ISCHEMIA

International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA)

Trial Summarized By: Yuvraj Singh Chowdhury, MD | Reviewed/Approved by: Manesh Patel, MD

The aim of the ISCHEMIA trial is to determine the best management strategy for higher-risk patients with stable ischemic heart disease (SIHD) and moderate to severe ischemia on stress test.

Key Findings

In SIHD patients with moderate-severe ischemia, initial revascularization + OMT compared to OMT alone did not reduce the risk for adverse CV outcomes.



Return to Scientific Sessions 2019 Science News coverage

Commentary


Results: ISCHEMIA - primary results from Judith Hochman

Judith S Hochman, MD explains the primary results from ISCHEMIA, a highly-anticipated trial to help determine the best management strategy for higher-risk patients with stable ischemic heart disease.

Dr. Hochman is a cardiology researcher at NYU.


Commentary: The ISCHEMIA Trials

Elliott Antman, MD, Alice Jacobs, MD, and John Spertus, MD, MPH discuss the significance of the results of the three highly anticipated ISCHEMIA trials.

Dr. Antman was a moderator for the session, Dr. Jacobs was a discussant, and Dr. Spertus presented Quality of Life outcomes.


Commentary: ISCHEMIA with Rasha Al-Lamee

Rasha Al-Lamee, MBBS, MRCP, PhD comments on the primary results of the ISCHEMIA trial which were presented during Scientific Sessions 2019.

Dr. Al-Lamee is on the faculty of the Medicine, National Heart & Lung Institute at Imperial College London.

 

Purpose: To evaluate clinical outcomes in the  comparison of an initial invasive approach (cardiac catheterization and feasible revascularization) + OMT to conservative, optimal medical therapy (OMT) alone  in patients with SIHD and moderate or severe ischemia.

Trial Design: N=5179, median age 64 years old; average 3.5 years follow-up. 320 sites; 37 countries.

Primary Composite Endpoint: CV death, non-fatal MI, resuscitated cardiac arrest, hospitalization for unstable angina, or HF.

Major Secondary Endpoint: CV death, MI.

Results: An initial invasive approach compared to  conservative approach in SIHD patients with moderate-severe ischemia did not reduce risk of the primary endpoint or the secondary endpoint of CV death or MI at a median of 3.3 years.

ISCHEMIA Data
 HRP value@ 4 years
Primary Composite0.930.34Conservative=15.5%
Invasive=13.3%
Major Secondary0.900.21Conservative=13.9%
Invasive=11.7%
CV Death0.870.33 
All-cause Death1.050.67Conservative=6.5%
Invasive=6.4%

Recommended

Key Findings:

  • The curves cross for the primary endpoint and the major secondary endpoint at approximately 2 years from randomization
    • ~2 in 100 higher estimated rate with INV at 6 months
    • ~2 in 100 lower estimated rate with INV at 4 years
  • Procedural MIs were increased with an invasive strategy
  • Spontaneous MIs were reduced with an invasive strategy
  • Low all-cause mortality in both groups despite high-risk clinical characteristics, high-risk ischemia and extensive CAD
  • No heterogeneity of treatment effect, including by type of stress test, severity of ischemia or extent of CAD
  • Very low rates of procedure-related stroke and death

Impression:

  • ISCHEMIA is the largest trial of an invasive vs conservative strategy for patients with SIHD
  • Overall, an initial INV strategy as compared with an initial CON strategy did not demonstrate a reduced risk over median 3.3 years for
    • Primary endpoint - CV death, MI, hospitalization for UA, HF, RCA
    • Major Secondary endpoint - CV death or MI
  • The probability of at least a 10% benefit of INV on all-cause mortality was <10%, based on pre-specified Bayesian analysis

Detailed Results

Primary Endpoint:
Time to CV death, MI, hospitalization for unstable angina, heart failure or resuscitated cardiac arrest

Adjusted Hazard Ratio INV vs CON
0.93 (0.80, 1.08); P-value = 0.34

Secondary Endpoint:
Time to CV death or MI

Adjusted Hazard Ratio INV vs CON
0.90 (0.77, 1.06); P-value = 0.21

Other Endpoints:

  • All-Cause Death
    Adjusted Hazard Ratio INV vs CON
    1.05 (0.83, 1.32); P-value = 0.67
     
  • Net clinical benefit (stroke added to primary endpoint)
    Hazard Ratio INV vs CON
    0.95 (0.82,1.10); P-value= 0.50
     
  • Cardiovascular Death
    Adjusted Hazard Ratio INV vs CON
    0.87 (0.66, 1.15); P-value = 0.33
     
