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#215 PCSK9 Inhibitors: Cardiovascular prevention panacea or pesky, pricey pokes?

Do pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors decrease cardiovascular events, and if so, are they cost-effective?

For patients with cardiovascular disease (CVD) already on maximally tolerated statins, adding evolocumab or alirocumab decreases new CVD events for an additional one in 65 patients compared to placebo over ~2.5 years. Routine use of these agents is not cost-effective at current prices.  

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  • Focusing on two largest, industry-sponsored, placebo-controlled trials evaluating clinical outcomes.1,Patients had existing CVD and LDL >1.8 mmol/L while on maximally tolerated statins.1,2  
    • Evolocumab: 27,564 patients randomized to evolocumab (140 mg every two weeks or 420 mg monthlyor placebo.1 At 2.2 years:  
      • New CVD eventsEvolocumab 9.8%, placebo 11.3%, statistically significant 
        • Number Needed to Treat (NNT)=67. 
        • CVD reduction: Independent of baseline LDL. 
      • Death (any cause): No difference. 
    • Alirocumab: (pending publication) 18,924 patients post-acute coronary syndrome randomized to alirocumab (75-150 mg every two weeks) or placebo.2 At 2.8 years statistically significant reduction in: 
      • New CVD events: Alirocumab 9.5%, placebo 11.1%, NNT=63. 
      • Death (any cause): Alirocumab 3.5%, placebo 4.1%, NNT=167. 
        • Note: Statistical difference in death based on six fewer deaths. 
  • Adverse events:1,2 
    • Primarily injection site reactions: Number Needed to Harm ~100. 
  • Other smaller randomized controlled trials limited by only reporting surrogate outcomes,3 lack of blinding,4,and enrolling familial hypercholesterolemia patientsor patients from previous studies.3,5 These studies found inconsistent effects on CVD.5,6 
  • Bococizumab research and development stopped due to development of drug-neutralizing antibodies.7 
    • Development of neutralizing antibodies to alirocumab and evolocumab is rare and usually clinically insignificant.1,8 
  • No studies on statin intolerant patients have evaluated clinical outcomes.9 
  • Some guidelines recommend considering PCSK9 inhibitors for patients with familial hypercholesterolemia or CVD whose LDL remains above target despite maximum-tolerated statin +/- ezetimibe.10,11 
  • Routine use of PCSK9 inhibitors in CVD patients is not cost-effective at current Canadian prices (~$7,100/year).12 A >90% price reduction would be required for cost-effectiveness.12 

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  • Michael R Kolber BSc MD CCFP MSc
  • Tony Nickonchuk BScPharm
  • Ricky D. Turgeon BSc(Pharm) ACPR PharmD

1. Sabatine MS, Giugliano RP, Keech AC, et al for the FOURIER Steering Committee and Investigators. N Engl J Med. 2017; 376:1713-22.

2. Alirocumab in Patients after Acute Coronary Syndrome; 2018. Available at: Last Accessed: April 24, 2018.

3. Blom DJ, Hala T, Bolognese M, et al for the DESCARTES Investigators. N Engl J Med. 2014; 370:1809-19

4. Raal FJ, Honarpour N, Blom DJ, et al for the TESLA Investigators. Lancet. 2015; 385: 341-50.

5. Sabatine MS, Giugliano RP, Wiviott SD, et al for the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. N Engl J Med. 2015; 372:1500-9.

6. Robinson JG, Farnier M, Krempf M, et al for the ODYSSEY LONG TERM Investigators. N Engl J Med. 2015; 372:1489-99.

7. Ridker PM, Revkin J, Amarenco P, et al for the SPIRE Cardiovascular Outcome Investigators. N Engl J Med. 2017; 376:1527-39.

8. Roth EM, Goldberg AC, Catapano AL, et al. Antidrug antibodies in patients treated with alirocumab. N Engl J Med. 2017; 376:1589-90.

9. Karatasakis A, Danek BA, Karacsonyi J, et al. J Am Heart Assoc. 2017; 6:e006910.

10. Anderson TJ, Gregoire J, Pearson GJ, et al. Can J Cardiol. 2016; 32:1263-82.

11. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. J Am Coll Cardiol. 2017; 70:1785-822.

12. CADTH Canadian Drug Expert Committee Recommendation. Evolocumab (REPATHA—AMGEN CANADA INC). Available at: Last Accessed: April 24, 2018.

Authors do not have any conflicts of interest to declare.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.