March 31st, 2014

Novartis Trial Was Stopped Early Because of a Significant Drop in Cardiovascular Mortality

The largest-ever trial in heart failure was stopped early because of a highly statistically significant reduction in cardiovascular mortality, according to one of the trial’s two primary investigators.

Earlier today I reported that the PARADIGM-HF trial testing LCZ696, a novel, first-in-class Angiotensin Receptor Neprilysin Inhibitor (ARNI), had been stopped early because the trial had demonstrated a significant reduction in the combined primary endpoint of cardiovascular death and heart failure hospitalization. This information was taken from a Novartis press release.

But it turns out that the press release wasn’t entirely accurate. For once, a company appears to have actually downplayed a positive finding in its trial. According to Milton Packer, the trial’s Co-Principal Investigator, the data are much more persuasive than might be gathered from the press release. (I spoke with Packer at the American College  of Cardiology meeting in Washington, DC.)

In general, when a trial has a combined endpoint — for PARADIGM-HF it was the combination of cardiovascular death and heart failure hospitalization — the results are largely driven by the “softer” component of the endpoint (in this case, heart failure hospitalization and not the “harder” endpoint of cardiovascular death.) This often leads to criticism when a trial has been technically superior in reducing a combined endpoint but shows little or no effect on the harder, more important, endpoint.

We won’t know the full results of PARADIGM-HF until they are presented at a medical meeting, perhaps the European Society of Cardiology meeting in August in Barcelona. But according to Packer, the trial will definitely show a large and convincing reduction in the more important endpoint component, cardiovascular death.

Packer told me that the stopping rule for the trial was “the most conservative stopping rule in any clinical trial I have ever been involved with.” More importantly, he said, “The stopping rule was not on the primary endpoint, it was on cardiovascular death. It was a stopping rule that required a very high level of statistical significance for early termination.” And it was based on this stopping rule that “the Data and Monitoring Board decided that stopping the trial was appropriate.”

Packer said, “The press release implies that the trial was stopped for the primary endpoint but that was not the case, the trial was stopped for a persuasive effect on cardiovascular mortality alone, and my enthusiasm was based on that very persuasive effect.”

Packer also told me that the trial had been powered to detect a difference in cardiovascular mortality, so the finding may not be quite so unexpected. This also explains the trial’s large size.

To view all of our coverage from the ACC meeting, go to our ACC.14 Headquarters page.

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