Contribution To Literature: The ISCHEMIA trial failed to show that routine invasive therapy was associated with a reduction in major adverse ischemic events compared with optimal medical therapy among stable patients with moderate ischemia.

Description: The goal of the trial was to evaluate routine invasive therapy compared with optimal medical therapy among patients with stable ischemic heart disease and moderate to severe myocardial ischemia on noninvasive stress testing.

Study Design Randomized

Parallel Patients with stable ischemic heart disease and moderate to severe ischemia were randomized to routine invasive therapy (n = 2,588) versus medical therapy (n = 2,591). In the routine invasive therapy group, subjects underwent coronary angiography and percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) as appropriate. In the medical therapy groups, subjects underwent coronary angiography only for failure of medical therapy. Total number of enrollees: 5,179

Duration of follow-up: 3.3 years

Mean patient age: 64 years

Percentage female: 23%

Percentage with diabetes: 41% Inclusion criteria: Patients >20 years of age

Moderate to severe ischemia on noninvasive stress testing (nuclear ≥10% ischemia; echo ≥3 segments of ischemia; cardiac magnetic resonance ≥12% ischemia and/or ≥3 segments with ischemia; exercise treadmill test ≥1.5 mm ST depression in ≥2 leads or ≥2 mm ST depression in single lead at <7 METs with angina) Exclusion criteria: ≥50% left main stenosis (from blinded computed tomography)

Advanced chronic kidney disease (estimated glomerular filtration rate <30 ml/min)

Recent myocardial infarction

Left ventricular ejection fraction <35%

Left main stenosis >50%

Unacceptable angina at baseline

New York Heart Association class III-IV heart failure

Prior PCI or CABG within last year Angina frequency at baseline: None, 34%

Several times per month, 44%

Daily/weekly, 22% Other salient features/characteristics: Over the entire follow-up period, cardiac catheterization was performed in 96% of the invasive group vs. 28% of the medical therapy group

Over the entire follow-up period, coronary revascularization was performed in 80% of the invasive group vs. 23% of the medical therapy group

Principal Findings: The primary outcome of cardiovascular death, myocardial infarction, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure at 3.3 years occurred in 13.3% of the routine invasive group compared with 15.5% of the medical therapy group (p = 0.34). The findings were the same in multiple subgroups. Invasive therapy was associated with harm (~2% absolute increase) within the first 6 months and benefit within 4 years (~2% absolute decrease). Secondary outcomes: Cardiovascular death or myocardial infarction: 11.7% of the routine invasive group compared with 13.9% of the medical therapy group (p = 0.21)

All-cause death: 6.4% of the routine invasive group compared with 6.5% of the medical therapy group (p = 0.67)

Periprocedural myocardial infarction: (invasive/conservative hazard ratio [HR] 2.98, 95% confidence interval [CI] 1.87-4.74)

Spontaneous myocardial infarction: (invasive/conservative HR 0.67, 95% CI 0.53-0.83) Quality of life outcomes: Seattle Angina Questionnaire (SAQ) summary score at 3 months for invasive vs. conservative therapy: 4.1 points (95% credible interval 3.2 to 5.0) overall 8.5 points (95% credible interval 5.8 to 11.1) daily/weekly angina at baseline 5.5 points (95% credible interval 4.3 to 6.9) monthly angina at baseline 0.1 points (95% credible interval -1.2 to 1.4) no angina at baseline

SAQ summary score at 12 months for invasive vs. conservative therapy: 4.2 points (95% credible interval 3.3 to 5.1) overall

SAQ summary score at 3 months for invasive vs. conservative therapy: 2.9 points (95% credible interval 2.2 to 3.7) overall

Relationship of ischemia and anatomy on clinical outcomes: There was no association between degree of ischemia and all-cause mortality (p for trend = 0.33). There was a weak association between degree of ischemia and myocardial infarction (p for trend = 0.04).

There was an association between extent of coronary disease (modified Duke prognostic score) on all-cause mortality (p for trend < 0.001) and myocardial infarction (p for trend < 0.001).

The invasive vs. conservative relationship on the primary outcome (death or myocardial infarction) was similar regardless of degree of ischemia (p for interaction = 0.28).

The invasive vs. conservative relationship on mortality was similar regardless of degree of ischemia (p for interaction = 0.23).

