Early Combo Therapy With Ezetimibe Lowers MACE Risk After MI

A strategy that combines high-intensity statin therapy with ezetimibe early after myocardial infarction results in a lower risk of recurrent events when contrasted with approaches that start combination therapy late or not at all, according to a new analysis of Swedish data.

Combination therapy is likely needed for most patients after a recent MI to achieve aggressive LDL-cholesterol targets laid out by US and European guidelines and should be started early to prevent “avoidable harms,” the report’s authors say.

“If ezetimibe, which is a generic drug, started early, ideally before hospital discharge for pragmatic reasons, is added to high-intensity statins, a large number of adverse events can be avoided,” Kausik Ray, MBChB, MD (Imperial College London, England), one of the study investigators, told TCTMD.

In other words, he said, “our current approach is causing harm” and placing an avoidable burden on the health system.

In the US guidelines, a high-intensity statin is recommended for patients with atherosclerotic cardiovascular disease (ASCVD) because there is a lower risk of recurrent events with greater reductions in LDL cholesterol. The broad target for patients with ASCVD is less than 70 mg/dL, but some US guidelines push levels to less than 55 mg/dL in high-risk ASCVD patients. In Europe, a target of less than 55 mg/dL also is recommended for patients with ASCVD.

“The way guidelines deploy combination therapy is through a series of steps based on measurement of LDL, which means that many, if not all, only get combination therapy very late,” said Ray. “We also know only one in five patients on high-intensity statin monotherapy get to goal, so the need for combination therapy is inevitable or [we should] forget being serious about the goals.”

In an accompanying editorial, Clara Chow, MBBS, PhD (University of Sydney, Australia), and colleagues say that up-front combination therapy can reduce “therapeutic inertia, which is a foible of the ‘step-up to achieve target’ approach endorsed by many cardiovascular guidelines.” Like Ray, the editorialists point out that many real-world patients do not get to the recommended LDL-cholesterol target after MI.

“Based on the evidence provided in the study and the culmination of evidence to date related to the topic, it seems reasonable and pragmatic to initiate combination lipid-lowering therapy early in MI patients, perhaps before hospital discharge,” write Chow and colleagues.

Only one in five patients on high-intensity statin monotherapy get to goal, so the need for combination therapy is inevitable. Kausik Ray

Marc Bonaca, MD (University of Colorado Anshutz Medical Campus, Aurora), who wasn’t involved in the study, stressed that these are high-risk patients.

“When we talk about patients with risk factors for cardiovascular disease, we try lifestyle, add a statin, and adjust over time to get LDL to goal,” he told TCTMD. “That may be right for people who have cholesterol as a risk factor who’ve never had an event or don’t have high-risk disease. For people coming in with a heart attack, this notion that we should wait to titrate over time doesn’t really quite fit.”

In this setting, using more-intensive combination therapy up front is warranted given that the goal post-MI is plaque stabilization. When rounding in the cardiac care unit, Bonaca said, he is very aggressive with up-front combination therapy and will add ezetimibe for patients when a statin alone won’t reduce LDL levels sufficiently.

“I think the data tell us that they will do better even if the relative risk reduction is modest,” he said.

Steven Nissen, MD (Cleveland Clinic, OH), believes “fervently” that lower is better when it comes to LDL cholesterol and that post-MI patients should aim for the lower LDL target of less than 55 mg/dL. He also believes that ezetimibe is a reasonable addition to high-intensity statin therapy.

Despite that, the decision to add ezetimibe during hospitalization or upon discharge should be made on a case-by-case basis, he advised.

“If someone comes in with an MI and their LDL is 100, and you give them rosuvastatin 40 mg, they’re going to get down below 50 mg/dL,” said Nissen. “There’s no real value in adding an additional agent to their regimen. If they come in with an LDL of 160, absolutely throw the book at them and try to get their LDL down really low with combination therapy. That’s the sensible approach.”

Emulating a Randomized Trial

The new analysis, which was led by Margret Leosdottir, MD, PhD (Lund University/Skåne University Hospital, Malmö, Sweden), and published last week in the Journal of the American College of Cardiology, was intended to help understand whether the delay in treatment escalation was inferior to earlier initiation of combination therapy. Given the potential ethical problems of delaying treatment to patients, Ray said the researchers sought to emulate a clinical trial using observational data from the SWEDEHEART registry. To do so, they used a “clone-censor-weight” approach, a method meant to overcome immortal time bias and confounding. 

