Adding Ezetimibe to Statin Therapy Reduces Risk of First and Subsequent CV Events: IMPROVE-IT Analysis

When every clinical outcome was counted in the IMPROVE-IT trial, including the first cardiovascular event and those that occurred thereafter, adding ezetimibe on top of simvastatin therapy provided additional cardiovascular risk protection compared with the statin alone, a benefit that goes beyond what was observed in the original trial analysis. 

Counting the first clinical outcome as well as subsequent events, adding ezetimibe 10 mg (Zetia, Merck/Schering-Plough) to simvastatin 40 mg in ACS patients reduced the risk of the primary endpoint, a composite of cardiovascular death, MI, stroke, unstable angina, and coronary revascularization, by 9% compared with treatment with simvastatin alone. In the main IMPROVE-IT analysis, which counted only the first event the patient experienced during the 6 years of follow-up, adding ezetimibe to simvastatin reduced the primary clinical endpoint by 6.4%.  

Lead investigator Sabina Murphy, MPH, of Brigham and Women’s Hospital (Boston, MA), told TCTMD that “evaluating total events more than doubled the number of events prevented with ezetimibe plus simvastatin compared with examining only the first event, which supports the benefit of continuing intensive combination lipid-lowering therapy after a recurrent cardiovascular event.”

The IMPROVE-IT study included more than 18,000 patients stabilized following ACS. In the latest analysis, which is published January 25, 2016, in the Journal of the American College of Cardiology, there were 9,545 primary endpoint events, of which 5,314 were first events and included in the primary IMPROVE-IT analysis. After the first event, there were an additional 4,231 primary endpoint events during the course of the trial. Cardiovascular death, stroke, and unstable angina occurred in equal proportion as a first and subsequent event, while there were fewer MIs and more coronary revascularizations occurring after the first clinical outcome was reported.

Overall, treatment with ezetimibe resulted in a significant reduction in the primary composite when first and subsequent clinical events were counted. The analysis also showed reductions in MI and stroke, but like the main analysis, the addition of ezetimibe had no clinical impact on mortality. An analysis of 3 prespecified secondary endpoints, which included different combinations of clinical events, also showed a significant benefit with ezetimibe.

Murphy said the present analysis points to the importance of considering all clinical events, and not just the first event, when looking at the totality of the treatment effect. “Unless it is a fatal event, thinking only in terms of first events is an artifact of clinical trial design,” she said. “A patient does not stop needing treatment when they have a nonfatal MI or nonfatal stroke, but that is when their time at risk ends in a traditional primary analysis of a trial. In reality, these patients continue to be treated and require medical care.”

No Miracles, but Support for Lower Is Better

The US Food and Drug Administration approved ezetimibe in 2002 for lowering LDL cholesterol levels, but for many years there were no data showing ezetimibe reduced the risk of cardiovascular events. While the IMPROVE-IT study showed the drug reduced the risk of hard clinical outcomes, an FDA advisory panel did not think the evidence of benefit was large enough to warrant an expanded claim for cardiovascular event reduction. As reported by TCTMD in late 2015, the majority of the Endocrinologic and Metabolic Drugs Advisory Committee felt the data from IMPROVE-IT was modest, if not “weak,” and questioned the real-world applicability of the results. 

R. Scott Wright, MD, of the Mayo Clinic (Rochester, MN), told TCTMD that based on the results from IMPROVE-IT, ezetimibe is not necessarily a “drug that does miracles,” but instead the trial supports the concept of lowering LDL cholesterol to levels beyond that which can be achieved with statins alone. In the 2 treatment arms, the median time-weighted LDL cholesterol level achieved with simvastatin alone was 69.5 mg/dL compared with 53.7 mg/dL with simvastatin and ezetimibe.

“What the study tells me is that the addition of ezetimibe is, number 1, safe, and number 2, effective as an adjunct to statins,” said Wright. “The analysis of the second, third, and fourth events of the primary endpoint showed that there is generally an event reduction consistent with the initial hypothesis that the athero-inflammatory/thrombotic disease state is modulated and mitigated by additional LDL lowering.”

For the ACS patient on statin therapy who achieves an LDL cholesterol level of 70 mg/dL, it makes sense to add ezetimibe to reduce LDL cholesterol levels to 55 mg/dL, he added.

Wright, who wrote an editorial along with Joseph Murphy, MD, also of the Mayo Clinic, noted that the American College of Cardiology/American Heart Association 2013 cholesterol treatment guidelines abandoned treating patients to a specific LDL cholesterol target. In high-risk patients, past clinical guidelines recommended treating to an LDL cholesterol target of less than 100 mg/dL, with an optional goal of treating to less than 70 mg/dL. Now, instead of those targets, the guidelines emphasize the “intensity” of statin therapy, recommending high-dose statins for high-risk patients and moderate-dose statins for those at lower risk.

To TCTMD, Wright said the IMPROVE-IT study, as well as analyses from other trials including PROVE-IT, challenges those new recommendations. He would like to see a return to cholesterol targets. “I think targets are supported by this study and many others,” he said. “Secondly, they’re very easy for providers and patients to understand.” While cholesterol targets might not necessarily be supported by evidence in every type of patient, Wright noted, the data support treating ACS patients to a specific goal.

At present, it is not known just how low LDL cholesterol levels should be reduced to achieve the maximal cardiovascular benefit in ACS, but IMPROVE-IT extends the evidence to suggest it might be at or around 50 mg/dL, he added. “In all of my patients post-ACS, I now try to get their LDL between 50 and 55 [mg/dL] if they can tolerate the therapies,” said Wright. “I think this study supports that.”

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Sources: 
1. Murphy SA, Cannon CP, Blazing MA, et al. Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome. J Am Coll Cardiol. 2016;67:353-361.
2. PROVE-IT to IMPROVE-IT: Why LDL-C goals still matter in post-ACS patients [editorial]. J Am Coll Cardiol. 2016;67:362-364.

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