for evaluation of a stent device. Because of budget constraints for CREST, Health Care Financing Administration (HCFA) reimbursement for hospital costs incurred by CREST patients will be essential. The involvement of academic scientists, industry, and three separate government agencies (NIH, FDA, HCFA) has presented many challenges in conducting the trial. A review of the pathways followed to meet these challenges may be helpful to others seeking to facilitate sharing of the costs and burdens of conducting innovative clinical research.

Statins reduce mortality of patients with coronary artery disease (CAD). However, by protocol, trials have excluded patients with chronic heart failure. Since the prevalent etiology of heart failure is CAD, preventing CAD may prevent heart failure progression. Statins may have other beneficial effects besides cholesterol lowering, such as anti-inflammatory properties and improvement of endothelial function. On the contrary, high levels of cholesterol can be beneficial in heart failure patients on the basis of the ability of serum lipoproteins to modulate inflammatory response. Furthermore, statins affecting mitochondrial function can have a deleterious effect on skeletal or cardiac muscles. Despite all these conflicting data, there is no evidence from trials on the effects of statins in patients with heart failure. For this reason, the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) investigators planned a controlled trial testing the effect of statins in patients with heart failure of different etiology.

The publication of the results of the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) and the termination of the doxazocin arm of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) study again raise the question of whether all antihypertensives deliver equal cardiovascular outcome benefits. Data from research on congestive heart failure and from the Heart Outcomes Prevention Evaluation (HOPE) trial illuminate the roles and possible mechanisms of humoral mediators of vascular damage, suggesting, first, that some antihypertensives (thiazides, beta-blockers, and angiotensin-converting enzyme inhibitors) can deliver more improvement in outcomes than other agents and, second, that decisions on whom to treat are best made based on risk appraisal, not merely pressures.

Clinical trialists and statisticians are very wary of subgroup analysis, for good reasons. Clinicians have to deal with situations in which subgroups of patients differ widely from one another in their prognosis and response to treatment. Few trials are large enough to demonstrate convincingly these differences in outcome, but often provide suggestive evidence. Should we ignore this and treat all patients as the same, or should we allow dubious statistical evidence to buttress biological plausibility in making clinical decisions?

Postmenopausal hormone replacement therapy (HRT) with oral oestrogen was predicted to reduce coronary heart disease (CHD) risk by 50%. Randomized controlled trials show no such benefit, however, pointing instead to an initial increase in CHD events. Although the cardiovascular effects of transdermal HRT are largely unknown, improvements in arterial function are maintained when oestrogen is administered transdermally. Transdermal HRT also avoids the increased plasma levels of C-reactive protein (CRP) that are seen with oral HRT. However, the clinical significance of this general reduction in hepatic over-synthesis of plasma proteins is difficult to assess. Nevertheless, the available evidence on transdermal HRT appears to justify a formal clinical trial.

Background Clinical events committees (CEC) are used routinely to adjudicate suspected end-points in cardiovascular trials, but little information has been published about the various processes used. We reviewed results of the CEC process used to identify and adjudicate suspected end-point (post-enrolment) myocardial infarction (MI) in the large Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial. Methods The PURSUIT trial randomised 10,948 patients with acute coronary syndromes to receive eptifibatide or placebo. A central adjudication process was established prospectively to identify all suspected MIs and adjudicate events based on protocol definitions of MI. Suspected MIs were identified by systematic review of data collection forms, cardiac enzyme results, and electrocardiograms. Two physicians independently reviewed all suspected events. If they disagreed whether a MI had occurred, a committee of cardiologists adjudicated the case. Results The CEC identified 5005 patients with suspected infarction (46%), of which 1415 (28%) were adjudicated as end-point infarctions. As expected, the process identified more end-point events than did the site investigators. Absolute and relative treatment effects of eptifibatide were smaller when using CEC-determined MI rates rather than site investigator-determined rates. The site-investigator reporting of MI and the CEC assessment of MI disagreed in 20% of the cases reviewed by the CEC. Conclusions End-point adjudication by a CEC is important, to provide standardised, systematic, independent, and unbiased assessment of end-points, particularly in trials that span geographic regions and clinical practice settings. Understanding the CEC process used is important in the interpretation of trial results and event rates.