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

Clinical Question

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

Bottom Line

The ISCHEMIA trial was not able to demonstrate improved outcomes with an initial revascularization strategy compared to medical therapy in patients with CAD and moderate to severe levels of ischemic burden.

Major Points

After the COURAGE trial in 2007 did not find a statistically significant advantage of percutaneous coronary intervention in patient's with stable angina, the benefit of PCI for stable CAD has been questioned. Criticisms of COURAGE contend that patients with more ischemic burden were not well-represented and would be expected to be the population most likely to benefit. Several trials have since evaluated whether certain subgroups of patients may benefit. Notable examples include BARI 2D and FAME 2. In BARI 2D, patients with CAD and diabetes were randomized to PCI vs medical therapy. In the FAME-2 trial, fractional flow reserve was used to identify patients with functionally significant obstruction, with findings of decreased urgent revascularization and possibly myocardial infarctions.

The ISCHEMIA trial attempted to answer the question of whether patients with higher degrees of ischemia may benefit from initial revascularization. The investigators enrolled patients with moderate or severe reversible ischemia on imaging tests or severe ischemia on exercise tests without imaging. CCTA was used to rule out patients with left main disease, which have been shown to benefit from revascularization with coronary artery bypass grafting previously. While the original outcome of the trial was cardiovascular death or myocardial infarction, it was expanded to include hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest to increase the power of the study. At the end of the study period, a statistically significant difference in the primary outcome was not able to be demonstrated between the invasive and conservative strategies. 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.



  • multicenter, randomized trial
  • N=5,179
    • medical therapy, angiography, and revascularization (PCI vs CABG) (n=2588)
    • medical therapy alone (n=2591)
  • Setting: 320 sites in 37 countries
  • Enrolment: 2012-2018
  • Median follow-up: 3.2 years
  • Analysis: Intention-to-treat
  • Primary outcome: composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest


Inclusion Criteria

  • at least moderate ischemia on stress test
    • Nuclear perfusion: >/= 10% myocardium ischemic
    • Echocardiography: >/= 3/16 segments with stress-induced severe hypokinesis or akinesis
    • Cardiac magnetic resonance: >/= 12% myocardial ischemia or >/= 3/16 segments with stress-induced severe hypokinesis or akinnesis
    • Exercise Test without imaging: (expansion of inclusion criteria to improve enrollment)
      • 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 >/= 1mm in a non-infarct territory
      • and either of following:
        • meets criteria by stage 2 of Bruce protocol or 7 METs
        • ST segment criteria met at <75% maximum predicted HR
  • age >/= 21 years

Exclusion Criteria

  • LVEF <35%
  • unprotected LM main >/= 50%
  • no obstructive CAD
  • unacceptable level of angina despite maximal medical therapy
  • history of medication non-compliance; or inability to take dual anti-platelet therapy
  • ACS within prior 2 months; PCI within previous 12 months
  • Stroke within previous 6 months or prior intracranial hemorrhage
  • NYHA class III-VI heart failure or heart failure hospitalization within previous 6 months
  • ESRD or eGFR <30 (not exclusion criteria for CKD ancillary study
  • severe valvular disease

Baseline Characteristics

  • median age (IQR): 64 (58-70)
  • male sex: 77.4%
  • Race or ethnic group:
    • white 66.3%
    • black 4.0%
    • asian 29.0%
    • Hispanic/Latino 15.8%
  • Hypertension: 73.4%
  • Diabetes: 41.8%
    • use of insulin (9.5%)
  • cigarette smoking
    • never smoked: 42.7%
    • former smoker: 45%
    • current smoker: 12.4%
  • previous PCI: 20.3%
  • previous CABG: 3.9%
  • Cardiac cath: before enrollment: 36.8%


Randomized to revascularization or conservative strategy

  • invasive strategy: medical therapy, angiography within 30 days after randomization of all ischemic territories if feasible
  • medical therapy alone, with angiography reserved for failure of medical therapy


Comparisons are invasive vs conservative strategy.

Primary Outcomes

Death from cardiovascular causes, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.
16.4 vs 18.2 at 5 years; difference -1.8 (95% CI -4.7 to 1.0)
HR 0.93 (95% CI 0.80 to 1.08; p=0.34)

Secondary Outcomes

Death from cardiovascular causes or MI
14.2 vs 16.5% at 5 years; difference -2.3 (95% CI -5.0 to 0.4)
Death from any cause
9.0 vs 8.3% at 5 years; difference 0.7 (95% CI -1.6 to 3.1)

Subgroup Analysis

There was no statistically difference in the primary outcomes when heterogeneity of treatment effect was analyzed for degree of baseline ischemia, anatomic severity of CAD, or diabetes.


Early myocardial infarctions occurred more frequently in the invasive group, which could have been periprocedural MIs that may not have the same clinical significance as spontaneous MIs. After 6 months, more MIs occurred in the conservative group, which would presumable be spontaneous MIs.


Funding for the study was through NHLBI, although medications and stents were provided by industry groups including Abbott, Amgen, Arbor, AstraZeneca, Medtronic, etc.

Further Reading