Ezetimibe and Cardiovascular Outcomes

Published - Written by Chana Sacks

As you walk into Mr. R’s room to see if he has last-minute questions about his discharge medications, you can’t believe how different – how much better – he looks dressed in his usual clothes, instead of an errantly-snapped hospital gown.   You met him 4 days ago, when he was wheeled, pale and groggy, onto your unit directly from the cardiac catheterization lab.  There, a coronary stent was placed to open the blockage responsible for the crushing chest pain that had gripped him while he was at home working on his car.

Over the past few days, you have tried to teach him a bit about what caused his heart disease – and how to treat it.  You have discussed diet, exercise, anti-platelet drugs, and you have spent a lot of time talking about cholesterol.  He has told you that he has never before taken a medication regularly – “I just never thought of myself as a med person, doc” – and that he hasn’t seen a primary care physician in years.  But he tells you he is ready to make some changes.

You have told him what we know: that treatment with statins lowers LDL cholesterol and reduces the risk of another heart attack.   And while you were telling him that with such confidence, it was all that we still don’t know about cholesterol-lowering therapy that ran through your mind:  what is the optimal LDL for someone who has had a heart attack?  Should that be achieved with a statin alone, or is some combination of lipid-lowering medications ideal?

In an attempt to address some of the uncertainty about the potential benefit of adding non-statin treatment to a statin, the IMPROVE-IT investigators conducted a randomized trial, now published in NEJM, to compare two lipid-lowering regimens: a statin alone versus a statin plus ezetimibe, a medication that reduces the intestinal absorption of cholesterol.  The data seem to suggest that lower LDL is better, perhaps independent of how that is achieved.

18,000 patients hospitalized for an acute coronary syndrome were randomized to either simvastatin 40mg plus placebo or to simvastatin 40mg plus ezetimibe 10mg.  Like your patient, about 75% of participants were men, with an average age in their early 60s; two thirds had been on no lipid-lowering agents prior to this hospitalization.

The results: at the start of the trial, LDL in both groups was 94mg/dl. At one year, the mean LDL cholesterol was lower in the simvastatin/ezetimibe group (53 mg/dL) as compared with the simvastatin/placebo group (70 mg/dL).  At 7 years of follow-up, the primary endpoint of cardiovascular death, major coronary event, or non-fatal stroke occurred in 32.7% of the simvastatin/ezetimibe arm versus 34.7% of the statin/placebo arm, a statistically significant 2% difference.  This means that about 50 patients would need to be treated for 7 years to prevent one event.  No differences were observed in the pre-specified safety endpoints.  Importantly, after a median of 6 years, 42% of patients in each group had discontinued treatment.

So for Mr. R – should you add an ezetimibe prescription to his already impressive stack of new medications?  Not necessarily.  In an accompanying editorial entitled “Proof that Lower is Better,” NEJM editors Drs. John Jarcho and John Keaney describe the significance of this trial and caution against drawing that conclusion: “IMPROVE-IT should not be interpreted as demonstrating anything uniquely beneficial about the use of ezetimibe. Indeed, the real implication of IMPROVE-IT is to suggest that all LDL reductions, regardless of mechanism, are of equivalent benefit.”

So, as you and Mr. R spend your last few minutes together before discharge, maybe the focus shouldn’t be on the modest improvement achieved in this trial, but rather on emphasizing the importance of taking these medications and making lifestyle changes for the long haul.  Today, he feels motivated by his harrowing experience and empowered by the knowledge you have shared.  You encourage him to keep those feelings and his goals in mind, even as the memories of this hospitalization fade.  He nods and heads out – soon, he says, he wants to get back to working on that car.

View the Quick Take video summary of this article, and join the discussion with the authors on the NEJM Group Open Forum.

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