James Januzzi, MD: Key Takeaways From PIONEER-HF

The results from the PIONEER-HF study presented at the American Heart Association Scientific Session in Chicago, Illinois, demonstrated that when compared with enalapril, administration of sacubitril—valsartan therapy over 8 weeks led to greater reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP), and reduced re-hospitalization for heart failure, and was well tolerated.

According to the results, the time-averaged reduction in the NT-proBNP concentration was significantly greater in the sacubitril—valsartan group with a “ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril–valsartan group as compared with 0.75 in the enalapril group (percent change, −46.7% vs. −25.3%; ratio of change with sacubitril–valsartan vs. enalapril, 0.71; 95% confidence interval [CI], 0.63 to 0.81; P<0.001).”

Additionally, the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups.

MD Magazine® sat down with James Januzzi, MD, Hutter Family Professor of Medicine at Harvard Medical School and a cardiologist at Massachusetts General Hospital to discuss the trial results and what cardiologists and hospitalists should know.

Interview transcript: (modified slightly for readability)

MD Magazine®: What do you think are the most important takeaways from the PIONEER-HF study?

Januzzi: Generally speaking PIONEER was a very important trial for 3 reasons. First, it illustrates that initiation of sacubitril valsartan in hospitalized patients with heart failure leads to a more substantial reduction in NT-proBNP compared to enalapril. This is important because reduction in natriuretic peptides are an excellent surrogate for the benefits of the drug.

Secondly, perhaps even more importantly, it shows that this strategy is safe. It’s important to understand that the PARADIGM-HF study which was the pivotal phase 3 trial that got sacubitril valsartan available to patients focused on [those] that were stable ambulatory patients. Whereas acutely decompensated heart failure patients were not studied in PARADIGM. The reason why this is important is because sacubitril valsartan is a relatively more potent vasodilator compared to other medicines we use in heart failure. And there were some concerns that initiation of this drug in the setting of acute heart failure might be associated with more hypotension or kidney complications. PIONEER-HF showed definitively that there was no excess risk associated with use of sacubitril valsartan in acutely decompensated patients.

Thirdly, it showed that although the study wasn’t powered for outcomes, use of sacubitril valsartan was associated with a significant reduction in cardiovascular events compared to enalapril, something that is so striking given how short the trial was in duration. Taken together, this is an important advance, specifically patients who are hospitalized for heart failure are a prime target for initiating titrating therapy with proven mortality benefit — patients are more receptive to new therapies when they are hospitalized; they’re more receptive to education about heart failure and the importance of medications and they are typically more compliant with medicines that are started in the hospital. The PIONEER study adds a much-needed piece to the puzzle in respect to understanding how to use the drug.

Another area of the trial that I think is worth highlighting is the primary endpoint. Some people say reduction in a NT-proBNP, why does that matter? The reason is because the biomarker NT-proBNP has been well validated at this point to be a very predictor of prognosis in patients with heart failure. In particular, the concentration of NT-proBNP at or around decompensated heart failure status very strongly predicts 30, 60, and 90-day post-discharge events. So, to see such a powerful reduction in NT-proBNP compared to standard practice, above and beyond the usual care we deliver to our patients with heart failure, really indicates we should be starting sacubitril valsartan in our hospitalized patients, not only to get their medicines in place for the long-term, but also to decrease the short-term risks that these patients are exposed to.

Specifically, for hospitalists, this trial has significant importance because sacubitril valsartan is a switch from pre-existing therapies. So, it’s not as if this can just add this on top of whatever the patient is taking, they actually have to think about stopping the inhibitor for 24 hours and start sacubitril valsartan or switch the ARB to sacubitril valsartan. It’s something that will take some forethought. Hospitalists play such an important role in the care of patients with decompensated heart failure that absolutely it is correct that this is a trial that hospital-based physicians really need to learn about, because we in the cardiology world will depend on that to help us improve the care for our patients.