OtherPractice

Do PCSK9 inhibitors reduce cardiovascular events?

Michael R. Kolber, Tony Nickonchuk and Ricky Turgeon
Canadian Family Physician September 2018; 64 (9) 669;

Clinical question

Do proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors decrease cardiovascular disease (CVD) events. If so, are they cost-effective?

Bottom line

For patients with CVD taking maximally tolerated statins, adding evolocumab or alirocumab decreases new CVD events for an additional 1 in 65 patients compared with placebo over about 2.5 years. Routine use of these agents is not currently cost-effective.

Evidence

  • Two large industry-sponsored, placebo-controlled trials evaluated clinical outcomes. Patients had existing CVD and a low-density lipoprotein (LDL) level of 1.8 mmol/L or greater while taking maximally tolerated statins.1,2

    • -A study randomized 27 564 patients to evolocumab (140 mg every 2 weeks or 420 mg/month) or placebo.1 At 2.2 years, the reduction in new CVD events (evolocumab 9.8%, placebo 11.3%) was statistically significant (number needed to treat [NNT] = 67) independent of the baseline LDL level; there was no difference in death by any cause.

    • -A study pending publication randomized 18 924 patients after acute coronary syndrome to alirocumab (75 to 150 mg every 2 weeks) or placebo.2 At 2.8 years, there was a statistically significant reduction in new CVD events (9.5% for alirocumab and 11.1% for placebo, NNT = 63) and death by any cause (alirocumab 3.5%, placebo 4.1%; 6 fewer deaths; NNT = 167).

    • -Adverse events were primarily injection site reactions (number needed to harm of about 100).1,2

  • Other smaller RCTs were limited by only reporting surrogate outcomes,3 lack of blinding,4,5 and enrolling familial hypercholesterolemia patients4 or patients from previous studies,3,5 and found inconsistent effects on CVD.5,6

Context

  • Bococizumab research stopped owing to development of drug-neutralizing antibodies.7

    • -Developing neutralizing antibodies to alirocumab or evolocumab is rare and usually clinically insignificant.1,8

  • No studies on statin-intolerant patients evaluated clinical outcomes.9

  • Some guidelines recommend PCSK9 inhibitors for patients with familial hypercholesterolemia or CVD whose LDL levels are above “target” despite taking a maximum-tolerated statin with or without ezetimibe.10

  • Routine use of PCSK9 inhibitors is not cost-effective at current Canadian prices (about $7100 per year).11

Implementation

Statins are first-line lipid-lowering therapy, as they have the best CVD risk reduction.12 Statin-associated muscle symptoms (SAMS) occur in 1% to 5% of users in trials and are dose-related.12 Statin discontinuation is associated with increased risk of death and CVD events.13 Most patients who report SAMS tolerate restarting statins at lower or alternate-day doses of the same or a different statin.12 Statin rechallenge should be attempted before using ezetimibe or PCSK9 inhibitors. Coenzyme Q10 does not prevent or alleviate SAMS beyond placebo.14

Notes

Tools for Practice articles in Canadian Family Physician are adapted from articles published on the Alberta College of Family Physicians (ACFP) website, summarizing medical evidence with a focus on topical issues and practice-modifying information. The ACFP summaries and the series in Canadian Family Physician are coordinated by Dr G. Michael Allan, and the summaries are co-authored by at least 1 practising family physician and are peer reviewed. Feedback is welcome and can be sent to toolsforpractice{at}cfpc.ca. Archived articles are available on the ACFP website: www.acfp.ca.

Footnotes

  • Competing interests

    None declared

  • The opinions expressed in Tools for Practice articles are those of the authors and do not necessarily mirror the perspective and policy of the Alberta College of Family Physicians.

References

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Do PCSK9 inhibitors reduce cardiovascular events?
Michael R. Kolber, Tony Nickonchuk, Ricky Turgeon
Canadian Family Physician Sep 2018, 64 (9) 669;
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