Ventricular remodeling in heart failure: a credible surrogate endpoint.

In heart failure, as in other syndromes of cardiovascular disease, we have seen substantial gain from drug therapy. Clinical trials conducted in thousands of patients with such agents as angiotensin converting enzyme (ACE) inhibitors, beta receptor blockers, and aldosterone receptor blockers have succeeded in demonstrating incremental benefits on clinically relevant endpoints, particularly survival and freedom from hospitalization for heart failure. Although morbidity and mortality rates remain substantial in patients with clinical heart failure and/or left ventricular (LV) dilation, in the setting of clinical trials a remarkable reduction in all cause mortality is being observed. The diminishing rates of these events in sequential trials, has therefore mandated progressively larger sample sizes to display benefit from the next therapeutic agent. Regulatory agencies, and to a lesser extent clinicians, have favored endpoints of obvious clinical benefit to the patient. The term surrogate is applied to an endpoint without direct importance to the patient, but one that is biologically relevant and shows a strong and consistent relationship with clinical benefit. Drug-induced decreases in blood pressure and in serum cholesterol concentration represent 2 surrogate endpoints, for which linkage with clinical benefit has been convincing enough to permit acceptance of a reduction by a given therapy as sufficient evidence for advocating that therapy’s clinical use. Should a drug’s effect on ventricular remodeling be considered a third such surrogate? Indeed, blood pressure and cholesterol are merely statistically associated with (though causally linked to) the disease, whereas structural remodeling may be the disease itself. The term ventricular remodeling refers to deviation in ventricular architecture from normal, with changes in

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