  • Myocardial Infarction
    Adjusted Hazard Ratio INV vs CON
    0.92 (0.76, 1.11); P-value = 0.38
     
  • Procedural MI (Type 4a or 5)
    Adjusted Hazard Ratio INV vs CON
    2.98 (1.87, 4.74); P-value < 0.01
     
  • Spontaneous MI (Types 1,2,4b or 4c)
    Adjusted Hazard Ratio INV vs CON
    0.67 (0.53, 0.83); P-value <0.01

Background

Purpose: To determine whether an initial invasive strategy of cardiac catheterization and optimal revascularization, if feasible, in addition to OMT, will reduce the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure in participants with SIHD and at least moderate ischemia over an average follow-up of approximately 3.5 years compared with an initial conservative strategy of OMT alone with catheterization reserved for failure of OMT.

Trial Design
COURAGE and BARI 2D, the two largest prior trials comparing coronary revascularization vs. medical therapy in SIHD patients, found that among patients selected on the basis of coronary anatomy after cardiac catheterization, an initial management strategy of coronary revascularization (PCI, PCI or CABG, respectively) did not significantly reduce the primary endpoints of death or MI (COURAGE), or death (BARI 2D) compared with OMT alone. The ISCHEMIA Trial was designed to compare outcomes with an initial invasive vs a conservative treatment strategy for managing SIHD patients with moderate or severe ischemia on stress testing.

ISCHEMIA is an NHLBI-supported trial where all 5179 randomized participants received secondary prevention that includes lifestyle advice and pharmacologic interventions referred to as optimal medical therapy (OMT). Participants randomized to the invasive strategy underwent routine cardiac catheterization followed by revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery, when feasible, as selected by the local Heart Team to achieve optimal revascularization. Participants randomized to the conservative strategy underwent cardiac catheterization only for failure of OMT.

Trial Population:

  • Males and females over age 18 with SIHD and at least moderate ischemia
  • Of 8518 enrolled patients, 5179 were determined to be eligible based on additional screening and randomized at 320 sites
  • Patients with a glomerular filtration rate (eGFR) <30 mL/min, recent myocardial infarction (MI), left ventricular ejection fraction <35%, left main stenosis >50%, or unacceptable angina at baseline were excluded from the study
  • Participants were 64 years old (median), 23% women, 34% 1726 nonwhite, 16% Hispanic, 41% diabetic, and 90% with a history of angina
  • The qualifying stress test modality was stress imaging in 3909 (75%); the remainder were non-imaging ETTs
  • Core laboratories judged that the trial-required level of ischemia was met in 85% of randomized participants
  • Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79% had multivessel CAD and 87% had left anterior descending (LAD) stenosis (proximal in 47%)

Primary Endpoint(s):

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

Secondary Endpoint(s):

  • The composite of CV death or MI
  • Angina symptoms and quality of life, as assessed by the Seattle Angina Questionnaire
  • All-cause mortality
  • Net clinical benefit assessed by including stroke in the primary and secondary composite endpoints
  • Individual components of the composite endpoints

Sponsor(s)/Collaborator(s): Montreal NYU Langone Health, New York University, Stanford University, National Heart, Lung, and Blood Institute (NHLBI), Albany, Stratton VA Medical Center, Cedars-Sinai Medical Center, Columbia University, Duke University, East Carolina University, Emory University, Harvard University, Massachusetts General Hospital, Montreal Heart Institute, University of British Columbia, University of Missouri - Kansas City, Vanderbilt University

References and sources:

  • Presented by: Judith S Hochman, MD, at AHA Scientific Sessions 2019, Philadelphia, PA
     
  • ClinicalTrials.gov Identifier: NCT01471522 (opens in new window)
     
  • Maron DJ, Hochman JS, O’Brien SM, Reynolds HR, Boden WE, Stone GW, Bangalore S, Spertus JA, Mark DB, Alexander KP, Shaw L, Berger JS, Ferguson TB, Williams DO, Harrington RA, Rosenberg Y; ISCHEMIA Trial Research Group. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: rationale and design. Am Heart J. 2018; 201:124–135. doi: 10.1016/j.ahj.2018.04.011
     
  • Hachamovitch R, Rozanski A, Shaw LJ, Stone GW, Thomson LE, Friedman JD, Hayes SW, Cohen I, Germano G, Berman DS. Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy.Eur Heart J. 2011; 32:1012–1024. doi: 10.1093/eurheartj/ehq500
Key Words
Stable ischemic Heart Disease, Optimal Medical Therapy, Stroke, Myocardial infarction, cardiac catheterization, coronary revascularization
Related clinical topics
Management of stable ischemic heart disease, initial management strategies for coronary revascularization, secondary prevention of coronary artery disease.