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Supplements PCSK9 Inhibitors: A Guide for Managed Care
Epidemiology and Management of Hyperlipidemia
Samantha Karr, PharmD, FCCP, BCPS, BCACP, BC-ADM
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PCSK9 Inhibitors and Managing Cost in the Managed Care Setting
Sheila L. Stadler, PharmD, BCPS-AQ Cardiology, CLS; and Thomas J. Cook, PhD, RPh

PCSK9 Inhibitors and Managing Cost in the Managed Care Setting

Sheila L. Stadler, PharmD, BCPS-AQ Cardiology, CLS; and Thomas J. Cook, PhD, RPh
Efficacy, Safety, and Tolerability
Alirocumab and evolocumab were approved in 2015 as adjunct therapies, in addition to diet and maximally tolerated statin therapy.19,20 They share indications for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or with clinical atherosclerotic cardiovascular disease (ASCVD) where additional lowering of LDL-C is necessary beyond maximally tolerated statin therapy and diet.19,20 Evolocumab has an added indication for treatment in adults with homozygous familial hypercholesterolemia (HoFH).20 Patients with HeFH inherit a pathogenic variant in 1 of 3 key genes that are involved in lipoprotein metabolism: APOB, LDLR, or PCSK9.21,22 HoFH is more rare than HeFH, with a prevalence rate of about 1 in 1 million births compared with up to 1 in 200 individuals with HeFH.21

Both approved PCSK9 inhibitors have been studied in numerous randomized, controlled clinical trials with patient populations that include HeFH, established CVD, and/or statin intolerance while evolocumab has been studied in patients with HoFH as well. Several robust meta-analyses also provide excellent guidance in analyzing the safety and efficacy of the PCSK9 inhibitors.23-25
In their meta-analysis, Navarese et al reviewed 24 phase 2 and 3 randomized, controlled trials with more than 10,000 subjects. Combined analyses of primary clinical endpoints and secondary safety endpoints were reported for alirocumab and evolocumab. The summary analysis of efficacy endpoints, primarily a reduction in LDL-C, was also reported as combined results of the 2 PCSK9 inhibitors, justified by additional analyses on the type of and dose of PCSK9 inhibitor. The authors’ primary conclusions were that treatment with PCSK9 inhibitors, either alirocumab or evolocumab, resulted in a significant reduction in LDL-C with PCSK9 antibody treatment compared with no anti-PCSK9 treatment (47.49%; 95% CI, 25.35%-69.64%; P <.001); a significant difference in all-cause mortality (0.31% vs 0.53%, respectively; OR, 0.45; 95% CI, 0.23-0.86; P = .015); and a significant difference in myocardial infarction (MI) (0.58% vs 1.00%; OR, 0.49; 95% CI, 0.26-0.93; P = .030), with no increase in serious AEs compared with controls.24

Zhang et al evaluated 25 randomized, controlled trials in their meta-analysis of alirocumab and evolocumab, and reported separate analyses for each. In the primary efficacy outcome of reduction of LCL-C at 12 weeks of follow-up, at a dosage of 420 mg monthly, evolocumab versus placebo significantly reduced LDL-C levels by 54.6% (95% CI, 50.5%-58.7%); at 140 mg biweekly, LDL-C was reduced by 60.4% compared with placebo (95% CI, 52.0%-68.8%). Further, compared with ezetimibe, evolocumab significantly reduced LDL-C at dosages of 420 mg monthly (36.3%; 95% CI, 33.9%-38.8%) or 140 mg biweekly (38.2%; 95% CI, 34.5%-41.5%).

Alirocumab also significantly reduced LDL-C, with the greatest reduction seen with biweekly dosing. Compared with placebo, 150-mg to 300-mg monthly dosages of alirocumab reduced LDL-C by 32.2% (95% CI, 15.6%-48.7%), while a biweekly dosage of 50 to 150 mg of alirocumab reduced LDL-C by 52.6% (95% CI, 47.0%-58.2%). Compared with ezetimibe, biweekly dosages of 50- to 150-mg dosages of alirocumab reduced LDL-C by 29.9% (95% CI, 26.9%-32.9%).

