#8 Does Ezetimibe IMPROVE-IT?

Introduction

The reason doctors like to lower their patients cholesterol is to decrease their risk of developing cardiovascular disease. There is no point decreasing cholesterol levels if it has no impact on cardiovascular disease.

Ezetimibe (Zetia, Ezetrol  or Vytorin when in combination with simvastatin), was on the market for 13 years before the manufacturers finally published a study to assess whether it actually had any benefit for cardiovascular disease. This was called the IMPROVE-IT trial and is the topic of this episode.

Background

The FDA approved Ezetimibe in 2002 without any evidence that it had patient oriented benefits like reducing cardiovascular disease. The approval was based entirely on trials that showed that it was able to lower LDL cholesterol over placebo.

This drug was marketed so aggressively in the following years that it had managed to make $5 billion dollars in its first 5 years, well before any trials were done to test whether it reduces cardiovascular disease. Remember, we want to lower cholesterol for the sake of reducing cardiovascular disease….not just to make blood tests look better.

Before the IMPROVE-IT trial came in 2015 the manufacturers of ezetimibe intermittently published studies – some on other surrogate markers like carotid artery wall thickness and other smaller ones on cardiovascular outcomes but they never looked good for ezetimibe. Let’s just go through some of these so we can get a complete picture of ezetimibe.

In 2008 they published the ENHANCE trial where they compared simvastatin and ezetimibe versus simvastatin alone for carotid intimal thickening – which is a measure of atherosclerosis in the carotid arteries. Carotid artery thickening,  is just another surrogate marker for cardiovascular disease – the thought being that the thicker your carotid arteries, the more likely one is to develop cardiovascular disease, and you could argue that this is a bit better than just showing its impact on cholesterol levels. In this study, there was no difference between the two groups. In fact the carotid artery walls were actually thicker in the ezetemibe group but this was not statistically significant.

Then, also in 2008, came the CEAS trial which compared ezetemibe plus simvastatin to simvastatin alone for 1,873 patients with Aortic Stenosis. They followed them up for 4.5 years to see if there were any differences in ischaemic events or aortic-valve events but there were none.  Concerningly, this trial showed a statistically significant increase in cancer with ezetimibe.

In 2009 came another one of these carotid artery wall thickness trials. This time they compared statin plus ezetimibe versus statin plus niacin. Niacin being another drug that has shown to reduce LDL and increase HDL. Again they were looking at the thickness of the carotid artery – and with this the niacin was better than the ezetimibe.

In 2011 there was finally a trial that showed benefits for hard outcomes with Ezetimibe, the SHARP trial. The problem, was that they compared statin plus ezetimibe versus nothing at all! ….Ezetimibe…together with a drug we already know reduces cardiovascular disease…..to nothing at all. So was it the statin doing all the work? Who knows? Its impossible to tease out how much of the benefit came from statins versus how much came from ezetemibe.

So up to this point we have a bunch of trials showing ezetimibe lowers cholesterol, and it consistently does this, lowering it by about 20%. But any trials that have tested hard outcomes have either shown no benefit for ezetimibe or have been a rediculous comparison.

IMPROVE-IT

That was all until 2015. 12 years after they got approval by the FDA they published the IMPROVE-IT trial

This came out in 2015 in the NEJM and was a multi-centre, international, double blinded placebo controlled trial to test whether ezetimibe with simvastatin is better than simvastatin alone in terms of cardiovascular outcomes. In other words, what is the added benefit of ezetmibe over statins?

Guess that acronym

Let’s play….guess that acronym…

So IMPROVE-IT stands for: IMProved Reduction of Outcomes -Vytorin Efficacy International Trial. So they took the I the M and the P from IMProved ….well played vytorin…well played.

And double points because it nicely played on the title of the PROVE-IT trial which was a trial comparing high dose statin to medium dose statin.

Study Design

They took  the highest risk patients you can possibly study. Men and women over the age of 50 who had just had a heart attack (within the last 10 days). They had to have an LDL cholesterol of over 1.3mmol/L (50mg/dL). They excluded those with kidney and liver disease. While they originally recruited 5000 patients, this number seemed to increase to 18,144 for reasons which will be discussed later.  They also extended this trial…twice. So the follow up ended up being 7 years on average.

They randomised these 18,000 patients to one of two group. One group got simvastatin at 40mg and the other group got simvastatin 40mg plus ezetimibe 10mg.

The primary outcome they were assessing was a composite of: Death from cardiovascular disease, myocardial infarction, unstable angina requiring hospital admission, revascularisation and stroke. A pretty controversial composite outcome because some argue that unstable angina and revascularisation which is just stents and things, should not be grouped together with heart attacks and strokes. They call them “softer” outcomes. But as we’ll see later from the breakdown of each of these outcomes, revascularisation and angina didn’t contribute much to the results of this composite.

Baseline characteristics of the patients in the study

All of the patients in the study had just had a heard attack within the last 10 days. But 20% of them had had a heart attack on another occasion as well as this one, so this was their second or third heart attack. The average age was 64. A quarter of them were women and a quarter had diabetes. The average LDL cholesterol was 2.4mmol/L (93.8mg/dL)

Results

LDL cholesterol decreased from 1.8mmol/L in the statin only group to 1.4mmol/L in the statin/ezetimibe group. So about a 20% reduction in LDL which is what we’ve seen in other trials with ezetimibe.

