The EPWG evaluated each of these possible additional primary endpoints in detail. These deliberations are summarized in , with particular attention to how each endpoint might meet the five criteria listed above.
Summary of EPWG deliberations regarding full range of possible endpoints
This deliberation led the EPWG to narrow the range of potentially acceptable endpoints to four: all-cause mortality, hospitalized angina, urgent revascularization, and hospitalized CHF. The rationale for excluding other endpoints was as follows: (1) Incident CKD, as defined by using serum creatinine to estimate glomerular filtration rate, was considered to have insufficient clinical importance; (2) cancer was too incongruent with our original endpoints and the evidence to determine which cancers are ‘obesity related’ was still unsettled; (3) LVH is primarily asymptomatic and suffers from disagreement about definition; (4) deep venous thrombosis/pulmonary embolism has a wide range of gravitas, is less related to atherosclerosis than are other vascular endpoints, and has not been widely used in trials or epidemiologic studies as part of a composite vascular endpoint; and (5) fractures have a wide range of severity and are inversely associated with body mass index.
Thus, the EPWG carefully considered the four remaining endpoints: all-cause mortality, hospitalized angina, urgent revascularization, and hospitalized CHF. These were reduced to three when the EPWG determined that virtually all of the urgent revascularizations in Look AHEAD occurred in participants who otherwise met criteria for hospitalized angina. The deliberations regarding all-cause mortality, hospitalized angina, and hospitalized CHF are summarized below.
The argument in favor was that all-cause mortality is the bottom line for patients and physicians and would provide a way to capture effects on important non-CVD events, like cancer or liver disease. The argument against was that (1) these non-CVD events are best treated as secondary endpoints, since the primary hypothesis focuses on CVD per se, and (2) all-cause mortality may introduce ‘noise’ in the form of accidental deaths and nonobesity-related cancers (e.g., brain and lung).
The argument in favor was that hospitalized angina would capture the ‘aborted’ myocardial infarctions related to secular improvements in acute cardiac care; would be consistent in tone, therefore, with recent thinking on CVD endpoints (see Luepker et al
]); and is fully congruent with the original hypothesis. The argument against was that (1) it might be difficult to distinguish ‘urgent’ cases from ‘chronic’ cases, the latter of which would be susceptible to ascertainment bias in an unblinded study, and (2) it might be difficult to agree upon a specific definition. However, the current Look AHEAD definition of hospitalized angina (see ) mitigated both concerns: the definition clearly excluded chronic stable angina and the definition had already been smoothly implemented by the Adjudication Committee for several years without generating significant disagreements among committee members.
The argument in favor was that CHF is common and important, it was already a component of the composite secondary endpoint, and it might be improved by weight loss along a variety of physiologic pathways (e.g., better exercise tolerance, reduced reliance on thiazolidinediones, and improved lung function). The argument against was that (1) CHF is a heterogenous syndrome related not only to atherosclerosis but also to hypertension, renal disease, and other causes (e.g., valvular heart disease) generally not discernable from the records available to the study adjudicators, and (2) it is often difficult to distinguish from other causes of acute dyspnea, especially chronic obstructive pulmonary disease and pneumonia.
After deliberation, the EPWG unanimously favored hospitalized angina and unanimously rejected hospitalized CHF. A large majority was against all-cause mortality, but a minority favored it. Further discussion led to a consensus that the additional primary endpoint plus all-cause mortality should be an additional major secondary analysis in the main results of this study.