Evolocumab and Outcomes in Patients with Peripheral Artery Disease (Bonaca) & Clinical Benefit of Evolocumab in Patients with a History of MI: An Analysis from FOURIER (Sabatine)

Background

Two clinical trial updates of the FOURIER study were presented during the AHA Scientific Sessions. The FOURIER trial evaluated the effect of the PCSK9 inhibitor evolocumab (140 mg Q@W or 420 mg QM) in high-risk patients with existing CV disease (previous MI or stroke, or symptomatic PAD), as compared with placebo on a background of high or moderate intensity statin therapy with or without ezetimibe. Median follow-up was 2.2 years. The primary endpoint was a composite of CVD, MI, stroke and coronary revascularization.

Previously, it has been published that PCSK9 inhibition with evolocumab lowers LDL-c with 59% to a median of 30 mg/dL, which lowers the primary endpoint with 15% in statin-treated patients.

This analyses specifically concerns patients with peripheral artery disease (PAD, claudication intermittens and ABI <0.85 and previous peripheral revascularization or amputation for ischemia, n=3642) in the lower limb, because they have an increased risk of MACE events and limb events (MALE: acute limb ischemia (ALI), major amputation (AKA or BKA), or urgent revascularization).

Another analysis concerned patients with previous MI (n=21162), with the objective to investigate if readily ascertainable clinical features of the CAD history identified patients at higher CV risk, or who derived greater benefit from PCSK9 inhibition. Patients were subdivided into three groups, based on 3 factors: time from qualifying MI, number of prior MI’s at baseline or presence of residual multivessel disease at baseline.

Main results

Findings in patients with PAD

• Evolocumab lowered the risk of CV death, MI and stroke in patients with PAD (RRR: 27%, HR: 0.73, 95%CI: 0.59-0.91, P=0.004, ARR: 3.5%, NNT-2,5jr: 29); a larger treatment effect than seen in patient without PAD (RRR: 19%, HR: 0.81, 95%CI: 0.73-0.90, P<0.001, ARR: 1.4%, NNT-2,5jr: 72).
• In patientst with PAD, but without MI and stroke (n=1505) ARR was 4.8% (NNT: 21, HR: 0.57, 95%CI: 0.38-0.88, P=0.0095).
• 42% Fewer MALE were seen in the evolocumab in the total study population (n=27.564, HR: 0.58, 95%CI: 0.38-0.88, P=0.0093).
• In evolocumab-treated patients with known PAD, the relative risk reduction in MALE was 37% (HR: 0.63, 95%CI: 0.39-1.03), and 63% in those without PAD (HR: 0.37, 95%CI: 0.16-0.88). No significant interaction was seen for PAD and treatment effect.
• In patients with PAD, but without MI and stroke, RRR for MALE on evolocumab was 57% (HR: 0.43, 95%CI: 0.19-0.99, P=0.042, ARR: 1.3%).

Findings in patients with MI

• Risk of CV death, MI or stroke was higher in placebo patients for whom qualifying MI was longer than 2 years ago (HR: 1.19, 95%CI: 1.04-1.37, P=0.01), as compared with <2 years.
• Risk of CV death, MI or stroke was higher in placebo patients with ≥2 previous MIs (HR: 2.04, 95%CI: 1.78-2.35, P<0.001), as compared with 1 previous MI.
• Risk of CV death, MI or stroke was higher in placebo patients with multivessel CAD (HR: 1.47, 95%CI: 1.27-1.70, P<0.001), as compared with no multivessel CAD.
• Multivariable adjusted analyses for the three factors yielded HR: 1.36 (95%CI: 1.18-1.57, P<0.001), HR: 1.90 (95%CI: 1.65-2.19, P<0.001) and HR: 1.34 (95%CI: 1.16-1.55, P<0.001) respectively.
• Treatment with evolocumab yielded 24% relative risk reduction in patients for whom the qualifying MI was <2 years ago and 13% for those for whom it was longer ago than 2 years. 21% RRR was seen in patients with ≥2 previous Mis and 16% with 1 previous MI. 30% RRR was seen with multivessel CAD and 11% in the absence thereof. All risk reductions were statistically significant.

Conclusion

Disclosures

• Our reporting is based on the information provided at the AHA 2017 congress -