ARNIs fail to show superiority over ACE-inhibitors in post-MI setting but still give new hope, PARADISE-MI study.

Although Heart Failure patients have been shown to acquire increased benefit in terms of HF hospitalization and mortality with angiotensin receptor neprilysin inhibitor (ARNIs) compared to ACE- inhibitors but for immediate post-MI patients, sacubitril/valsartan does not significantly decrease the risk of heart failure (HF) or CV death compared with an ACE inhibitor as studied the PARADISE-MI trial, the results of which were presented at ACC 2021 conference this week. But the comparable safety profile of ARNIs and ACE-inhibitors is a silver lining that opens the door for future studies with this drug in post-MI setting.

PARADISE-MI missed its primary endpoint of a 15% reduction in events needed to demonstrate superiority of the (ARNI) over an ACE inhibitor, ramipril, in this acute MI population. Nevertheless, there was a 10% reduction in the sacubitril/valsartan group and positive reports of reduced events.

"Our prespecified observations of reductions in both the composite for CV total events, as well as investigator-reported events, support an incremental clinical benefit of sacubitril/valsartan," said lead investigator Marc A. Pfeffer, MD, PhD (Harvard Medical School and Brigham and Women's Hospital, Boston, MA), in his late-breaking presentation today at the virtual American College of Cardiology 2021 Scientific Session. "The safety and tolerability of sacubitril/valsartan in this acute MI population without a run-in was comparable to that of a proven, well-used ACE inhibitor."

Pfeffer said while PARADISE-MI can't answer that question at this time, the positive safety data should allow researchers to "take a deep breath and take a deep dive" in search of patient subgroups who may benefit most from sacubitril/valsartan in this clinical scenario.

For PARADISE-MI, Pfeffer and colleagues enrolled 5,669 patients from 41 countries who had had an acute MI within the previous 7 days (mean 4.3 days). None had HF, but all had transient pulmonary congestion and/or LVEF ≤ 40%, plus at least one additional risk factor for HF or death: age ≥ 70 years, estimated glomerular filtration rate < 60 mL/min/1.73m2, diabetes, prior MI, atrial fibrillation, LVEF < 30%, Killip class ≥ III, or STEMI without reperfusion. In each group, 92% were on dual antiplatelet therapy, 85% were on a beta-blocker, and 78% were on an ACE inhibitor or ARB.

Patients were randomized to ramipril (target dose of 5 mg BID) or sacubitril/valsartan (target dose of 97/103 mg BID), with three matching blinded dose titrations.

• The primary outcome of cardiovascular (CV) death, first HF hospitalization, or outpatient HF for sacubitril/valsartan vs. ramipril, was: 11.9% vs. 13.2% (p = 0.17).

For all secondary endpoints (CV death/MI/stroke/ all cause mortality, Total HF hospitalizations, out-patient HF events, CV mortality and Hypotension), the comparisons favored sacubitril/valsartan.

Among the 23 prespecified subgroups, only two—patients age ≥ 65 and those who received PCI—showed a trend toward greater benefit with sacubitril/valsartan than ramipril.

In exploratory analysis looking at total events, however, the difference between ramipril and sacubitril/valsartan reached statistical significance for reduction in events. Similarly, investigator-reported outcomes showed an advantage for sacubitril/valsartan over ramipril for the primary endpoint (HR 0.85; 95% CI 0.75-0.96), as well as for development of outpatient HF (HR 0.69; 95% CI 0.54-0.88).

Looking at adverse events, the sacubitril/valsartan group had more hypotension than did the ramipril group (28.4% vs 22.0%) but fewer reports of cough (9.0% vs 13.1%) or liver abnormalities (4.7% vs 5.9%; P < 0.05 for all comparisons). Drug discontinuation was similar in both groups, with fewer discontinuations for cough or hypotension in the sacubitril/valsartan group.

But the disappointing results mean physicians now have more questions as to whether this drug might have a niche in a broader patient group, and whether that incremental benefit has clinical value, particularly given the drug's already-low uptake.

To summarise, rates were numerically lower in the sacubitril/valsartan arm, and the composite endpoint that included all HF events, not just the first one, showed a benefit with sacubitril/valsartan. These are interesting findings and add to the available data with angiotensin receptor-neprilysin inhibitors (ARNIs).

Source: ACC 2021: https://www.acc.org/latest-in-cardiology/clinical-trials/2021/05/14/01/22/paradise-mi