Benefits of Early, Aggressive Cholesterol-Lowering After Myocardial Infarction

By Michael H. Crawford, MD

Synopsis: A large national registry study of myocardial infarction patients has shown that achieving target levels of non-high-density lipoprotein cholesterol by one month and maintaining them for at least one year reduces subsequent major adverse cardiac events and argues for aggressive early cholesterol management rather than the usual stepwise approach.

Source: Schubert J, Leosdottir M, Lindahl B, et al. Intensive early and sustained lowering of non-high-density lipoprotein cholesterol after myocardial infarction and prognosis: The SWEDEHEART registry. Eur Heart J. 2024;45(39):4204-4215.

Current data suggest a stepwise approach to achieving low levels of cholesterol post-myocardial infarction (MI). However, this could lead to a delay in achieving target levels and potentially cause harm. Thus, these investigators from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry hypothesized that the early achievement of non-HDL cholesterol (nHDL-C) levels (total C-HDL) < 85 mg/dL would result in better outcomes than usual care.

SWEDEHEART collects data on acute MI patients from 74 cardiac care units in Sweden. From this database, patients 18-79 years of age without previous cardiovascular disease and a first MI between 2005 and 2022 were selected. The 56,262 subjects who had an admission and one-year post-MI cholesterol levels measured were included in this study. They had a median age of 64 years and 26% were women. By protocol, they had two-month and one-year follow-up visits. The primary outcome was major adverse cardiovascular events (MACE), which included all-cause mortality, MI, and ischemic stroke.

At admission, mean nHDL-C was 152 mg/dL and low-density lipoprotein (LDL) cholesterol was 129 mg/dL. At one-year, nHDL-C averaged 90 mg/dL and LDL averaged 70 mg/dL. At one-year, nHDL-C was unchanged or increased in 12%, < 46% reduced in 52%, and ≥ 46% reduced in 37%. After a median follow-up of 5.4 years, MACE occurred in 17%, 10% died, and 7% had recurrent MI. Comparing the lowest quartile of nHDL-C to the highest at one year, MACE was significantly less in the low group (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.71-0.81).

A landmark analysis of the relative effect of nHDL-C levels at two months or change in nHDL-C between the index event and two months on early events (occurring between two months and one year) vs. late events (occurring after one year) showed that the benefits of lower on-treatment nHDL-C levels or larger changes in nHDL-C on MACE, mortality, and MI already were apparent within the first year, with greater relative benefits observed after one year. Sensitivity analyses in subgroups with diabetes, body mass index > 30 kg/m², statin use on admission, estimated glomerular filtration rate, age, and sex exhibited results nearly identical to the main analysis.

The authors concluded that the lowest risk of MACE post-MI was observed when target nHDL-C was achieved within two months of MI and sustained thereafter. These findings challenge the current stepwise approach for cholesterol lowering after MI.

Commentary

Since this is not a randomized trial of early aggressive therapy compared to the usual stepwise approach, one might question how different the findings of this observational study are compared to usual care.

Other observational studies have shown that only about 20% of post-MI patients achieve the guideline-recommended goal of an LDL < 55 mg/dL; 40% to 45% achieve this goal if ezetimibe is added. Thus, there seems to be a real need for more aggressive therapy.

Some have worried that too low an LDL might be harmful, but studies that achieved LDL down to 20 mg/dL have not shown harm. Consequently, the authors recommend starting a high-potency statin plus ezetimibe immediately post-MI, with lipid level reassessment at two months. At my institution, the practice is to start atorvastatin 80 mg/day, but not necessarily with ezetimibe. Then, at two months, the authors suggest adding other non-statins if the patient is not at target.

For patients who are taking high-potency statins at admission, the authors suggest going right to the injectable drugs that target PCSK9. Previous studies have shown that it is the level of cholesterol achieved that is important, not how it is accomplished.

The strengths of this study are its large size and robust comprehensive data collection. Also, it has an observation period of up to 13 years. Three-quarters of the patients < 80 years of age were enrolled in a cardiac rehabilitation program. In addition, they used nHDL-C as the measure of the intervention, which is known to include other atherogenic lipoproteins in addition to LDL. However, apolipoprotein B was not available for the entire study period, so it was not included.

Limitations included that this was an observational study, but a randomized trial of this topic would be difficult to accomplish and may not be ethical. There were no patients on admission 80 years of age or older. Few patients received PCSK9 agents. There are no data on adherence to therapy. Finally, the role of lifestyle changes was not assessed.

In summary, this study shows that getting cholesterol levels to guideline targets within two months post-MI and sustaining them results in superior long-term outcomes, which are not different in subgroups based on age, sex, or comorbidities.

Michael H. Crawford, MD, is a Professor of Medicine and Consulting Cardiologist, University of California Health, San Francisco.