ISCHEMIA Data Offer More Questions Than Answers for Patients With Stable Angina

The ISCHEMIA trial was the final nail in the coffin for revascularization in most patients with stable coronary disease.¹ Or was it? A prespecified analysis from the study indicated that complete revascularization in the trial’s invasive arm may have shown greater benefit than conservative medical therapy.²

Researchers randomized 5179 patients with stable coronary disease and at least moderate ischemia without significant left main disease, heart failure with reduced ejection fraction, or New York Heart Association class III-IV heart failure to receive either an initial invasive strategy (INV; angiography and revascularization) or conservative medical therapy (CON). Importantly, patients with an unacceptable level of angina were excluded.

The INV group received percutaneous coronary revascularization (PCI; 74%) or coronary artery bypass grafting (CABG; 26%). Over a median of 3.2 years, there was no difference in the primary composite end point of cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest through up to 5 years of follow-up. Notably, nearly a quarter (21%) of patients in the CON group underwent revascularization prior to a primary outcome event. The ISCHEMIA-EXTENDED study compared mortality outcomes through a median follow-up of 5.7 years, finding reduced cardiovascular mortality in the INV group counterbalanced by increased noncardiovascular mortality in the CON group, yielding no difference in all-cause mortality.

Not all patients in the INV group received the same degree of revascularization. The COMPLETE trial previously showed that patients with ST-elevation myocardial infarction and multivessel coronary artery disease who had undergone successful culprit-lesion PCI and were randomized to staged PCI of angiographically significant non-culprit lesions for complete revascularization had improved outcomes compared with patients who did not receive complete revascularization (26% reduction in cardiovascular death or MI; 49% reduction in cardiovascular death, MI, or ischemia-driven revascularization over a median of 3 years of follow-up).³

More recently, the FIRE trial showed that the benefit of complete revascularization extends to older patients (age, ≥75 years) presenting with MI who received physiologically indicated non-culprit lesion PCI without excess procedural risk (27% reduction in death, MI, stroke, or any revascularization at 1 year; 36% reduction in cardiovascular death or MI).⁴ Taken together, these data indicate a clear benefit of complete revascularization in the setting of acute coronary syndrome, but the value in stable coronary disease had been untested until now.

In a recent issue of the Journal of the American College of Cardiology, Stone et al presented the ISCHEMIA Completeness of Revascularization study, a prespecified analysis from the ISCHEMIA trial testing the predicted value of complete revascularization for the treatment of chronic coronary disease.⁵ They analyzed outcomes for anatomic complete revascularization (ACR) and functional complete revascularization (FCR) compared with incomplete revascularization for those in the INV arm, as well as the predicted outcomes if all patients in the INV arm had received complete revascularization.

Based on independent core laboratory adjudication of complete revascularization using quantitative coronary angiography, researchers determined that ACR and FCR were achieved in 43.4% and 58.4% of evaluable patients in the INV arm. Those with prior CABG or missing information were excluded. Critically, patients with less extensive coronary disease were more likely to have received complete revascularization. Unadjusted comparisons showed that patients receiving ACR or FCR had lower rates of the prespecified primary end point of cardiovascular death or MI compared with those who had received incomplete revascularization (ACR: hazard ratio [HR], 0.60; 95% CI, 0.44-0.83; FCR: HR, 0.67; 95% CI, 0.50-0.91). However, after adjusting for clearly relevant variables like disease complexity, these differences became statistically insignificant.

Despite the lack of statistically significant outcomes in differences between complete and incomplete revascularization, the analysis proceeded to extrapolate what the results of the main ISCHEMIA trial would have been if all patients in the INV arm had received complete revascularization based on inverse probability weighted modeling. The 4-year rate of cardiovascular death or MI for the INV group versus the CON group would have been −3.5% (95% CI, −7.2% to 0.0%) if all INV patients had received ACR and −2.7% (95% CI, −5.9% to 0.3%) if all INV patient had received FCR. Neither result would have been statistically significant.

Overall, approximately half of the INV cohort received complete revascularization. There were trends toward greater benefit for complete versus incomplete revascularization, as well as for the predicted outcomes if all INV patients in the ISCHEMIA trial had received complete revascularization, though these results were not significant. This outcome may have been due to insufficient statistical power. Alternatively, these results may reflect that patients with less complex coronary disease (eg, patients who are likely to have worse outcomes) were more likely to get complete revascularization. It seems plausible that complete revascularization may truly yield greater benefit in patients with stable coronary disease, but this notion remains hypothetical. This question is ripe for the next major randomized, controlled trial for the management of stable angina.

References:

1. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med. 2020;382:1395-1407. doi:10.1056/NEJMoa1915922
2. Stone GW, Ali ZA, O’Brien SM, et al. Impact of complete revascularization in the ISCHEMIA trial. J Am Coll Cardiol. 2023;82(12):1175-1188. doi:10.1016/j.jacc.2023.06.015
3. Mehta SR, Wood DA, Storey RF, et al. Complete revascularization with multivessel PCI for myocardial infarction. N Engl J Med. 2019;381(15):1411-1421. doi:10.1056/NEJMoa1907775
4. Biscaglia S, Guiducci V, Escaned J, et al; FIRE trial investigators. Complete or culprit-only PCI in older patients with myocardial infarction. N Engl J Med. 2023;389:889-898. doi:10.1056/NEJMoa2300468