Practical Implications of the ISCHEMIA Trial

Introduction
Ischemic heart disease is a major global public health problem and the leading cause of death in in the United States.1 The goals of treating stable ischemic heart disease (SIHD) are to improve survival and reduce angina. The initial management of SIHD should include optimal medical therapy (OMT) consisting of intensive lifestyle change and medications to treat risk factors and symptoms. The incremental impact of adding revascularization to improve outcomes for patients with SIHD, particularly those with moderate or severe ischemia, is uncertain.2

Previous strategy trials comparing revascularization plus OMT with OMT alone did not demonstrate a reduction in death or myocardial infarction (MI).3-5 Limitations of prior studies included not requiring a threshold of ischemia severity for trial eligibility, cardiac catheterization prior to randomization (introducing selection bias), little use of drug-eluting stents,3,5 and small size and short duration.4

In this context, ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) evaluated whether an initial invasive strategy improved clinical outcomes when added to OMT in patients with SIHD and moderate or severe ischemia.6,7

ISCHEMIA Design
ISCHEMIA enrolled patients with SIHD and moderate or severe ischemia as assessed locally by stress testing performed for clinical indications.6 Stress modalities included myocardial perfusion imaging, stress echocardiography, cardiac magnetic resonance imaging, and exercise tolerance testing without imaging. Exclusion criteria included those with unprotected left main disease (≥50% stenosis), estimated glomerular filtration rate <30 ml/min, acute coronary syndrome within the previous 2 months, unacceptable or medically refractory angina, and left ventricular ejection fraction <35% at baseline. In most participants with normal renal function, pre-randomization blinded coronary computed tomography angiography (CCTA) was performed to exclude those with obstructive left main coronary disease or those without obstructive coronary artery disease (CAD). Participants were randomized to either an initial invasive or conservative strategy. Sites were instructed to provide OMT consistent with contemporaneous guidelines to all participants. Those in the invasive strategy were expected to undergo cardiac catheterization, followed by revascularization with percutaneous coronary intervention or coronary artery bypass grafting if feasible. Cardiac catheterization was reserved for participants in the conservative strategy for failure of OMT. The primary outcome was a composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Key secondary endpoints were the composite of cardiovascular death or nonfatal MI and angina-related quality of life (QoL) as assessed by the Seattle Angina Questionnaire. The primary definition used for MI was similar to the definition used by the Society for Cardiovascular Angiography and Interventions.8 A secondary analysis was performed using the secondary definition of MI, which was similar to the Third Universal Definition of MI.9

Summary of Results
ISCHEMIA randomized 5,179 patients (2,588 patients in the invasive strategy and 2,591 in the conservative strategy).7,10 Approximately 75% of patients were randomized after stress imaging. Per core laboratory assessment, 54% had severe ischemia, 33% had moderate ischemia, and 12% had mild or no ischemia. The majority of participants (90%) had a history of angina, with daily or weekly angina in 20%, angina several times per month in 44%, and no angina in the previous month in 35%. There were no between-group differences in risk factor management during the trial. Median low-density lipoprotein cholesterol was 64 mg/dL, and systolic blood pressure was 129 mmHg at the last visit. Statin use was 95% (66% used high-intensity dosages), and aspirin use was 97% at the last visit.

Median follow-up was 3.2 years. Overall, an initial invasive strategy compared with an initial conservative strategy did not demonstrate a reduced risk for the primary outcome, with an adjusted hazard ratio of 0.93 (95% confidence interval, 0.80-1.08; p = 0.34). The curves crossed at approximately 2 years, with a higher estimated rate in the invasive group at 6 months and lower estimated rate in the invasive group at 5 years. Procedural MI were more frequent early in the follow-up period with an invasive strategy, and spontaneous MI were less frequent later with an invasive strategy. When the secondary MI definition was used, there were greater differences in early event rates between the two groups because procedural MI were sensitive to MI definition. The primary outcome occurred more frequently in the invasive strategy throughout the follow-up period when the secondary definition of MI was used (i.e., the curves did not cross).

