Rates of all-cause death align between invasive and conservative strategies in ISCHEMIA-EXTEND

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Judith S Hochman

Extended follow-up of the ISCHEMIA-EXTEND trial has shown no difference in rates of all-cause mortality with an initial invasive strategy when compared to a conservative strategy in patients with chronic coronary disease and moderate or severe ischaemia.

Judith S Hochman (New York University School of Medicine, New York, USA) presented this interim conclusion, taken at a median of 5.7 years of follow-up, at a late-breaking trial session at the American Heart Association Scientific Sessions (AHA 2022; 5–7 November, Chicago, USA). The findings were simultaneously published in Circulation.

ISCHEMIA-EXTEND follows on from the ISCHEMIA trial, looking at the potential benefit in adding cardiac catheterisation and revascularisation—with either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery—to optimal medical therapy in stable patients with at least moderate ischaemia on a stress test.

Both patient groups in the study received guideline-directed medical therapy, with those in the conservative group treated invasively if symptoms worsened despite drug therapy or in the case of an emergency.

Hochman delivered the initial results of the trial at AHA 2019 (16–18 November, Philadelphia, USA), which were taken at a median of 3.2 years, and showed that the revascularisation strategy conferred no additional benefit when compared to the conservative approach.

Interim findings from the extended study presented at AHA 2022 included all 5,179 patients for whom data were collected in the initial trial, discounting patients who had withdrawn consent after the initial phase of the study or declined participation in extended follow-up. In total, 557 deaths occurred from the start of the trial up to the end of the current study period which ran through to December 2021, roughly doubling the total of 289 deaths that had occurred after the initial study time point.

The objective of the long-term follow-up is to assess whether there are between-group differences and to increase precision around the treatment effect estimates for endpoints including all-cause mortality, CV mortality, and non-CV mortality, Hochman noted in her presentation at AHA 2022. Reporting the interim findings from the study Hochman relayed that all-cause death occurred in 13.4% of patients in the conservative treatment group, compared to 12.7% in the invasive treatment group (hazard ratio [HR]: 1; 95% confidence interval [CI]: 0.85, 1.18; p=0.741 (log rank).

“For cardiovascular death, we had the hypothesis that spontaneous MI reduction would lead to a reduction in cardiovascular death,” Hochman commented, before going on to note that this “appears to be the case,” with the rate of CV death standing at 8.6% in the conservative treatment arm and 6.4% in the invasive treatment arm (HR: 0.78, 95% CI: 0.63, 0.96; p=0.008). Finally, non-CV death stood at 4.4% in the conservative arm, and 5.6% in the invasive arm (HR: 1.44, 95% CI: 1.08, 1.91; p=0.016).

“Extended follow-up of the ISCHEMIA randomised trial over a median of 5.7 years demonstrated that an initial invasive strategy compared to an initial conservative strategy resulted in no difference in all-cause mortality, with nearly twice the number of deaths, lower risk of cardiovascular, but higher risk of non-cardiovascular mortality,” Hochman commented in the concluding remarks of her presentation. “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.”

Summing up the findings after her presentation, Hochman said: “These longer-term results build on our original findings, which is that patients with daily or even weekly angina will likely see improved quality of life, but we have more robust data that an invasive approach is not going to prolong life.

“Although cardiovascular mortality was reduced, with an invasive approach it was offset by higher non-cardiovascular mortality, so all-cause mortality is the same over time in both groups. Either strategy is acceptable, which is good news for patients, who have different preferences.”

Providing a commentary on the results at AHA 2022, Cecilia Bahit (INECO Neurociencias, Rosario, Argentina) said that the findings presented by Hochman appeared to be in line with prior research.

“When we look at the results and we put them into perspective, we see that the findings of all-cause mortality in the ISCHEMIA-EXTEND report are comparable to other previously recorded trials of revascularisation versus medical therapy,” she commented.

“During the extended follow up investigators were able to identify more death, and were able to identify lower risk of cardiovascular death in the invasive strategy, and this was in benefit of an invasive strategy with a 21% relative risk reduction, compared to the conservative arm.”

However, Bahit noted that the high risk of non-cardiovascular mortality in the invasive arm was “unexpected and remains unclear”, particularly in light of the fact that baseline prevalence of malignancy in both arms appeared to be similar.

Follow-up from ISCHEMIA-EXTEND is ongoing out to median 10 years, and Hochman reported that the final results from the trial are likely to be presented in 2026.


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