The ISCHEMIA Trial

On November 16, 2019, the article, “ISCHEMIA: Invasive Strategy No Better Than Meds for CV Events," was published in TCTMD. The story highlights a presentation from the 2019 American Heart Association Scientific Sessions that showed patients with severe but stable ischemic heart disease who underwent routine procedures like stent implantation or bypass surgery didn’t fare better in the long-term than those who received optimal medical therapy and lifestyle advice alone.

Dr. Thomas E. MacGillivray describes the article, what it means for the cardiothoracic surgery specialty, and his view on the topic of lifestyle changes and medications vs. stents or bypass surgery.

The ISCHEMIA Trial

The clinical outcomes of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial was presented at the 2019 Scientific Sessions of the American Heart Association. The ISCHEMIA trial is the largest randomized controlled trial comparing optimal medical therapy vs. optimal medical therapy plus invasive evaluation and revascularization in patients with stable ischemic heart disease. The study addressed whether, in addition to optimal medical therapy, there was benefit to invasive coronary angiography and “if feasible,” revascularization in patients with stable ischemic disease and at least moderate ischemia on stress testing or stress imaging.

Of 8,518 patients who underwent blinded coronary computed tomography angiography (CCTA) to identify at least one major epicardial coronary artery with at least 50% stenosis, 3,339 were excluded as screening failures (insufficient ischemia, unprotected left main coronary artery stenosis ≥ 50%, or no obstructive coronary disease). The remaining 5,179 patients were randomized into two groups: a conservative (CON) cohort (n=2,591) managed with optimal medical therapy (OMT), reserving coronary angiography for OMT failure, and an invasive (INV) cohort (n=2,588), managed with OMT plus coronary angiography plus optimal revascularization.

The primary endpoint was a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, heart failure, or resuscitation from cardiac arrest.  Secondary endpoints were time to cardiovascular death or myocardial infarction. While 95% of the patients in the INV cohort had coronary angiography, approximately 20% of them did undergo revascularization due to not having significant enough disease (67%) or disease that was too extensive and “unsuitable” for revascularization by PCI or CABG (33%). In the CON cohort, 28% ultimately had coronary angiography and 23% of them underwent revascularization during the study period. Median time to follow-up was 3.3 years with greater than 99% completion follow up in each group.

The major finding of the ISCHEMIA trial was that an initial conservative strategy of optimal medical therapy was as effective as the invasive strategy. At 6 months, conservative therapy appeared more favorable; whereas at 4 years, the invasive strategy looked better. The curves for the primary and major secondary endpoints crossed at the 2-year time point. The incidence of myocardial infarctions was similar in both groups, but procedural myocardial infarctions were higher in the INV group and spontaneous myocardial infarctions were higher in the CON group.

From the perspective of a cardiac surgeon, the findings of the ISCHEMIA trial do not add any new or disruptive information. This trial reinforces the well-established recommendation that optimal medical therapy is effective treatment for many patients with stable ischemic heart disease even with severe ischemia on stress testing. The ISCHEMIA trial does not negate or even contradict the multiple previous clinical trials demonstrating the superiority of surgical revascularization over medical therapy (or PCI) in patients with specific anatomic patterns of coronary artery disease. Of note, the ISCHEMIA trial excluded from enrollment patients with evidence-based benefit for revascularization including: significant left main disease, multi-vessel disease with severely impaired left ventricular function, ischemic heart failure, acute coronary syndromes, and unstable angina.

The trial included stable patients with at least a 50% stenosis on CCTA in one major epicardial vessel, the majority of which would not have met evidenced-based guidelines for surgical revascularization. Less than half of the patients had three-vessel coronary artery disease. Although 87% of the patients had disease in the left anterior descending artery (LAD), less than half of the patients had proximal LAD disease. Perhaps these findings explain why the majority (74%) of the patients who underwent revascularization received PCI rather than CABG. Although analyzed in this study as the same treatment, CABG vs. PCI are distinctly different interventions with demonstratively different outcomes.

The ISCHEMIA trial does not negate or even contradict the multiple previous clinical trials demonstrating the superiority of surgical revascularization over medical therapy (or PCI) in patients with specific anatomic patterns of coronary artery disease.

Thomas E. MacGillivray, MD

The conclusion of the ISCHEMIA trial implies that the two randomized groups received distinctly different treatments yet there were a large number of crossovers. That is, 20% of patients in the INV group did not undergo revascularization, and 23% of the patients in the CON group underwent revascularization in addition to OMT. This reflects the real world practice that optimal medical therapy and coronary revascularization are complementary rather than competitive management strategies.

In large trials, composite endpoints can be statistically clear yet clinically opaque. These data points, like the disease, may potentially progress over time. Perhaps with longer follow-up the conclusions will be different. In the meantime, the appropriate management of coronary artery disease continues to be optimal medical therapy with appropriate utilization of evidenced-based guidelines for revascularization.


 

Thomas E. MacGillivray, MD, is the Chief of Cardiac Surgery and Thoracic Transplant Surgery, as well as the Jimmy Howell Endowed Chair in Cardiovascular Surgery, at Houston Methodist Hospital.