Did a pricey cholesterol-lowering drug really reduce deaths, as headlines claim?

Mary Chris Jaklevic is a reporter-editor at HealthNewsReview.org. She tweets as @mcjaklevic.

A highly anticipated clinical trial result for an expensive cholesterol-lowering drug drew plenty of news coverage over the weekend, with some stories declaring the drug, Praluent, reduced the risk of death.

The Associated Press wrote:

It’s the first time a cholesterol-lowering drug has reduced deaths since statins such as Lipitor and Crestor came out decades ago.

“It’s the ultimate outcome; it’s what matters to patients,” said study leader Dr. Philippe Gabriel Steg of Hospital Bichat in Paris.

STAT had a similar take:

Praluent’s effect on mortality is a landmark in the field of cardiology, doctors said, marking the first time since the statin era that a cholesterol-lowering drug has demonstrated a significant effect on whether patients live or die.

While the coverage we saw was fairly even-handed–including the nuance that the drug showed modest benefits for patients–some stories missed a key detail: The ballyhooed mortality benefit was not the “primary endpoint” that researchers had set out to measure.

Rather, the stated aim of the randomized controlled trial was to determine how many serious complications the drug prevents.

Why should that matter?

Positive changes more likely due to chance

A trial’s primary endpoint determines how it’s designed and how many patients are enrolled.

This pricey cholesterol-lowering drug was “associated with” reduced mortality.

Secondary endpoints — which in this trial included overall mortality — are less reliable and need to be viewed cautiously.

According to a physicians’ guide called the General Practice Notebook, “secondary endpoints do not have the same statistical authority as the primary endpoint, and it is more likely that positive changes in secondary endpoints are due to chance. It has been stated that secondary endpoint results should only be used to help interpret the primary result of the trial or to provide information, or prompts, for future research.”

Those caveats didn’t make it into most of the coverage we saw.

And despite its weaker status, that mortality data captured the headlines of both the AP and STAT:

By contrast, Reuters lead with the more robust primary endpoint in its story, Regeneron/Sanofi heart drug succeeds in major trial; Will insurers pay?

The Reuters headline reflected the fact that the drug reduced a composite endpoint of four complications — heart attack, stroke, heart-related death, or serious chest pain — by 15%.

After about three years, 9.5% of patients taking Praluent versus 11.1% of those taking a placebo experienced one of those events. That outcome was the focus of the trial.

Regeneron, which markets the drug along with Sanofi, trumpeted in its news release that the drug “was associated with reduced death from any cause.” Overall mortality was 3.5% in the group that took the drug versus 4.1% in the placebo group, it said.

But as Larry Husten of CardioBrief wrote, that mortality finding “has an asterisk attached to it.”

Mortality benefit ‘isn’t statistically valid’

Husten pointed out that Praluent did not significantly lower the risk of heart-related death — one of the four components of the primary outcome. And without hard proof that the drug reduces deaths related to heart disease, the researchers cannot confidently claim that the drug reduces overall mortality, Husten said.

The reduction in overall mortality “was considered an observational finding,” Husten wrote. Observational data are a weaker form of evidence that cannot demonstrate proof of cause-and-effect.  “As a result,” he wrote “this means the company will not be able to make a mortality reduction claim without qualification.”

Cedars-Sinai Heart Institute cardiologist Sanjay Kaul, MD, “commented that the mortality finding should not be considered robust,” Husten wrote.

Writing in Forbes, Matthew Herper also picked up this point, and also quoted Kaul that the mortality benefit “isn’t statistically valid.”

To their credit, all of the stories we saw contained caveats about the modest scope of the drug’s benefits and all but STAT and the Wall Street Journal gave some absolute numbers to help readers interpret their impact.

For example, the AP wrote that “the benefit was small — 167 people would need to use Praluent for nearly three years to prevent a single death.”

The AP also included cautionary takes from two doctors:

“We need to reset our expectations” and realize that benefits for any new drug are going to be fairly small when added to already good treatments such as statins, said Dr. Jeffrey Kuvin, conference leader and cardiology chief at Dartmouth-Hitchcock Medical Center. The new drugs clearly help people at high risk and are not aimed at people at low risk, such as those who have high cholesterol but have never had a heart attack, he said.

“I’ve been unconvinced” of the drugs’ benefits but now may prescribe them for certain very high risk patients, said Duke University cardiologist Dr. Christopher Granger. But preventing fewer than one heart problem a year at the drug’s current price is not cost-effective, he said.

Business coverage zeroes in on modest impact

Some news outlets including STAT and the Wall Street Journal focused on what this trial will mean for business — namely that the findings didn’t seem to be strong enough to convince payers to cover Praluent, a type of drug known as PCSK9 inhibitor. After the trial results were announced, Praluent’s makers announced they’d cut its $14,000-a-year price for a subset of high-risk patients who appeared to respond the most.

Praluent and another PCSK9 inhibitor, Repatha, haven’t been commercially successful as payers have pushed back on their high prices and uncertain benefits.

Regeneron’s news release declared that the drug “met its primary endpoint” by showing that high-risk patients who injected Praluent along with taking statins had “significantly fewer major adverse cardiovascular events” compared to those who took statins alone.

While some of the news coverage reflected that optimistic take, Bloomberg wrote that the 15% reduction in complications was “less than the 20 percent benefit analysts say would be needed to force insurers to loosen their stranglehold.”

The cautious tone of this reporting contrasts with portrayals of Praluent as a “breakthrough” when it was approved in 2015.

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Comments (1)

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Sanjay Kaul

March 13, 2018 at 2:04 pm

While it is tempting to view mortality as the ‘ultimate’ endpoint, it must respect the laws of probability. The likelihood that mortality benefit in ODYSSEY represents a spurious (false-positive) finding due to a play of chance cannot be ruled out. Thus, it is not statistically valid to use mortality data to reliably inform and guide regulatory, clinical or insurance/payer decision-making!