Ezetimibe With Statin Therapy: Biggest Bang in Higher-Risk ACS Patients

Higher-risk ACS patients identified with the use of various biomarkers and treated with the cholesterol-lowering medication ezetimibe on top of statin therapy have a larger clinical benefit than lower-risk patients also treated with the combination lipid-lowering strategy, a new analysis of the IMPROVE-IT trial shows.

The results suggest that this approach, using biomarkers like C-reactive protein (CRP) and high-sensitivity cardiac troponin T (hs-cTnT), could identify higher-risk patients in the post-ACS setting. This could translate into more personalized and potentially more intensive secondary prevention, say investigators.

“Because ezetimibe is generic, its addition to statin therapy offers an economical approach to reduce LDL cholesterol,” Arman Qamar, MD (Brigham and Women’s Hospital, Boston, MA), and colleagues write online August 19, 2019, in the Journal of the American College of Cardiology. “However, several factors need to be considered before adding LDL cholesterol-lowering therapies, including the patient’s cardiovascular risk, preferences regarding use of additional pharmacotherapy, potential for impact on adherence, and cost-effectiveness.”

And because patients with stable ischemic heart disease differ in the absolute clinical benefit derived from therapy, “consideration of the absolute benefit from a particular therapy may guide the discussion with patients and further inform therapeutic decision-making,” the researchers advise.

Khurram Nasir, MD (Yale University School of Medicine, New Haven, CT), who was not involved in the study, said physicians and researchers have largely realized that the benefit of a given treatment in randomized trials differs across patient populations. “The benefit of any intervention is going to be proportional to the absolute risk,” he told TCTMD. “The higher the risk, the more likely you’re going to benefit, and the larger absolute reduction achieved will be related to a lower number needed-to-treat.

This “risk gradient” has been observed in primary and secondary patient groups, as well as in other lipid-lowering trials, including the FOURIER trial with the PCSK9 inhibitor evolocumab (Repatha; Amgen), said Nasir. For example, analyses have shown that the reduction in the risk of clinical events with evolocumab was larger in the higher-risk subgroups, such as those with diabetes, prior MI, extensive CAD, or multiple cardiovascular disease risk factors.  

IMPROVE-IT: No CVD Event Reduction Claim From FDA

The IMPROVE-IT study was a large-scale randomized trial testing the safety and effectiveness of adding ezetimibe to statin therapy in ACS patients. After 7 years of treatment, the addition of ezetimibe lowered the risk of cardiovascular death, nonfatal MI, rehospitalization for unstable angina, revascularization beyond 30 days, or stroke compared with simvastatin 40 mg alone. The benefit was modest, however, with investigators reporting a 2.0% absolute risk reduction in the primary composite endpoint with ezetimibe/simvastatin. There was a 1.8% absolute reduction in the risk of cardiovascular death, MI, or stroke with the addition of ezetimibe to statin therapy.

In a bit of a twist, the study famously did not lead to a cardiovascular event reduction indication from the US Food and Drug Administration, because advisory committee members didn’t feel the modest efficacy data supported the label change. Ezetimibe, approved in 2004 for lowering LDL cholesterol, is now available as a generic medication and is recommended in the US guidelines for high-risk patients with cardiovascular disease currently taking maximally tolerated statins but who have an LDL level of 70 mg/dL or higher. It can also be used as a cost-effective addition to statins ahead of the pricier PCSK9 inhibitors. 

In this prespecified, nested analysis, investigators evaluated the role of several cardiovascular biomarkers as a possible means to identify clinical benefit with ezetimibe. The biomarkers—hs-cTnT, CRP, N-terminal pro-B type natriuretic peptide (NT-proBNP), and growth-differentiation factor-15 (GDF-15)—have all been shown to be “useful in identifying high-risk patients post-ACS,” say researchers. They note that hs-cTnT is a marker of myocardial injury, NT-proBNP is a marker of myocardial stress, and CRP and GDF-15 are markers of inflammation. High-risk patients were defined as those with elevations in three or more of the biomarkers, while intermediate-risk patients had one or two positive biomarkers. Low-risk patients did not have any elevations in the biomarkers.

In this era of precision medicine, we have to attune our ability to identify the highest-risk groups so that we can focus our efforts and allocate our resources there to maximize our use. Khurram Nasir

With respect to the composite of cardiovascular death, MI, or stroke, which was the primary endpoint of the biomarker substudy, there was no statistically significant heterogeneity in the relative effect of ezetimibe across the three risk categories (P = 0.11 for interaction).

Investigators did observe a gradient of increasing absolute benefit from the low-risk to the higher-risk patients. For the high- and intermediate-risk ACS patients, adding ezetimibe to simvastatin reduced the absolute risk of cardiovascular death, MI, or stroke by 7.3% and 4.4%, respectively, when compared with simvastatin alone. Adding ezetimibe to statin in low-risk patients did not lead to any apparent clinical benefit. The number of high- and intermediate-risk patients needed to treat over 7 years to prevent one event was 14 and 23, respectively. In the higher-risk patients, the benefit of treatment was largely driven by a reduction in MI risk.

Different Ways to Stratify Risk  

To TCTMD, Nasir said different strategies can be used to identify higher-risk patients. While the investigators selected a biomarker-based approach, coronary artery calcium screening in the primary-prevention setting also can be used to highlight patients who won’t need to start lipid-lowering therapy or who may require more intensive interventions to modify their cardiovascular risk factors. He noted that of the 7,195 patients with stabilized ACS included in the subgroup analysis, roughly 20% were considered high-risk based on the clinical biomarkers.

“The main message here is that we need to mindful in assessing risk, even in a group with ACS,” he said. “In this era of precision medicine, we have to attune our ability to identify the highest-risk groups so that we can focus our efforts and allocate our resources there to maximize our use. Also, we could identify a group that is least likely to benefit and where they might have some flexibility or choice [in treatment].”

In an editorial, Arthur Schwartzbard, MD, and Amier Ahmad, MD (both from NYU Langone Medical Center, New York, NY), state that inflammatory biomarkers, such as CRP and GDF-15, can play an important role in risk stratification and the present study highlights the benefits of a “more nuanced risk profile,” one that incorporates inflammatory biomarkers with traditional risk factors. Such an approach would help “identify patients who would derive the most benefit from additional nonstatin therapies,” they write.

Nasir noted that the highest-risk patients treated with ezetimibe had significantly more clinical events than intermediate-risk patients who were treated with placebo. While ezetimibe reduced the risk in high-risk patients, it didn’t compete with having fewer abnormal biomarkers. “I would rather be in the intermediate-risk group and be on a placebo than be in the intervention arm in the highest-risk group,” said Nasir. “The risk really climbs in these high-risk patients. The intervention reduces the risk by a much larger gradient in the high-risk patients, but the risk level remains high.”

Finally, Nasir said that the highest-risk patients were older and more likely to have diabetes, hypertension, heart failure, PAD, prior MI, prior stroke, and chronic kidney disease than their lower-risk counterparts. While the investigators adjusted for these variables, it’s possible there is still residual confounding in the analysis. In a future study, Nasir said he’d like to see the analysis stratified by the presence/absence of diabetes, heart failure, hypertension, and so on, to know if the biomarker-based approach is effective in various subgroups, although he suspects it would be.