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


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


BOTTOM LINE
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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EVIDENCE
  • 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 
Context:  
  • 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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Author(s):

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

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: https://accscientificsession.acc.org/~/media/ScientificSessions/ACC18/PDFs/Sanofi-stream/Session-401-ODYSSEY-slides.pdf. 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: https://www.cadth.ca/sites/default/files/cdr/complete/SR0515_Repatha_Resubmission_complete_Nov_24_17.pdf. Last Accessed: April 24, 2018.

Authors do not have any conflicts of interest to declare.