Abstract and Introduction
Abstract
Background The COURAGE trial reported similar clinical outcomes for patients with stable ischemic heart disease (SIHD) receiving optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI). The current post hoc substudy analysis examined the relationship between baseline stress myocardial ischemia and clinical outcomes based on randomized treatment assignment.
Methods A total of 1,381 randomized patients (OMT n = 699, PCI + OMT n = 682) underwent baseline stress myocardial perfusion single-photon emission computed tomographic imaging. Site investigators interpreted the extent of ischemia by the number of ischemic segments using a 6-segment myocardial model. Patients were divided into those with no to mild (<3 ischemic segments) and moderate to severe ischemia (≥3 ischemic segments). Cox proportional hazards models were calculated to assess time to the primary end point of death or myocardial infarction.
Results At baseline, moderate to severe ischemia occurred in more than one-quarter of patients (n = 468), and the incidence was comparable in both treatment groups (P = .36). The primary end point, death or myocardial infarction, was similar in the OMT and PCI + OMT treatment groups for no to mild (18% and 19%, P = .92) and moderate to severe ischemia (19% and 22%, P = .53, interaction P value = .65). There was no gradient increase in events for the overall cohort with the extent of ischemia.
Conclusions From the COURAGE trial post hoc substudy, the extent of site-defined ischemia did not predict adverse events and did not alter treatment effectiveness. Currently, evidence supports equipoise as to whether the extent and severity of ischemia impact on therapeutic effectiveness.
Introduction
The management of chronic angina and stable ischemic heart disease (SIHD) has been the focus of considerable controversy with recent randomized, controlled trials reporting that optimal medical therapy (OMT) as an initial strategy was equally effective as OMT combined with prompt coronary revascularization. The COURAGE trial reported no difference in the primary end point of death from all causes or nonfatal myocardial infarction (MI) for patients with SIHD randomized to OMT with or without percutaneous coronary intervention (PCI). Five-year death or MI rates were 18.5% and 19% for those receiving OMT alone and PCI + OMT (P = .62). These results in the setting of SIHD were discordant with acute coronary syndrome trials reporting a clinical advantage from interventional as compared with conservative management strategies. Although many have posited reasons for the lack of added benefit from PCI in the COURAGE trial, multiple secondary analyses to date have failed to identify any patient subset that benefited from revascularization.
Eligibility criteria for the COURAGE trial included minimum standards for objective evidence of ischemia (eg, new-onset resting ST-T wave changes, ≥1 mm exercise-induced ST-segment changes, or an ischemic imaging defect). In large observational series, cardiac risk increases proportionately with the extent and severity of stress-induced ischemia and, in the setting of moderate to severe ischemia, an elevated hazard for death in patients treated medically when compared with coronary revascularization (P < .0001). The COURAGE nuclear substudies included an aim to explore the effectiveness of PCI + OMT when compared with OMT in patients with severe and extensive ischemia. The current analysis included a post hoc analysis of differences in clinical outcomes by randomized treatment based on the extent and severity of prerandomization myocardial ischemia and was defined as substudy 0. Preliminary analysis of these results incorrectly reported a significant probability value with regard to worsening survival for OMT patients as compared with PCI + OMT for those with moderate to severe ischemia. Programming errors in terms of concatenating files as well as in variable list selection resulted in an incorrect coding of the variable moderate to severe ischemia. The current results have been approved for submission by the COURAGE data safety monitoring board after independent review of the results.