ISCHEMIA

Published

Maron DJ, et al. "Initial Invasive or Conservative Strategy for Stable Coronary Disease". The New England Journal of Medicine. 2020. 382(15):1395-1407.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with stable coronary artery disease (CAD) and moderate to severe ischemia, does initial revascularization improve outcomes compared to medical therapy alone?

Bottom Line

ISCHEMIA found no benefit to initial revascularization compared to medical therapy alone among patients with stable CAD and moderate to severe ischemia.

Major Points

Despite the negative COURAGE trial in 2007, the use of PCI in patients with stable angina remains a subject of debate. Critics of COURAGE contend that patients with greater ischemic burden — those hypothesized to respond best to PCI — were poorly represented in the study. This prompted a series of studies, including BARI 2D, evaluating whether specific higher-risk patient subgroups may benefit from PCI.

ISCHEMIA asked whether patients with more severe ischemia may benefit from initial revascularization versus medical management alone. The investigators enrolled 5,179 patients with moderate or severe reversible ischemia on imaging tests or severe ischemia on exercise tests without imaging. Coronary CT angiography (CCTA) was used to rule out patients with left main disease, a subgroup shown to benefit from revascularization with coronary artery bypass grafting previously. While the original outcome of the trial was CV death or myocardial infarction, the protocol was amended to include hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest as coprimary outcomes. Among patients in the early revascularization group, 96% underwent angiography and 79% underwent revascularization (PCI 74%, CABG 26%); in the medical management group, 26% underwent angiography and 21% underwent revascularization prior to a primary outcome event. At the end of the study period, there was no statistically significant difference in event rates between initial revascularization and medical therapy alone. The statistical analysis was somewhat complicated as the Cox proportional hazard assumptions were violated, so the study reported estimated event rates instead. At 6 months, 5.3% of patients in the early revascularization arm experienced a primary endpoint event, compared to 3.4% in the medical therapy alone arm. There was a notable increase in the risk of early procedural MIs in the invasive group, with some questioning the clinical significance of such events. Interestingly when the definition of MI was changed from using site-reported MI decision limits to 99% upper reference limit from the assay manufacturer's package, the invasive strategy group had a higher risk of the primary outcome compared to the conservative strategy group.

Taken together, the available evidence suggests that among patients with stable CAD and severe ischemia on stress testing, early revascularization does not improve outcomes relative to optimal medical therapy.

Guidelines

As of January 2021, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, randomized controlled trial
• N=5,179 patients with stable CAD
  • Early revascularization (n=2,588)
  • Medical therapy alone (n=2,591)
• Setting: 320 sites in 37 countries
• Enrollment: 2012-2018
• Median follow-up: 3.2 years
• Analysis: Intention-to-treat
• Primary outcome: Composite of CV death, MI, or hospitalization for unstable angina, HF, or resuscitated cardiac arrest

Population

Inclusion Criteria

• Age ≥21 years
• Underwent clinically indicated stress testing showing moderate or severe reversible ischemia:
  • Nuclear perfusion: ≥10% myocardium ischemic
  • Echocardiography: ≥3/16 segments with stress-induced severe hypokinesis or akinesis
  • Cardiac MRI: ≥12% myocardial ischemia or ≥3/16 segments with stress-induced severe hypokinesis or akinesis
  • Exercise test without imaging:
    • Clinical history of typical angina or typical angina during exercise test
    • Absence of resting ST-segment depression ≥1.0 mm or confounders
    • Exercise-induced ST segment depression ≥1.5 mm in 2 leads or ≥2.0 mm in any lead; ST-segment elevation ≥1 mm in a non-infarct territory
    • and either meets criteria by stage 2 of Bruce protocol or 7 METs or ST segment criteria met at <75% maximum predicted HR

Exclusion Criteria

• GFR <30 ml/1.73 m² BSA
• Recent acute coronary syndrome
• Unprotected left main stenosis ≥50%
• LVEF <35%
• NYHA class III or IV heart failure
• Unacceptable angina despite maximal medical therapy

Baseline Characteristics

• Median age: 64 years (IQR 58-70)
• Female sex: 22.6%
• Race or ethnic group:
  • White 66.3%
  • Black 4.0%
  • Asian 29.0%
  • Hispanic/Latino 15.8%
  • Other or multiple groups 0.7%
• Hypertension: 73.4%
• Diabetes: 41.8%
  • Use of insulin (9.5%)
• Cigarette smoking
  • Never smoked: 42.7%
  • Former smoker: 45.0%
  • Current smoker: 12.4%
• Previous PCI: 20.3%
• Previous CABG: 3.9%
• Cardiac catheterization prior to enrollment: 36.8%

Interventions

Randomized 1:1 to early revascularization or medical management alone:

• Early revascularization: medical therapy, angiography, and revascularization of all ischemic territories when able (within 30 days of randomization if feasible)
• Medical therapy alone: angiography reserved for failure of medical therapy

Guidelines were provided to sites regarding use of FFR, etc. Local investigators decided on the appropriate revascularization procedure (PCI or CABG).

Outcomes

Comparisons are early revascularization vs. medical therapy alone.

Primary Outcome

Composite of CV death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest

6 months: 5.3% vs. 3.4%

5 years: 16.4% vs. 18.2%

HR 0.93 (95% CI 0.80-1.08; P=0.34)

Secondary Outcomes

CV death or MI

This was the "Key Secondary Endpoint" that was the original outcome of this trial.

6 months: 4.8% vs. 2.9%

5 years: 14.2% vs. 16.5%

Death from any cause

6 months: 0.8% vs. 0.4%

5 years: 9.0% vs. 8.3%

HR 1.05 (95% CI 0.83-1.32)

MI

6 months: 4.3% vs. 2.6%

5 years: 10.3% vs. 11.9%

Additional Analyses

Crossover to revascularization in the medical therapy alone group

At any point

Angiography only: 26%

Revascularization: 21%

Prior to primary outcome event

Angiography only: 19%

Revascularization: 15%

Subgroup Analysis

There was no statistically difference in the primary outcome among groups based on baseline ischemia severity, anatomic severity of CAD, or presence of diabetes.

Criticisms

• Did not meet initial enrollment target of n=8,000 and the event rate was lower than expected, so underpowered for the original primary outcome of CVD mortality or MI (which is now the "key secondary endpoint"). The protocol was changed and the current primary endpoint is adequately powered with 5,000 and the updated primary outcome that is reported here.
• Early MI events in the early revascularization group might have been related to procedure complications (see Figure 2A on page 1403 of the publication). The event rate at 2 years was similar between arms. At about 3-4 years, the event rate might have been lower in the early revascularization group, possibly because of fewer late ACS events among those who were revascularized. It's possible that with additional follow-up, there might be a benefit for early intervention.
• Cox proportional hazard model was inappropriate for use in this trial because of violation of the proportional hazard assumption
• Low enrollment over an extended period of time at many of the sites might represent selection bias.
• Crossover to revascularization was 21%, possibly leading to attenuation of the effect.
• Less than moderate ischemia was present in 14% of participants.

Funding

• NHLBI
• Medications and stents were provided by industry groups including Abbott, Amgen, Arbor, AstraZeneca, Medtronic, etc.