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CHICAGO -- An early interventional strategy for stable ischemic heart disease didn't hold a long-term mortality advantage over initial medical managment in extended follow-up from the landmark ISCHEMIA trial.

All-cause mortality at 7 years came out 12.7% among patients initially randomized to intervention and 13.4% for those initially assigned conservative therapy (adjusted HR 1.00, 95% CI 0.85-1.18), reported Judith S. Hochman, MD, of NYU Grossman School of Medicine in New York City,

The lower 7-year cardiovascular mortality with early intervention (6.4% vs 8.6%, aHR 0.78, 95% CI 0.63-0.96) was counterbalanced by higher non-cardiovascular mortality at the late time point (5.6% vs 4.4%, adjusted HR 1.44, 95% CI 1.08-1.91).

Bayesian posterior distribution analysis suggested an "essentially null" probability that the early interventional strategy was superior for all-cause mortality, Hochman said in presenting the results at the American Heart Association annual meeting in Chicago. The findings were also published simultaneously in .

The results match the main analysis' 3.2-year follow-up data suggesting elevated non-cardiovascular mortality in the invasive arm but no overall mortality difference compared with an initially conservative strategy.

Main findings at that point indicated no significant advantage to early intervention for cardiovascular mortality, although there was a suggestion that the curves might be diverging late, Hochman noted.

The high rate of non-cardiovascular mortality in the invasive arm was unexpected, and the explanation is unclear, said AHA session study discussant M. Cecilia Bahit, MD, of INECO Neurociencias in Santa Fe, Argentina.

Causes of non-cardiovascular death were predominantly malignancy, despite a similar prevalence of malignancy across groups at baseline. "Better understanding of specific causes of cardiovascular and non-cardiovascular death warrants further evaluation," Bahit noted.

Still, she concluded: "These findings might help physicians to share decision-making whether to add invasive strategy to guideline-directed medical therapy in selected patients with chronic CAD [coronary artery disease] and moderate-to-severe ischemia."

The main analysis of ISCHEMIA included 5,179 patients stable with moderate or severe ischemia who were randomized to treatment strategy if the coronary CT angiogram ruled out left main disease and affirmed ≥50% stenosis in a major epicardial vessel, or at least 70% blockage in a proximal or mid-vessel. Recent acute coronary syndromes or an "unacceptable" level of angina were exclusion criteria.

For the invasive strategy group, the protocol called for angiography within 30 days after randomization and complete revascularization (percutaneous in 74%) of all ischemic territories, if feasible. The conservative management group got only the optimal medical therapy that all the patients were to receive, comprised of intensive secondary prevention with lifestyle and pharmacologic interventions based on treat-to-target algorithms. By the end of 4 years, 23% in the conservative group underwent revascularization.

After the initial randomized phase of the trial, patients transitioned to the ISCHEMIA-EXTEND study, in which they were followed for mortality by participant contact by sites or by central death index. The analysis Hochman presented was for a median 5.7 years of follow-up of the planned 10 years of total follow-up.

The analysis had data on a total of 4,540 patients of the 4,825 eligible for extended follow-up as ones who survived and did not withdraw consent or decline long-term follow-up. The number of deaths (557) was nearly twice that at the earlier follow-up point, Hochman pointed out.

"The trial definition of cardiovascular mortality was broad and included undetermined cause of death," she noted.

No subgroups stood out for an interaction between initial assigned treatment strategy and mortality, including severity of baseline ischemia, diabetes, or number or type of affected vessels.

The posterior probability of an absolute difference of more than one percentage point between the groups favoring the invasive group at 7 years was 13%, while the chance of the same difference favoring conservative management was 17%.

Limitations included lack of data collection on non-fatal events, use of medications, revascularization procedures, or quality of life after the initial median 3.2-year follow-up and no adjudication of cause of death in the extended follow-up phase.

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