IMPROVE-IT heart drug trial news: Game-changer? Or balderdash?


The drumbeat of heart news coming out of the American Heart Association is loud and clear.  But some who read and listen closely are seeing and hearing arrhythmias – disturbances in the signal.

The New York Times reported:

For the first time since statins have been regularly used, a large study has found that another type of cholesterol-lowering drug can protect people from heart attacks and strokes.

The finding can help millions at high risk of heart attacks who cannot tolerate statins or do not respond to them sufficiently. And it helps clarify the role of LDL cholesterol, the dangerous form. Some had argued that statins reduced heart attack risk not just by lowering LDL levels but also by reducing inflammation. The new study indicates that the crucial factor is LDL, and the lower the levels, the better.

A physician wrote to me and several others:

“I literally cannot believe this coverage and fist pumping. Currently the most emailed NYT article.

No mention this study was conducted with people within days of an MI  (myocardial infarction or heart attack).   So only secondary prevention.

Plus a vanishingly small absolute benefit. Plus company sponsored. Plus not peer reviewed (though they’ve already influenced the jury). Plus using these marginal unreviewed results to close the entire case on LDL as an intrinsic cause of disease.

If this is how the cardiology and AHA communities want to most nobly represent their work I think we’re reaching an existential endgame for the specialty among a sea of diminishing returns on healthcare investment.

The media fascination remains. This article and what it represents seems to me a robust antipode to our work.

How do we best support just-in-time public counterweights to these parades?”

I can’t dig on this today because I’m dealing with another in a long line of caregiving issues for my 94-year old Dad.  But I turned to one of my most trusted and smartest contributors, Harold DeMonaco, to analyze the news coverage that he had seen.

A game changer!

As I dress this morning, I overheard a physician reporter on a morning news program exclaim, “This is really a game changer,”  in reference to the announcement of the results of the IMRPOVE-IT trial. Balderdash was my first thought.  There are few game changers is medicine.

Over the years I have become accustomed to the hyperbole of television news reporting.  I find it mildly amusing at times.  It was with great hope that I explored the print media’s handling of the results of the IMPROVE-IT study.  My hopes however were dashed as once again with the general reporting of this latest chapter of the eztimibe story.

Zetia(ezetimibe) has been around for over a decade.  It was approved by the Food and Drug Administration to reduce total cholesterol, LDL cholesterol, apoliprotein B and non-HDL cholesterol in patients with elevated levels.  Notice that the approval says nothing about lowering cardiovascular risk.

The drug works by reducing absorption of cholesterol from the diet.  Statins on the other hand work to reduce formation of cholesterol in the liver by blocking a key enzyme. The two modes of action have long been thought to provide an advantage to people whose “numbers’ aren’t optimal on a statin alone or who cannot take high enough doses of a statin.

Zetia is approved alone, with diet and exercise and in combination with a statin.  While the drug alone and in combination does lower cholesterol levels, evidence of  lowering of cardiovascular risk has been a bit elusive.  An earlier trial in patients with a genetic form of elevated cholesterol comparing eztimibe alone or in combination with simvastatin(brand name Vytorin)  failed to demonstrate a difference in surrogate markers of cardiovascular disease.

The hype today is due to a presentation at the American Heart Association Annual meeting in Chicago.  Researchers provided results of the IMPROVE-IT trial.  The study enrolled 18,000 subjects who had suffered heart attacks or chest pain and randomized them to either Vytorin or the statin, called simvastatin, alone. Over the six year duration of the study, 34.7% of the subjects who were being treated with simvastatin alone had a heart attack, stroke, acute hospitalization or revascularization procedure.  This compares to 32.7% of those treated with the combination of simvastatin and ezetimibe (aka Vytorin)  Yes, indeed, that is a 2% absolute difference.  At first glance, not very impressive although it was a statistically significant difference and the greatest impact was in heart attack and stroke.  But it is still only a 2% difference.  LDL-cholesterol levels were lower in the people treated with the combination as compared to those who only received the statin (54mg/dl vs. 69mg/dl).  Many would argue that the study confirmed that lowering of LDL-cholesterol is important.  And, the lower the better.

Going down the standard criteria used by HNR, most reporting to date would not score very well.  One article, by Mathew Herper of  Forbes  did the best, in my estimation, in putting the study results into context and perspective.

If you are one of the millions of American adults taking your daily ration of a statin, you should read the Forbes article before you run off to your primary care physician asking for the “game changer”.  Here is perhaps the most important portion in Herper’s article

1. The Result Is Modest
The result is, in a word that came up regularly during interviews with 15 cardiologists and industry executives, “modest.” No deaths were prevented by using the $7-a-day Vytorin pill instead of a 25-cent generic.

Researchers at Duke and Harvard’s Brigham & Women’s Hospital said in a press release that 50 patients had to be treated to prevent a heart attack or stroke – an impressive figure. But that’s over seven years. Over five years, the number would be 70, compared to 44 for other statin trials according study author Christopher Cannon. It would cost $880,000 to prevent that heart attack or stroke, at least until Zetia goes generic in 2016. “As expensive as it is, it’s less expensive than the cost of a stroke,” argues Duke University’s Robert Califf, one of the researchers who designed the study.

To some cardiologists who have been critics of the drug, the size of the effect – a 6.4% relative decrease – remains an issue.  “I will be the first to say it is a positive result, that it is a meaningful, it shows that lowering LDL with a non-statin, in this case ezetimibe, does in fact reduce morbidity and mortality a little bit,” says Steven Nissen of the Cleveland Clinic. “But it’s a very specific population, it is a very small population, and it took a very long time. It should not be overstated.”

Allen Taylor, chief of the cardiology division at Medstar Georgetown University Hospital, was even stronger: “Risk reduction of 6% is nothing to dance around about,” he says. “It’s very clinically marginal. It’s positive only because it’s so big and so long they brought it down to such a low chance of failing that even a marginal clinical result like this could be statistically in the bounds of value.”

The results of the IMPROVE-IT study will likely be presented to the Food and Drug Administration as evidence that ezitimibe used in combination with a statin (more specifically when used in combination with simvastatin) lowers cardiovascular risk.  Regardless of the FDA actions however, there is a strong likelihood that sales of Vytorin will soar over the coming weeks and months.   If you own stock, you should be happy.  If you are represented by the subjects enrolled in the trial, you have another option to reduce your risk of a cardiovascular event.  I can only hope that we will see a reintroduction of the people who look like food ad in the near future.


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Comments (5)

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Marilyn Mann

November 25, 2014 at 6:58 am

I agree with your take on this. I just want to point out an error in the following sentence:

“An earlier trial in patients with a genetic form of elevated cholesterol comparing eztimibe alone or in combination with simvastatin(brand name Vytorin) failed to demonstrate a difference in surrogate markers of cardiovascular disease.”

The trial you are referring to is the ENHANCE trial. In ENHANCE, *simvastatin* alone was compared with simvastatin plus ezetimibe.

Someone who is on a moderate dose of a statin could benefit more from switching to a more intensive statin, as compared with adding ezetimibe. For example, in the PROVE IT-TIMI 22 trial, patients with acute coronary syndrome benefited from being treated with 80 mg atorvastatin, as compared with 40 mg pravastatin. After 2 years, the rate of patients reaching a composite primary end point was significantly lower with atorvastatin (22.4 versus 26.3 percent). That’s a much larger and faster benefit as compared with ezetimibe, and atorvastatin is available in a generic.