PARADIGM-HF: Blockbuster is not Just a Defunct Video Store

Henry R. Black, MD


December 08, 2014

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I am Dr Henry Black, adjunct professor of medicine at the Langone New York University School of Medicine.

Some very interesting things have been going on in the most important chronic disease in older people: heart failure. We no longer call it "congestive heart failure." We call it "heart failure," because it's not necessarily associated with pulmonary congestion.

Over the past 25 years, since the introduction of therapies directed at heart failure, we have seen a progressive reduction in the risk for heart failure, although the rate is certainly not anywhere near zero.The basis for this has been the use of angiotensin-converting enzyme (ACE) inhibitors—primarily enalapril—which was tested in the early 1990s and showed about a 25% reduction in cardiovascular events. To this has been added the beta-blockers—which we were afraid to use, and now are standard therapy—and also such mineralocorticoid antagonists as spironolactone or eplerenone. All of these therapies have reduced the event rate substantially.

In my world, "blockbuster" was a failed DVD rental store, but people in the pharmaceutical industry talk about "blockbusters" as being outstanding drugs. LCZ696 has that potential. LCZ696 is a combination of valsartan at a dose of approximately 160 mg daily [Editor's note: The approximate dose of valsartan is 160 mg twice daily.] (which has been shown to be useful in systolic dysfunction, and is something we use instead of ACE inhibitors in people with a history of angioedema or who are intolerant of ACE inhibitors), and a neprilysin inhibitor, which reduces the production of vasculotoxic agents.

This was a very complicated and beautifully done study[1] that began with about 11,000 subjects and ended up randomizing about 4000 subjects to each group. To get into the study, participants had to be tolerant of ACE inhibitors at a dose that was increased from 10 mg to 20 mg (twice daily). Participants also took the neprilysin inhibitor, starting at 100 mg and increasing to 200 mg (twice daily), for 4-6 weeks. Only about 12% of people dropped out of the study because of adverse events.

Patients were followed for three interim visits. In the middle of 2014, after the third interim visit, the data safety monitoring board recommended that the study be stopped because of overwhelming benefit of the combination of angiotensin receptor blocker plus a neprilysin inhibitor, compared with enalapril alone.

The most interesting finding was that in all of the subgroups (a total of 18, including men, women, different races, country of origin, and presence of diabetes), the benefit was seen uniformly across the board. In fact, most interesting is the so-called number needed to treat, which is the reciprocal of absolute risk. One only needed to treat 21 people to achieve benefit of a reduction in the primary endpoint (cardiovascular death or hospitalization for heart failure) or 32 people to reduce cardiovascular death. This is a very impressive finding, and it may be possible that we can replace ACE inhibitors and not the occurrence of angioedema. This is not unusual, because we stopped using digitalis, which was the hallmark of heart failure therapy for hundreds of years. But it's a little too soon to jump on this bandwagon until we have further studies. Participants tended to have mild to moderate symptoms (not New York Heart Association stage 3 or 4), but the drug is very promising.

As a "hypertension person," I am looking forward to the benefits of this agent, because 79% of the patients had hypertension. It may be available soon.


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