With regards to the primary outcome, the composite of heart attacks, strokes, angina and revascularisation – it  went from 34.7% in the statin only group to 32.7% in the ezetimibe-statin group.

So there was a 2% reduction in cardiovascular disease when adding ezetimibe to a statin for these extremely high risk patients when given for 7 years. To put it another way: 98% of people who have just had a heart attack and take this drug for 7 years will not derive any benefit from it.

To put these numbers in perspective: 35% developed cardiovascular disease over 7 years in this trial. A statin would reduce a 35% risk to about 26% if it was low dose and to about 23% if it was high dose. Ezetimibe reduced it from 35% to 33%.

While this trial required 18000 patients and 7 years of follow up to show a 2% reduction in CVD, a different trial that gave statins immediately after a heart attack only needed 3000 patients and 16 weeks to show  2% reduction in CVD. This was the MIRACL trial.

The relative decrease in cardiovascular disease was about 6% with ezetmibe (range from 1%-11%). Compare this to statins which give about a 25% relative risk reduction. Going from low dose to high dose statin even gives you more bang for your buck than ezetimibe – it offers about a 10%-15% further reduction in cardiovascular disease on top of that already given by the low dose statin

Now lets break down that composite outcome. The good thing, is that the bulk of the 2% reduction came from hard outcomes. They mostly came from heart attacks and strokes. There was a 1.7% reduction in non-fatal heart attacks and a 0.6% reduction in strokes.

But! there was no difference in cardiovascular mortality. Or in overall mortality. Compare this to statins which consistently show a reduction in mortality – at least for secondary prevention by about 10%. But alas, ezetimibe could not show a difference in mortality even in this very high risk population

In terms of harms, they did a good job of looking very thoroughly at all sorts of side effects, and there was really no difference in harms between the two groups. Importantly, no difference in cancer rates, because previous studies had signalled an increased risk of cancer with ezetimibe.

Discussion

  • Firstly, 42% of patients stopped therapy in each group. Now that is a very high drop out rate. So make of that what you will.
  • Secondly, there were 5 amendments to the protocol during the study! One being to increase the sample size. Was this because they didn’t like the results they were seeing? They reported in their methods that they were looking for a certain number of events 5,200 to be exact. But was that the plan from the beginning? Or did that become the plan while the study was going on? There was a lot riding on this trial. 3 billion dollar a year in sales, they really couldn’t afford not to show a benefit. Even at the expense of sound methodological quality perhaps?
  • When they ran the statistics before the study, they calculated that they needed 5000 people to detect a 9% relative risk difference in cardiovascular outcomes, but they ended up with 18,144! So my question is: where was that interim analysis for 5000 people? They must have done one to then decide to increase the number to 18,000…where is that report?
  • This drug is being heavily marketed for use in primary prevention. But, there is no evidence that it works at all in primary prevention. You could argue it barely works for secondary prevention.  But let’s assume that this 6% relative reduction carries true even in primary prevention, what benefits might patient who haven’t had heart attacks be getting from this drug? In Australia, guidelines recommend initiating cholesterol therapy once the 5 year risk reaches 15%. A statin would reduce that risk to about 10% over that five years. Whereas ezetimibe would reduce it to 14.1%. So a 0.9% reduction in cardiovascular disease if taken every day for 5 years. In America and the UK their guidelines are recommend starting therapy at a 10 year risk of 10%. So if a patient with this risk took ezetimibe every single day for 10 years, only 0.6% of them would get any sort of benefit from this drug.
  • Another criticism of this trial that has been published is that standard of care after a myocardial infarction is high dose statins at a dose of 80mg of simvastatin. While the majority of the cardiovascular benefit comes from the first 10mg, there is evidence that 80mg provides a small but significant benefit on top of this. This study only used 40mg, which is below the recommended post MI dose of statin. So would we still see a benefit for ezetemibe on top of the recommended 80mg simvastatin? That is anyones guess.
  • This is the second drug that lowers cholesterol and also lowers cardiovascular disease. So I guess it adds to the argument for the lipid hypothesis. But its important to not get carried away and use drugs that lower cholesterol but don’t have evidence on cardiovascular outcomes There have been several drugs like: fibrates, torcetrapib and niacin that improve the lipid profile but have shown no improvement in cardiovascular outcomes – some even showing harms. So while the authors, in their conclusion make a very bold statement that “this study clearly proves the lipid hypothesis” I am still cautious.

Bottom Line

For patients who have just had a heart attack, adding ezetimibe to statin therapy will at best (given other studies showing no benefit) reduce cardiovascular disease with a 6% relative reduction. Compare this to statins and blood pressure medications which offer a relative risk reduction of around 30%.  Ezetimibe will not reduce death, compared to statins which consistently show reductions in death in secondary prevention. There is no evidence that ezetimibe has any benefit in primary prevention.

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