Intensive Lipid-Lowering Therapy May Reduce MACE Risk in ACS

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Intensive lipid-lowering therapies, such as ezetimibe or PCSK9 inhibitors, administered with background statin therapy could reduce the risk of three-point major cardiovascular events (MACE) in patients with prior acute coronary syndrome (ACS).¹

Current therapeutic guidelines recommend initiating high-dose statin treatment early after ACS, while combination therapy is typically given to patients with unsatisfactory low-density lipoprotein cholesterol (LDL-C) levels after a high-intensity statin prescription.²

“The results of the present meta-analysis may assist in clinical decision-making for the secondary prevention of cardiovascular events to initiate intensive lipid-lowering therapies immediately after ACS,” wrote the investigative team, led by Jing-Chao Sun, department of cardiology, Taizhou Municipal Hospital.¹

Many patients with atherosclerotic cardiovascular disease (ASCVD) struggle to achieve guideline-recommended lipid targets with statin therapy alone. Across the field, there is an increasing interest in using combination statin and non-statin lipid-modifying treatment regimens.³ Prior meta-analyses have found combination ezetimibe plus statin treatment to be associated with a significant reduction in MACE and nonfatal myocardial infarction risk in patients with ASCVD.⁴

However, as most studies have focused on patients with ASCVD, there are limited data available on the cardiovascular benefit of combination therapy for secondary prevention in ACS.¹

In the current meta-analysis, Sun and colleagues sought to value the benefit of intensive lipid-lowering therapies with background statin therapy in a population with ACS. A search was performed in PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases for articles published until April 2023.

Those that matched the inclusion criteria were randomized controlled trials (RCTs) comparing intensive lipid-lowering therapies and background statin therapy and recording the outcome of three-point MACE in patients with prior ACS. For the analysis, a risk ratio with 95% confidence intervals (CIs) was used to evaluate the primary and secondary outcomes.

After the search, 80 potentially relevant studies were identified and 9 RCTs met inclusion criteria. These 9 trials enrolled 38,640 patients with ACS, including 9,984 females (25.6%), with an average follow-up duration of 4.7 years.

In a pooled analysis, intensive lipid-lowering therapies were linked to a reduction in three-point MACE relative to background statin therapy (RR, 0.88; 95% CI, 0.83–0.94; P <.001). Investigators noted a lack of significant differences in benefits between regimens including ezetimibe and those including PCSK9 inhibitors.

Compared with background statin therapy, intensive lipid-lowering therapy significantly lowered ACS recurrence, despite demonstrating notable heterogeneity (RR, 0.82; 95% CI, 0.71–0.96; P = .013). Lipid-lowering therapies additionally led to notable reductions in nonfatal myocardial infarction (RR, 0.87; 95% CI, 0.81–0.93; P <.001), stroke (RR, 0.83; 95% CI, 0.73–0.94; P = .003), and unstable angina-related hospitalization (RR, 0.57; 95% CI, 0.33–0.99; P = .046).

On the other hand, Sun and colleagues identified no significant differences in all cause-mortality (RR, 0.94; 95% CI, 0.82–1.07; P = .329), cardiovascular disease-related mortality (RR, 0.96; 95% CI, 0.88–1.06; P = .457), nor coronary revascularization (RR, 0.89; 95% CI, 0.79–1.00; P = .057).

Overall, the team noted the lack of significant differences between the ezetimibe and PCSK9 inhibitor regimens for any relevant endpoint, despite achieving greater reductions in LDL-C levels. These data remained consistent with previous meta-analyses investigating patients with high or very high cardiovascular risk on high-dose statin treatment.

“Heterogeneity with respect to baseline patient LDL-C levels may explain these discrepancies, and the relatively short follow-up durations of the enrolled studies additionally restricted the acquisition of sufficient events when attempting to reliably compare the differences between ezetimibe and PCSK9 inhibitors administered in combination with statins,” they wrote.

References

1. _{Wu XD, Ye XY, Liu XY, et al. Benefits of intensive lipid-lowering therapies in patients with acute coronary syndrome: a systematic review and meta-analysis. Ann Med. 2024;56(1):2389470. doi:10.1080/07853890.2024.2389470}
2. _{Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes [published correction appears in Eur Heart J. 2024 Apr 1;45(13):1145. doi: 10.1093/eurheartj/ehad870]. Eur Heart J. 2023;44(38):3720-3826. doi:10.1093/eurheartj/ehad191}
3. _{Gao Y, Shah LM, Ding J, Martin SS. US Trends in Cholesterol Screening, Lipid Levels, and Lipid-Lowering Medication Use in US Adults, 1999 to 2018. J Am Heart Assoc. 2023;12(3):e028205. doi:10.1161/JAHA.122.028205}
4. _{Zhan S, Tang M, Liu F, Xia P, Shu M, Wu X. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. Cochrane Database Syst Rev. 2018;11(11):CD012502. Published 2018 Nov 19. doi:10.1002/14651858.CD012502.pub2}