Patients with heart failure (HF) who had an interatrial shunt inserted did not see any significant benefits overall, compared with those who underwent a placebo procedure, after a median 22-month follow-up, but results suggest the benefits of an interatrial shunt may vary by HF type, according to results from the RELIEVE-HF study presented during a Late-Breaking Clinical Trial session at ACC.24.

The first placebo-procedure controlled trial of interatrial shunting (with the Ventura shunt) in patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) randomized 508 patients (74 years old, 64% men) at 94 sites in North America, Europe, Israel, Australia and New Zealand to a shunt (n=250) or placebo procedure (n=258). All participants had symptomatic HF despite taking medications at maximally tolerated doses. About 40% of participants had HFrEF and 60% had HFpEF. Only operators knew which procedure a patient received.

Results showed no significant difference between groups for the primary effectiveness endpoint, a hierarchical composite ranking of death from any cause; heart transplant or left ventricular assist device; HF hospitalizations; worsening of outpatient HF events; and change in quality of life, as measured using the Kansas City Cardiomyopathy Questionnaire. Total wins were 28,662 and total losses were 32,305, for an unweighted win ratio of 0.89 (0.72-1.09); the win ratio that was phase weighted for the interim analysis was 0.86 (0.61-1.22; p=0.20).

Additionally, the risk of all cardiovascular events was 219 among 114 patients in the shunt group vs. 222 in 108 patients in the placebo group. The annualized rate of events in the shunt and placebo groups, respectively, was 55.7% and 56.0% (relative rate ratio [RRR], 1.00; p=0.96).

A marked improvement in quality of life across all groups was observed, including those who received a placebo procedure, suggesting a placebo effect. The change from baseline through year one was 9.5 vs. 10.2 (p=0.74).

A prespecified analysis comparing outcomes by baseline left ventricular ejection fraction suggested that the Ventura shunt may be beneficial in patients with HFrEF, who experienced improvements across all outcomes, in particular HF hospitalizations, and worsen outcomes in patients with HFpEF, who experienced increased rates of death and HF hospitalizations. In patients with HFrEF, the unweighted win ratio was 1.21 (0.87-1.67), while in patients with HFpEF it was 0.70 (0.54-0.92). Among patients with HFrEF, the annualized rate of events in the shunt and placebo groups, respectively, was 49.0% and 88.6% (RRR, 0.55; p<0.0001), while among patients with HFpEF it was 60.2% and 35.9% (RRR, 1.68; p=0.001).

In addition, for the primary safety outcome, no device-related or procedure-related major adverse cardiovascular or neurologic events were observed in either group.

"There was a tremendous placebo effect," said Gregg W. Stone, MD, FACC, et al. "These observations, especially the fact that quality of life improved in HFpEF patients who were more likely to be hospitalized for [HF] and had reduced survival after shunt treatment, raise questions about the interpretation of this quality-of-life measure in these kinds of trials."

Moreover, the authors noted that, "Although the observed differences in outcomes among people with different types of HF may inform future research and development for interatrial devices," the trial was not powered to show differences in the two types of HF and the results are exploratory. Furthermore, they noted the results may not be applicable to other interatrial shunts beyond the Ventura shunt.