The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, blinded, placebo-controlled trial of the effect of 0.625 mg of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate daily on coronary heart disease (CHD) event risk among 2763 postmenopausal women with documented CHD.¹ Overall, during 4.1 years of follow-up, there were no significant differences between the hormone and placebo groups in the primary outcome of CHD events (nonfatal myocardial infarction [MI] plus CHD-related death) or in any secondary cardiovascular outcomes.^2-5 However, post-hoc analyses showed a statistically significant time trend, with more CHD events in the hormone group than in the placebo group during the first year of treatment, and fewer in years 3 to 5.² HERS investigators speculated that early increased risk might be due to a prothrombotic, proarrhythmic, or proischemic effect of treatment that is gradually outweighed by a beneficial effect on the progression of underlying atherosclerosis mediated by the observed favorable changes in low- and high-density lipoprotein cholesterol.²

There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. This scientific statement reviews current concepts of risk evaluation and proposes standards for the critical appraisal of risk assessment methods. An adequate evaluation of a novel risk marker requires a sound research design, a representative at-risk population, and an adequate number of outcome events. Studies of a novel marker should report the degree to which it adds to the prognostic information provided by standard risk markers. No single statistical measure provides all the information needed to assess a novel marker, so measures of both discrimination and accuracy should be reported. The clinical value of a marker should be assessed by its effect on patient management and outcomes. In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.