• ISCHEMIA-EXTEND Shows No Long-Term All-Cause Mortality Difference in Chronic CAD Patients

    However, the invasive strategy did show lower cardiovascular mortality risk and higher non-cardiovascular mortality risk at 5.7-year follow-up

    Extended follow-up of the ISCHEMIA randomized trial over a median of 5.7 years demonstrated no difference in all-cause mortality between an initial invasive strategy and an initial conservative strategy for patients with chronic coronary disease, and a lower risk of cardiovascular mortality and higher risk of non-cardiovascular mortality for the initial invasive strategy.

    This study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health and was presented Sunday at the American Heart Association Scientific Sessions 2022 in Chicago by Judith S. Hochman, MD, from the NYU Grossman School of Medicine. The results were also published simultaneously online in Circulation.

    The ISCHEMIA trial tested an initial invasive vs. conservative strategy for chronic coronary disease (CCD) patients with moderate or severe ischemia with an original median follow-up of 3.2 years.

    The original trial follow-up showed similar mean event-free time for the primary outcome, major adverse clinical events, consisting of cardiovascular death, myocardial infarction, unstable angina hospitalization, heart failure or resuscitated cardiac arrest, for patients with or without percutaneous coronary intervention. The same was true of all-cause death, cardiovascular death and non-cardiovascular death.

    The ISCHEMIA-EXTEND trial’s main objectives are to determine whether there are differences between the invasive- and conservative-treatment groups and to increase precision around treatment effect estimates for all-cause, cardiovascular and non-cardiovascular mortality. The interim results were released Sunday, and the projected median follow-up for ISCHEMIA trial survivors is 10 years and for ISCHEMIA-CKD survivors is 9 years.

    The ISCHEMIA trial randomized 5,179 patients to the invasive (n=2,588) or conservative (n=2,591) arm. Of these, 145 invasive-treatment patients and 144 conservative-treatment patients died during the original trial’s follow-up period, and 18 in the invasive arm and 11 in the conservative arm withdrew their consent.

    For the extended follow-up phase, 18 more patients in the invasive arm and 18 in the conservative arm withdrew their consent, leaving 2,407 in the invasive arm and 2,418 in the conservative arm eligible.

    At baseline, the median age of the patients was 64 years, and 67 years for the 65 patients who withdrew consent. About 66% of the patients were white and 29% were Asian; of those who withdrew consent, 54% were white and 43% Asian. About 42% of the original trial patients had diabetes, as did 43% of those who withdrew consent. Finally, the median ejection fraction was 60% for the original trial cohort and 62% for those who withdrew consent.

    At the original trial’s median 3.2-year follow-up, 289 patients had died. Another 268 died during the extended follow-up period, for a total of 557 deaths at median 5.7-year follow-up.

    At extended follow-up, there was no difference in all-cause death (hazard ratio [HR]: 1.00; 95% confidence interval [CI]: 0.85, 1.18; log-rank p = 0.741) between the invasive- and conservative-management groups. Cardiovascular death was significantly lower in the invasive-management group (invasive 6.4% vs. conservative 8.6%; HR: 0.78; 95% CI: 0.63, 0.96; Fine-Gray p = 0.008), while non-cardiovascular death was significantly higher (invasive 5.6% vs. conservative 4.4%; HR: 1.44; 95% CI: 1.08, 1.91; Fine-Gray p = 0.016). 

    In the subset of patients with evaluable cardiac computed tomography angiography (CCTA) for multivessel disease, defined as stenoses of 70% or greater, and excluding patients with low estimated glomerular filtration rate, the invasive group showed a significantly lower rate of cardiovascular death at extended follow-up (adjusted HR: 0.68; 95% CI: 0.48, 0.97). However, in subgroup analyses and for patients with evaluable CCTA, there were no significant differences in all-cause or non-cardiovascular death for multivessel or non-multivessel disease, as well as in cardiovascular death for patients with non-multivessel disease.

    Among the limitations Hochman listed in her slide presentation were that ISCHEMIA-EXTEND was designed as a pragmatic long-term follow-up study of mortality with limited data collection; no data were collected on non-fatal events, use of medications, revascularization procedures, or quality of life after the initial median 3.2-year follow-up; and the cause of death was adjudicated during the original trial follow-up but not during the extended phase; the strategy did not test routine revascularization for those with angiographic findings suitable for revascularization.

    These findings provide evidence for patients with chronic coronary disease and their physicians as they decide whether to add invasive management to guideline-directed medical therapy, Hochman said in her slides.

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