The dataset included 35,826 patients (median age 65.1 years; 26.0% female) hospitalized for an MI between 2015 and 2022 who were discharged on a high-intensity statin. Of these, 16.9% were prescribed ezetimibe within 12 weeks of discharge (early group) and 18.1% were prescribed ezetimibe at 13 weeks or later (late group). Roughly two-thirds of patients (65.0%) weren’t dispensed ezetimibe within the first 16 months after discharge. Those who weren’t prescribed ezetimibe were older, had more comorbidities, and had a lower baseline LDL-cholesterol level.

The proportion of patients prescribed combination therapy in the 16 months after the index MI increased from 14% in 2015 to roughly 60% in 2021. Over the study period, it was more common for post-MI patients to be prescribed ezetimibe early rather than late.

Patients started on ezetimibe early were more likely than those who were started late or not at all to achieve the LDL-cholesterol target of less than 1.4 mmol/L (< 55 mm/dL) and to have a 50% or greater reduction in LDL at 1 year. Overall, 38.4% of patients started early were at goal compared with 28.8% of those started late and 25.3% of those who didn’t start ezetimibe at all.

During a median follow-up of nearly 4 years, 2,570 patients had a major adverse cardiovascular event. The unadjusted incidence rates were 1.79, 2.58, and 4.03 per 100 person-years in those who started combination therapy early, late, or not at all, respectively. Patients started on ezetimibe late after the index event had a significantly higher risk of major adverse events at 1 and 2 years compared with those started on ezetimibe early, while the risk of MACE was significantly higher at 1, 2, and 3 years among those not started on ezetimibe at all.

The risk of MACE during follow-up was 29% higher among those who didn’t receive ezetimibe at all (HR 1.29; 95% CI 1.12-1.55) compared with early combination therapy, but there was only a nonsignificant trend toward higher MACE between the early and late combination groups. For cardiovascular mortality, the respective risks at 3 years were 64% and 83% higher for patients receiving ezetimibe late or not at all when compared with those who started combination therapy early.

Wholesale vs Selective Combo Therapy

For hospitals, the post-MI checklist should include the addition of ezetimibe to high-intensity statin therapy, said Ray. “This means more get to goal early, [there are] better outcomes early, and reducing the number of steps for those who may need a third agent like a PCSK9 inhibitor,” he said.

Nissen noted that a US Food and Drug Administration advisory committee voted against approving a label claim that ezetimibe reduced the risk of cardiovascular events in ACS patients on the basis of IMPROVE-IT. Published in 2015, that study showed only a modest reduction in MACE events with the addition of ezetimibe to statin therapy compared with statin therapy alone.

“In a very similar population—the IMPROVE-IT randomized, controlled trial—the hazard ratio was 0.94,” said Nissen. “That’s a 6% reduction with ezetimibe during a 7-year trial.”

For Nissen, the large increased risk of MACE and cardiovascular mortality in those not treated with ezetimibe, especially when contrasted against the modest 6.4% reduced risk seen in IMPROVE-IT, means the SWEDEHEART analysis is likely confounded. He pointed out that the decision to prescribe ezetimibe is made for a variety of reasons not captured in the observational study.

This doesn’t mean that aggressive treatment after MI isn’t warranted at times, but these data “do not add to the evidence for combination therapy immediately after MI,” he said.

To TCTMD, Bonaca noted that while confounding is likely in the observational study, the modest benefit seen in IMPROVE-IT would be expected given that patients had relatively low LDL-cholesterol levels: 70 mg/dL at 1 year in the statin monotherapy arm versus 53.2 mg/dL in the combination group. That 15-mg/dL difference in LDL cholesterol in IMPROVE-IT would lead to a small relative reduction in MACE.

Still, the randomized trial showed that ezetimibe works when added to a statin, and also that less than 55 mg/dL is better when it comes to LDL after MI, he said.   

Other studies are testing more potent agents added to statin therapy. EVOLVE-MI, for instance, is evaluating evolocumab (Repatha; Amgen) given early on top of statin therapy in patients hospitalized for MI. Right now, physicians don’t have access to PCSK9 inhibitors as part of the inpatient formulary, Bonaca said, but EVOLVE-MI will help shed light on whether it would be beneficial.