Evolocumab for Early Reduction of LDL-Cholesterol Levels in Patients with Acute Coronary Syndromes (EVOPACS)

Literature - Koskinas KC, Windecker S, Pedrazzini G et al. - J Am Coll Cardiol. 2019 DOI: 10.1016/j.jacc.2019.08.010

Introduction and methods

Risk of recurrent events in patients with acute coronary syndromes (ACS) is particularly high early after the index event [1]. Early, in-hospital initiation of high-intensity statin treatment lowers the occurrence of early events. While statins have additional favorable effects that may play a role in this risk reduction in the acute period after ACS [2], the benefit is thought to be at least partly mediated by the reduction of LDL-related risk.

Statins have a delayed onset of action. Many ACS patients fail to attain treatment targets with intensive statin therapy alone [3]. Thus, rapid and more potent lowering of LDL-c might be of potential therapeutic benefit in these patients.

PCSK9 antibodies have been demonstrated to rapidly and effectively lower LDL-c levels. Evolocumab reduced major CV events in the context of secondary prevention [4]. Evolocumab has been evaluated from several months up to 11 years following a myocardial infarction (MI) [5], but PCSK9 antibody treatment has not been evaluated in the very high-risk, acute (within days) phase of ACS.

Thus, a randomized, placebo-controlled trial was conducted to assess evolocumab administered in-hospital in patients presenting with ACS, compared with high-intensity statin alone. This EVOPACS study was investigator-initiated. Patients not at guideline-recommended targets despite prior high-intensity statin therapy, or who were projected not to attain these targets under newly-initiated high-intensity statin therapy were included. Patients hospitalized for non-ST-elevation ACS (NSTE-ACS) with symptom onset<72 hours or ST-elevation MI (STEMI) with symptom onset <24 hours before screening were potentially eligible. 308 Eligible patients were randomly assigned (1:1) to evolocumab 420 mg every 4 weeks or placebo. Study drug at baseline was administered as early as possible (within 24 hours) following randomization. The primary efficacy endpoint was % change in calculated LDL-C from baseline to 8 weeks.

Main results

• %Change in calculated LDL-c from baseline to week 8 differed significantly between the evolocumab (-77±15.8%, from mean 3.61 to 0.79 mmol/L) and the placebo group (-35.4±26.6%, from mean 3.42 to 2.06 mmol/L). Least-squares mean difference was -40.7% between groups (95%CI: -45.2 to -36.2).
• Reduction in LDL-c levels was evident at 4 weeks and maintained at 8 weeks.
• 95.7% Of patients in the evolocumab group had LDL-c <1.8 mmol/L at 8 weeks, as compared with 37.6% in the placebo group.
• Compared to placebo, evolocumab treatment was associated with reductions of 26.5% in total cholesterol, 34.2% in apolipoprotein B, 34.6% in non-HDL-c (all P<0.001) and 20% in triglycerides (P=0.024). HDL-c was higher by 4.8% (P=0.03), and apolipoprotein A1 was not significantly altered.
• Both treatment groups showed similar rates of patients experiencing adverse events, serious adverse events and adverse events leading to study drug discontinuation. Musculoskeletal pain was most commonly reported (5.8% vs. 2.6%, P=0.16). 7.7% vs. 7.2% of patients experienced serious adverse events in the evolocumab and placebo groups.

Conclusion

References

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