“Initial Invasive or Conservative Strategy for Stable Coronary Disease“
Maron DJ, Hochman JS, Reynolds HR, et al. for the ISCHEMIA Research Group.
N Engl J Med. 2020 Apr 9;382(15):1395-1407. [Full Text]
Summary by Ilan Vavilin
Prior to the ISCHEMIA trial, the COURAGE trial showed that revascularization of patients with ischemia from stable coronary disease did not decrease mortality or prevent future myocardial infarctions. However, the COURAGE trial was criticized because patients were not enrolled in the trial until after their coronary anatomy was known. This raised the possibility that patients with the high degree of stenosis would not be referred to the trial due to concern with not revascularizing these perceived higher risk patients.
The ISCHEMIA trial was a multi-center, parallel, randomized trial of patients with moderate to severe ischemia that sought out to assess optimal medical therapy alone vs optimal medical therapy in addition to cardiac catheterization +/- revascularization.
A total of 5179 patients underwent randomization. Those eligible who ere over the age of 21 with moderate to severe ischemia defined as
- ≥10% LV ischemia on nuclear imaging
- ≥3 segments hypokinesis or akinesia on ECHO
- CMR Perfusion ≥12% ischemia and/or ≥ 3 segments with hypokinesis or akinesia, or
- Exercise Tolerance Testing (ETT) with ≥1.5mm ST depression in ≥2 leads or a single ≥2mm ST depression at ≤ 7 METS with angina.
Patients with NYHA Class III-IV Heart Failure, unacceptable angina despite medical therapy, LVEF <35%, acute coronary syndrome within 2 months, PCI or CABG within 1 year, eGFR <30mL/min, and ³ 50% stenosis in unprotected left main coronary artery were excluded.
The median age was 64 with a Caucasian male predominance. 73% of the population had hypertension, 42% had diabetes mellitus, 20% had prior myocardial infarction, and 4% had heart failure. 90% of the patients had a history of angina with approximately 26% of patients developing the angina within 3 months of enrollment.
Optimal medical therapy consisted of “intensive secondary prevention with lifestyle and pharmacologic interventions applied equally in both groups with the use of treat-to target algorithms (Table S3)”. The invasive strategy group underwent angiography within 30 days and revascularization was guided by fractional flow
algorithms (Fig. S3a and S3b).
The primary outcome was the composite of death from cardiovascular causes, myocardial infarction (spontaneous infarction based on Third Universal Definition of Myocardial Infarction types 1 and 2), hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.
Key secondary outcomes were the composite of death from cardiovascular causes or myocardial infarction (MI, defined as peri-procedural infarction types 4 a,b,c and 5) and angina-related quality of life.
Over the median 3.2 years of follow-up, the primary outcome occurred in 318 patients in the invasive arm and 352 patients in the conservative arm with an estimated HR 0.93 [95% CI 0.80-1.08; P=0.34].
Overall the secondary outcome of cardiovascular death or MI occurred in 276 patients in the invasive arm and 314 in the conservative arm with an estimated HR 1.05 [95% CI 0.82 to 1.32, P=0.21]. At 6 months, this secondary outcome occurred with an event rate was 4.8% in the invasive-strategy group and 2.9% the conservative-strategy group (difference, 1.9 percentage points; 95% CI, 0.9 to 3.0). At 5 years, the cumulative event rate was 14.2% in the invasive-strategy group and 16.5% in the conservative-strategy group (difference, −2.3 percentage points; 95% CI, −5.0 to 0.4).
Evaluation of MI showed that procedural MIs occurred with HR 2.98 [95% CI 1.87-4.74; P=<0.01] within the invasive arm whereas spontaneous MIs occurred with HR 0.67 [95% CI 0.53-0.83; P=<0.01] in the invasive arm. Of note, there were more hospitalizations for heart failure (HR 2.23, 95% CI: 1.38 to 3.61) and fewer hospitalizations for unstable angina (HR 0.50, 95% CI: 0.27 to 0.91) with the invasive strategy.
There was a modest improvement in symptom benefit at 3 months in the invasive arm, especially among those with daily/weekly angina, determined by Seattle Angina Questionnaire which persisted to 12 and 36 months.
The outcome of this trial turned out to be neutral: There was no overall mortality benefit to an invasive approach in patients with stable ischemic coronary artery disease. This study cannot be generalized to patients with acute coronary syndromes within the last 2 months, >50% left main coronary artery disease, LVEF <35%, NYHA Class III or IV heart failure, eGFR <30%, and those with significant persistent symptoms despite optimal medical therapy.
The clinical implications from this trial are that for patients who experience frequent angina, revascularization via PCI or CABG in addition to medical management can improve quality of life, albeit modestly. Spontaneous myocardial infarctions are more clinically relevant as they tend to have higher associated morbidity and mortality. The invasive arm was noted to have an improvement in spontaneous myocardial infarction when compared to the conservative arm; howeverm peri-procedural MIs were increased in the invasive arm.
Based on the results of this trial, it is reasonable for providers to manage patients medically who have stable ischemia without concomitant heart failure, without referring for catheterization and revascularization, as there is no mortality benefit to revascularization and only a small decrease in spontaneous MI. It should be noted that medical therapy was “intensive”, followed an algorithm and patients had frequent follow up (i.e. 5 visits in the first year). One would have to likely strive for this to replicate the results.
In patients who continue to have anginal symptoms several times per week, revascularization improves symptoms and reduces the need for anti-anginal medications. It should remain an option for these patients, at the least for the improvement in quality of life.