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Trials  2000 

Debate: The slippery slope of surrogate outcomes

DOI: 10.1186/cvm-1-2-076

Keywords: antihypertensive therapy, cardiovascular disease, clinical trials, surrogate outcomes

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Abstract:

There has been growing literature in recent years questioning the use of surrogate outcomes in medical research [3,4,5].Two major randomized clinical trials, HERS [6] and ALLHAT [7], have underscored the fallacy of surrogate outcomes. The first question one must address is: What is a 'surrogate outcome'? A classic definition is provided by Temple [8]: "A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint."However, drugs have multiple effects that are often not reflected by a surrogate measure, which is especially true for safety problems. In the HERS [6] study, for instance, the women receiving the active treatment (estrogen-progestin) had significantly more thromboembolic events than those patients on placebo (relative hazard [RH]=2.89, 95% confidence interval [CI] = 1.50-5.58; P = 0.002). This adverse drug effect is unrelated to the 'favorable' hormone effect on lipoprotein levels, generally thought of as a surrogate for a reduction in coronary events.Let us consider some of the reasons why surrogates should or should not be employed in cardiovascular medicine. In a perfect world, more information is clearly better than less. Understanding and measuring the true relationship between any therapy, on the one hand, and mechanistically and clinically meaningful endpoints, on the other, would thus be the natural goal of research. Measuring surrogate outcomes in addition to clinically meaningful endpoints would be quite useful in such studies. Having both surrogate outcomes and clinically meaningful disease outcomes measured on the same individuals may allow one to understand better the underlying pathophysiology.So why would one suggest measuring the surrogate outcome and not the clinically me

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