PCSK9 inhibitor reduces MI risk across multiple MI subtypes and sizes
Effect of Evolocumab on Type and Size of Subsequent Myocardial Infarction: A Prespecified Analysis of the FOURIER Randomized Clinical Trial
Introduction and methods
By treatment of CV patients with PCSK9 inhibitor evolocumab, the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial demonstrated a reduction in primary composite endpoint of CVD outcomes by 15% over a median of 2.2 years, including a robust 27% reduction in MI . However, notwithstanding the benefit of LLT for treating MI [1-5], prognosis of MI subtypes is not uniform when taking different clinical circumstances (spontaneous or procedural), subtypes (STEMI, non-STEMI), or sizes into account [6, 7].
For this reason, by focusing on a prespecified descriptive analysis of endpoints, the present study examined MI outcomes in the FOURIER trial. In the FOURIER trial, patients (n=27564, aged 40-85 years) with clinically evident CVD (prior MI, prior nonhemorrhagic stroke, or symptomatic peripheral arterial disease) were randomized to receive either evolocumab or placebo on a background of statin therapy. Either 140 mg every 2 weeks or 420 mg monthly was taken as treatment, per patient preference.
For the current analysis, regarding subtypes, primary MI endpoints were categorized into universal MI subtypes and subtypes related to ECG (STEMI, non-STEMI). Universal subtypes included 1 (spontaneous atherothrombotic), 2 (myocardial oxygen supply-demand mismatch), 3 (presenting with typical symptoms and dying before cardiac biomarkers could be drawn), 4 (percutaneous coronary intervention [PCI]–related), and 5 (associated with coronary artery bypass grafting). Regarding size, MI endpoints were categorized by peak cardiac troponin level elevation in multiples of the upper limit of normal (UNL). To assess timing of benefit, serial landmark analyses were performed of MI from 0 to 6 months, 6 to 12 months, 12 to 18 months, and >18 months. Acute and chronic myocardial injury not associated with ischemia were classified as no MI. Exclusions from the FOURIER trial relevant to the current analysis included MI within 4 weeks of randomization and planned or expected cardiac surgery or revascularization within 3 months after randomization.
- Evolocumab significantly reduced risk of first MI by 27% (HR, 0.73; 95% CI, 0.65-0.82; P <0.001). Type 1 (spontaneous) MI was reduced by 32% (HR, 0.68; 95%CI, 0.59-0.79; P <0.001) and type 4 (procedural) was reduced by 35% (HR, 0.65; 95%CI, 0.48-0.87; P=0.004), with no effect on type 2.
- Similarly, evolocumab significantly reduced risk of non-STEMI by 23% (HR, 0.77; 95% CI, 0.68-0.88; P <0.001) and STEMI by 36% (HR, 0.64; 95%CI, 0.49-0.84; P <0.001). Pattern and timing of benefit for STEMI and non-STEMI were similar with an apparent separation of event curves beginning at approximately 6 months for each and continuing to separate throughout follow-up.
- Benefit of evolocumab was consistent regardless of MI size with a 34% reduction in MIs with troponin level ≥10 times the UNL (HR, 0.66; 95%CI, 0.56-0.77; P <0.001). HRs ranged from 0.64 to 0.72 across differing troponin level thresholds.
- For ≤12 months of treatment, there was a 20% reduction in MI (HR, 0.80; 95%CI, 0.68-0.94; P=0.006), with >12 months of treatment a 35% reduction (HR, 0.65; 95% CI, 0.55-0.77; P <0.001). On closer examination, there were risk reductions for MI of 31% from 6 to 12 months (HR, 0.69; 95% CI, 0.55-0.87), 34% from 12 to 18 months (HR, 0.66; 95%CI, 0.51-0.85), and 35% (HR, 0.65; 95% CI, 0.55-0.77) from >18 months of treatment.
This prespecified analysis of the FOURIER trial showed that LDL-c lowering with evolocumab significantly reduced risk of MI across multiple MI subtypes related to plaque rupture, smaller and larger MIs, and both STEMI and non-STEMI.