The invasive vs. conservative relationship on myocardial infarction was similar regardless of degree of ischemia (p for interaction = 0.15).

The invasive vs. conservative relationship on the primary outcome (death or myocardial infarction) was similar regardless of extent of coronary disease (p for interaction = 0.17).

The invasive vs. conservative relationship on mortality was similar regardless of extent of coronary disease (p for interaction = 0.83).

The invasive vs. conservative relationship on myocardial infarction was similar regardless of extent of coronary disease (p for interaction = 0.26). Relationship of heart failure on clinical outcomes: Among subjects with heart failure/left ventricular dysfunction, the cumulative incidence rate was 22.7 compared with 13.8 among those without heart failure/left ventricular dysfunction. Among those with heart failure/left ventricular dysfunction, invasive versus conservative therapy was associated with a lower rate of the primary outcome (17.2% vs. 29.3%). Among those without heart failure/left ventricular dysfunction, invasive therapy was not associated with benefit (13.0% vs. 14.6%; p-interaction = 0.055).

Interpretation: Among patients with stable ischemic heart disease and moderate to severe ischemia on noninvasive stress testing, routine invasive therapy failed to reduce major adverse cardiac events compared with optimal medical therapy. There was possible enhanced benefit for invasive compared with conservative therapy among those with heart failure/left ventricular dysfunction. There was also no benefit from invasive therapy regarding all-cause mortality or cardiovascular mortality/myocardial infarction. One-third of subjects reported no angina symptoms at baseline. There was a modest improvement in symptom benefit at 3 months, especially among those with daily/weekly angina, which persisted to 12 and 36 months. Routine invasive therapy was associated with harm at 6 months (increase in periprocedural myocardial infarctions) and associated with benefit at 4 years (reduction in spontaneous myocardial infarction). These results do not apply to patients with current/recent acute coronary syndrome, highly symptomatic patients, left main stenosis, or left ventricular ejection fraction <35%. Severe ischemia on stress testing was associated with myocardial infarction, while severe extent of coronary disease (modified Duke prognostic score) was associated with both mortality and myocardial infarction. However, the overall lack of benefit for invasive vs. conservative therapy was similar among those with severe ischemia on noninvasive testing and extensive coronary disease. Although the overall interpretation of this trial was negative, there were mixed findings with evidence for both harm and benefit. This signals that: 1) invasive therapy for stable ischemic heart disease patients needs to be carefully considered in the context of angina burden and background medical therapy, and 2) likelihood that optimal coronary revascularization can be achieved with low procedural complications.

References: Lopes RD, Alexander KP, Stevens SR, et al. Initial Invasive versus Conservative Management of Stable Ischemic Heart Disease Patients With a History of Heart Failure or Left Ventricular Dysfunction: Insights From the ISCHEMIA Trial. Circulation 2020;Aug 29:[Epub ahead of print]. Presented by Dr. Renato Lopes at the European Society of Cardiology Virtual Congress, August 29, 2020. Maron DJ, Hochman JS, Reynolds HR, et al., on behalf of the ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020;382:1395-407. Spertus JA, Jones PG, Maron DJ, et al., on behalf of the ISCHEMIA Research Group. Health-Status Outcomes With Invasive or Conservative Care in Coronary Disease. N Engl J Med 2020;82:1408-19. Editorial: Antman EM, Braunwald E. Managing Stable Ischemic Heart Disease. N Engl J Med 2020;382:1468-70. Presented by Dr. Harmony R. Reynolds at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 29, 2020. Presented by Judith S. Hochman at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019. Presented by John A. Spertus at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019 (quality of life outcomes).

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Acute Heart Failure, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Magnetic Resonance Imaging, Nuclear Imaging, Chronic Angina

Keywords: ESC20, ESC Congress, acc20, ACC Annual Scientific Session, AHA19, AHA Annual Scientific Sessions, Acute Coronary Syndrome, Angina, Stable, Angina, Unstable, Cardiac Catheterization, Constriction, Pathologic, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Exercise Test, Heart Arrest, Heart Failure, Magnetic Resonance Imaging, Myocardial Infarction, Myocardial Ischemia, Percutaneous Coronary Intervention, Renal Insufficiency, Chronic, Secondary Prevention, Stroke Volume, Tomography