Safety results, in the form of common AEs for evolocumab and alirocumab, did not show significant differences compared with placebo or ezetimibe, except for 2 parameters for alirocumab. Treatment with alirocumab resulted in an increased rate of injection-site reactions (RR, 1.48; 95% CI, 1.05-2.09) compared with placebo. Also, alirocumab exhibited an overall significantly lower rate of death compared with placebo (RR, 0.43; 95% CI, 0.19-0.96).25

Through the Drug Effectiveness Review Project (DERP),26 McDonagh et al produced a systematic review of 17 clinical studies of evolocumab or alirocumab.23 These included 7 studies for alirocumab10,27-32 and 10 for evolocumab.33-42 The clinical studies were evaluated for quality using methods developed through DERP43 and with respect to strength of evidence, based on the guidance from the Agency for Healthcare Research and Quality (AHRQ).44 In the absence of clinical trials that directly compare alirocumab and evolocumab in a face-to-face, controlled manner, this type of systematic review may provide a valuable guidepost for evaluating the efficacy of the 2 PCSK9 inhibitors.

The clinical studies evaluated by McDonagh et al were stratified based on the characteristics of the patient populations (eg, HeFH or HoFH with high CV risk, patients with varied CV risk). Based on the AHRQ’s strength-of-evidence criteria, alirocumab performed best in studies of patients at high CV risk, leading to greater reductions in LDL-C levels and more patients reaching defined goals for LDL-C (ie, <70 mg/dL). In patients with HeFH, most of whom were concurrently taking a statin and ezetimibe, the strength of evidence for a greater reduction in LDL-C was higher for evolocumab at either 140 mg biweekly or 420 mg monthly compared with placebo. Evolocumab in patients with HoFH concurrently taking a statin and ezetimibe was determined to significantly reduce LDL-C.23 To date, alirocumab has not been studied in patients with HoFH, which is reflected in the approved indications.15 The analysis of AE data concluded that no differences in safety were observed for either PCSK9 inhibitor compared with placebo, with the possible exception of injection-site reactions. Overall, the review by McDonagh et al concluded that “moderate to large” reductions in LDL-C were evident when a PCSK9 mAb is used in conjunction with statin therapy with or without ezetimibe. The authors caution that long-term benefits and risks of the PCSK9 inhibitors are generally unknown at this time.23

The reviews of PCSK9 inhibitor efficacy and safety studies provide evidence that alirocumab and evolocumab are effective at reducing LDL-C levels in at-risk populations. Although no direct comparison study is available, the meta-analyses seem to show that the compounds are almost comparable in their efficacy and safety. One major difference is that only evolocumab has shown efficacy in patients with HoFH. From the multiple studies, the results show that PCSK9 inhibitors may reduce LDL-C levels by at least 47% composite, compared with placebo (range: 23%-71%).24,25 No major concerns are evident with respect to AEs.

CV outcomes trials for PCSK9 inhibitors, which are longer in duration, add to the body of literature to evaluate safety and efficacy. The FOURIER trial enrolled 27,564 patients with established ASCVD on moderate- to-high-intensity statin therapy and added evolocumab at 140 mg every other week or 420 mg monthly, or placebo. The median duration of follow-up was 2.2 years, and there was a 15% reduction in the primary composite outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization with evolocumab compared with placebo (HR, 0.85; 95% CI, 0.79-0.92; P <.001). 45

The authors estimate that 74 patients would need to be treated with evolocumab for 2 years to prevent 1 CV death, MI, or stroke. There was no significant difference in CV death or death from any cause between evolocumab and placebo. Adverse events were similar between groups, including new-onset diabetes and neurocognitive events. Injection-site reactions were more common with evolocumab than with placebo (2.1% vs 1.6%).45 The ODYSSEY Outcomes trial, expected to be completed in December 2017, is evaluating alirocumab versus placebo on the occurrence of major adverse CV events in 18,000 patients who recently experienced an acute coronary syndrome.46



 
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