Navarese et al’s meta-analysis of elective coronary revascularization and medical therapy versus medical therapy alone was recently published in the European Heart Journal.
This is an area of great controversy because there is evidence that revascularization does not improve prognosis in stable coronary artery disease. Naturally, the revascularization industry is disappointed by this. Revascularization did not reduce myocardial infarction and death in the COURAGE or ISCHEMIA trials. Navarese et al’s meta-analysis of 25 trials didn’t find a reduction in these outcomes with revascularization either. Nor did Chacko et al’s 2020 meta-analysis. If the case wasn’t closed after ISCHEMIA, surely it should be now.
Or should it? Navarese et al found, “In stable coronary artery disease patients, randomisation to elective coronary revascularisation plus medical therapy led to reduced cardiac mortality compared with medical therapy alone. The cardiac survival benefit after revascularisation improved with longer follow-up times and was associated with fewer spontaneous MIs.”
Why is the message so different? Is there truly a glimmer of hope that revascularization might have advantages over medical therapy alone?
The primary endpoint of the new meta-analysis was cardiac death. The finding of a reduction in cardiac death with a rate ratio of 0.79 (95% CI 0.67–0.93) was shown to be robust (i.e. consistent even when certain categories of trials were removed e.g. post-ACS). The meta-analysis appears to have been well-conducted.
However, it is more usual to consider all-cause mortality or all-cause mortality and myocardial infarction. To recommend a therapy as having prognostic value, the therapy needs to be shown to reduce all-cause mortality, not just disease-specific mortality. This distinction is important because it is easily possible to reduce disease-specific mortality whilst increasing mortality from other conditions, or having an overall null effect on mortality. Clinically, what matters is that death has happened. Disease-specific mortality is worth measuring but only as a secondary endpoint to explore how the therapy is reducing mortality.
Not all trials can assess for mortality benefit because the nature of the disease and the therapy might mean the trial would need to be too long to be feasible. In that situation the primary endpoint can be a composite of all-cause mortality and events that signify poor prognosis or disease progression. In the case of coronary artery disease the best event to look at is myocardial infarction because it is objective and clearly associated with worse outcomes. Admissions for unstable angina and heart failure are less objective (especially in unblinded trials) but are also fair game for inclusion in a composite primary endpoint as they are associated with worse outcomes and are indicative that the patient has started to experience complications of the disease. By itself cardiac death isn’t enough. The absence of an overall benefit for all-cause mortality and myocardial infarction strongly suggests that the therapy isn’t working as intended.
Navarese et al state that “Recommendations for medical therapy alone based on trials with limited follow-up have likely underestimated the benefits of revascularisation plus medical therapy.” This seems like wishful thinking to me. The benefits we need to be seeing (reduced death and MI) just aren’t there.