Sacubitril/valsartan not superior to ramipril for prevention of HF, death after MI
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Sacubitril/valsartan did not significantly reduce the rate of CV death, HF hospitalization or outpatient HF requiring treatment following acute MI compared with ramipril, according to results of the PARADISE-MI trial.
Presenting data from the trial during the American College of Cardiology Scientific Session, Marc Pfeffer, MD, PhD, Distinguished Dzau Professor of Medicine at Harvard Medical School and cardiologist at Brigham and Women’s Hospital, said the rate of the composite primary endpoint was 10% lower among participants assigned sacubitril/valsartan (Entresto, Novartis) compared with ramipril, adding that prespecified observations of reductions in both investigator-reported events and total recurrent adjudicated events support “incremental clinical benefits” with sacubitril/valsartan.
“Ramipril is a very effective drug. ACE inhibitors are proven post-MI to reduce risk for death and development of HF — and by the way, so is valsartan,” Pfeffer told Healio. “We wanted to see whether we could mirror what we saw in HF with sacubitril/valsartan. We chose high-risk MI patients, randomized them within 4 days of their MI with no run-in period, which is unique, and then started both therapies in a blinded fashion. We found our primary endpoint — a composite of CV death, hospitalization for HF and outpatient HF — was reduced by 10%, and we would have needed a 15% reduction to clear statistical significance.”
Primary results
PARADISE-MI enrolled 5,669 patients in 41 countries with acute MI less than 1 week before enrollment, with left ventricular EF less than 40% and/or pulmonary congestion, plus any risk enhancer. Patients with prior HF, clinical instability or an eGFR of 30 or lower were excluded. Most of those enrolled were already receiving antiplatelet therapy (92%), beta-blockers (85%) and statin therapy (95%).
Researchers randomly assigned participants to 97 mg to 103 mg sacubitril/valsartan twice daily (n = 2,830; 23% women; 17% Black) or 5 mg ramipril twice daily (n = 2,831; 25% women; 17% Black) for a median of 23 months. More than 40% of participants in both groups had diabetes and most had hypertension.
The primary outcome was a composite of CV death, first HF hospitalization or outpatient HF requiring treatment.
There were numerically fewer primary events among patients assigned sacubitril/valsartan vs. ramipril: with 338 events (6.7 per 100 patient-years) and 373 events (7.4 per 100 patient-years) respectively. However, the difference did not reach statistical significance, with an HR of 0.99 (95% CI, 0.78-1.04; P = .17), Pfeffer said during the presentation.
Similarly, secondary endpoints of CV death or HF hospitalization, HF hospitalization or outpatient HF, CV death, nonfatal MI or nonfatal stroke, CV death and total hospitalizations for HF, MI or stroke and all-cause death all numerically favored sacubitril/valsartan vs. ramipril, with the event reductions not reaching statistical significance, according to the results.
In an exploratory analysis of the total burden of HF, including recurrent events, researchers observed a 21% reduction with sacubitril/valsartan compared with ramipril (HR = 0.79; 95% CI, 0.65-0.97; P = .02)
“When you look at the [endpoint] components and all of our secondary endpoints, they all moved in the right direction,” Pfeffer told Healio. “If you do not limit yourself to time to first event and allow second and third events of hospitalization for HF, then we do see something that would reach the .05 level, but it would have to be considered exploratory.”
Pfeffer also highlighted investigator-reported primary endpoint events for sacubitril/valsartan vs. ramipril (443 vs. 516) vs. total (first and recurrent) adjudicated primary events (452 vs. 539). In assessing investigator-reported events, the HR reached significance for sacubitril/valsartan (HR = 0.85; 95% CI, 0.75-0.96), he said.
“What we saw with the investigator-reported events ... really makes us feel like [the benefit] was there,” Pfeffer told Healio. “But we can’t stand up and shout it definitively.”
Safety ‘should not be debated’
Pfeffer said the PARADISE-MI trial is a strong demonstration of the drug’s safety and tolerability. The rate of adverse events was equivalent in both groups, with no between-group differences in angioedema, abnormal potassium levels, renal impairment or liver abnormalities. Patients assigned sacubitril/valsartan had a slightly higher rate of hypotension; those assigned ramipril were slightly more likely to report coughing.
“This is a big study of acutely ill patients, blinded to two active therapies without a run-in period,” Pfeffer told Healio. “We can now reassure people that sacubitril/valsartan is as well tolerated as an active ACE inhibitor. That is the one aspect should not be debated and should allow clinicians treating patients with HF to overcome that barrier, which is a benefit. In HF, there is no question of benefit; now, showing it is safe and well tolerated should help clinicians use it more effectively.”
Additionally, Pfeffer noted that patients entering the trial were already well-treated, which he called a credit to the cardiology community implementing the information coming from large trials.
“We saw that the use of angioplasty was impressive [and there was] high use of statins and dual antiplatelet therapy,” Pfeffer said. “This is not something the trialist does; this is something the community does. Because of this, total mortality of our high-risk population was multifold less than when we finished SAVE and multifold less than when we finished VALIANT. Good things are happening in the community.”
Perspective
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Javed Butler, MD, MPH, MBA, FACC, FAHA
Statistically speaking, the PARADISE-MI trial did not reach significance; however, taking these results with totality of evidence for sacubitril/valsartan, these results are encouraging. Sacubitril/valsartan has a positive trial in chronic HF and in acute HF with reduced ejection fraction, and in patients with HF and preserved EF, albeit mainly if the EF was less than 57%. With this background, PARADISE-MI included patients post-MI who had low EF or pulmonary congestion. All primary and secondary outcomes improved clinically and numerically, but did not reach statistical significance, except for nominally significant results for CV death, total HF hospitalization, stroke or MI.
There are two issues are worth noting. First, there were more than 200 events noted by investigators that were not included in adjudication. If you include them, the trial’s primary endpoint is positive. How to best adjudicate and include events in clinical trials needs a discussion. Second, those patients who underwent PCI tended to benefit. Could there be a synergistic benefit with revascularization and optimal medical therapy? Investigational therapy working better for patients on optimal background treatment has been noted before. Thus, while these and the issue of age and sex will be discussed, the important take-home message is that post-MI patients with low EF — not necessarily only congestion — may be considered for treatment with sacubitril/valsartan.
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Pfeffer M, et al. Joint American College of Cardiology/Journal of the American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
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