There was no heterogeneity-of-treatment effect based on core-laboratory-assessed extent of ischemia or anatomic severity of disease based on CCTA. Interestingly, risk of the primary endpoint did not increase as ischemia severity increased. In contrast, risk of the primary endpoint increased as anatomic severity increased, although an invasive strategy did not ameliorate that risk. The invasive strategy did not demonstrate a reduced risk for the major secondary outcome of cardiovascular death or MI. All-cause mortality was low in both groups (6.5% invasive; 6.4% conservative).

Among patients with angina at baseline, an initial invasive strategy led to durable improvement in angina control and QoL compared with the conservative strategy.11

Practical Implications
The ISCHEMIA results suggest that for patients with stable CAD similar to those enrolled in the trial, the clinical outcomes will be similar with either initial strategy. In patients with angina, the invasive strategy will be superior in controlling angina. These findings should be discussed with patients through the process of shared decision-making, during which the patient's values and preferences should guide the decision about revascularization.

Event rates were low in this patient population with moderate or severe ischemia and a substantial burden of atherosclerosis, supporting the importance of optimizing medical therapy regardless of the initial strategy (conservative versus invasive).

ISCHEMIA performed blinded CCTA after stress tests documented at least moderate ischemia but prior to randomization. Of those screened with CCTA, 9% had unprotected left main disease, and 17% had no obstructive CAD (these patients were excluded).10 This design supports the utility of CCTA in practice to evaluate for left main disease and to confirm the diagnosis of obstructive disease. The association of anatomic severity with events additionally supports the prognostic value of anatomic imaging, although an invasive strategy did not mitigate this risk. The lack of association of events with the severity of core-laboratory-assessed ischemia on stress testing calls into question our use of stress imaging in the evaluation of patients with suspected CAD.

The ISCHEMIA results show that it is not necessary to rush to the catheterization laboratory when a stress test demonstrates moderate or severe ischemia in a stable patient. Medical therapy should be optimized. It may be helpful to assess symptoms with a validated self-report tool such as the Seattle Angina Questionnaire. This should be followed by a shared decision-making discussion of treatment options with the patient's expected cardiovascular and QoL outcomes.

In this time of the COVID-19 pandemic, ISCHEMIA offers timely reassurance that for patients with stable CAD and acceptable symptoms who meet trial criteria, invasive management may be reasonably deferred while OMT is implemented. Shared decision-making is key when considering an initial invasive strategy in patients with SIHD with angina.

Extended follow-up and analyses of ISCHEMIA data to assess completeness of revascularization as well as potential long-term differences in mortality will help to further inform care of patients with SIHD.

References

  1. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126:e354-471.
  2. Stone GW, Hochman JS, Williams DO, et al. Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia: The Case for Community Equipoise. J Am Coll Cardiol 2016;67:81-99.
  3. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-16.
  4. De Bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014;371:1208-17.
  5. BARI 2D Study Group, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-15.
  6. ISCHEMIA Trial Research Group, Maron DJ, Hochman JS, et al. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design. Am Heart J 2018;201:124-35.
  7. Maron DJ, Hochman JS, Reynolds HR, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020;382:1395-407.
  8. Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol 2013;62:1563-70.
  9. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60:1581-98.
  10. Hochman JS, Reynolds HR, Bangalore S, et al. Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial. JAMA Cardiol 2019;4:273-86.
  11. Spertus JA, Jones PG, Maron DJ, et al. Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease. N Engl J Med 2020;382:1408-19.

Keywords: Angina, Stable, Coronary Artery Disease, Exercise Test, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Factors, Acute Coronary Syndrome, Quality of Life, Myocardial Perfusion Imaging, Drug-Eluting Stents, Exercise Tolerance, Glomerular Filtration Rate, Blood Pressure, Stroke Volume, Constriction, Pathologic


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