Nonfatal Outcomes in the Primary Prevention of Atherosclerotic Cardiovascular Disease
Is All-Cause Mortality Really All That Matters?
There is considerable debate in the literature regarding appropriate end points for studies of primary prevention of atherosclerotic cardiovascular disease (ASCVD), most notably with regard to statin therapy for hypercholesterolemia. Some authors have argued that large clinical trials of primary prevention interventions must demonstrate an overall mortality benefit1,2 or a combined overall mortality and serious morbidity benefit.3 Others feel that such a high bar would lead to the erroneous dismissal of several beneficial strategies that can substantially decrease incident ASCVD.2,4
Although several meta-analyses have now shown a modest mortality benefit of statins in primary prevention,5–8 the debate will undoubtedly be rekindled with the recent revision of the American College of Cardiology Foundation/American Heart Association (ACC/AHA) guidelines for the treatment of hypercholesterolemia.9 In this article, we advocate for the importance of nonfatal cardiovascular outcomes (nonfatal myocardial infarction [MI], nonfatal stroke, and peripheral arterial disease) in the assessment of ASCVD primary prevention strategies, illustrate this principle already in use in the management of hypertension, and advocate for the relevance of both nonfatal and fatal ASCVD events in the treatment of hypercholesterolemia in the primary prevention setting.
The definition of benefit in the primary prevention of clinical ASCVD has recently been debated. Some authors suggest that an improvement in total mortality, of which cardiac death is only one part, is the only relevant benefit.1,2 Prasad and Vandross1 refer to examples of medications that improve surrogate end points but subsequently fail to improve overall survival, such as fibrates and niacin in certain patient populations. Importantly, no distinction is made between clinical, nonmortality end points (eg, nonfatal MI and stroke) and surrogate markers of clinical ASCVD risk (eg, low-density lipoprotein-cholesterol). This line of reasoning suggests that nonmortality end points are …