PCSK9 inhibitor (ALN-PCS)
Jump to navigation
Jump to search
Indications
- dyslipemia, with increased LDL cholesterol
- may be used with statin
- very high-risk of cardiovascular disease with multiple prior major cardiovascular events or a single such event plus multiple high-risk conditions when LDL choleseterol is >= 70 mg/dL on maximally tolerated statin + ezetimibe[10]
- hypercholesterolemia regardless of 10-year cardiovascular risk if LDL >= 190 mg/dL & does not decrease to < 100 mg/dL on a high-intensity statin + ezetimibe[10]
- statin intolerant, LDL cholesterol above goal, taking ezetimibe
Benefit/risk
- statistically significant reduction in myocardial infarction in patients with hypercholesterolemia
- reduction in mortality in patients with hypercholesterolemia
- for secondary prevention of cardiovascular events, cost effectiveness ratio of $681,000/quality-adjusted life-year[7] (not cost-effective)
- alirocumab added to statin after myocardial infarction not cost-effective[12]
- PCSK9 inhibitor added to statin +/- ezetimibe of benefit vs placebo in high-risk patients[13]
- data on PCSK9 inhibitors vs statins inconclusive[13]
Dosage
- 0.40 mg/kg IV infusion (ALN-PCS)
* MK-0616 is an investigational oral PCSK9 inhibitor[14]
Adverse effects
- nasopharyngitis
- injection site reactions
- uncertain effects on cognitive function[8]
- increased incidence of cataracts with LDL cholesterol < 25 mg/dL[8]
Mechanism of action
- inhibits PCSK9
- decreases LDL cholesterol (50%)
- inclisiran (ALN-PCS) has an siRNA-based action[3]
- may reduce risk of cardiovascular events when used in combination with statin[4]
Notes
- a single infusion of ALN-PCS (0.40 mg/kg IV), results in a 40% reduction of LDL cholesterol after 28 days[3]
- annual cost (2015) = $14,000[7]
- cost-effectiveness in question[9]
More general terms
More specific terms
- alirocumab (Praluent)
- bococizumab
- evolocumab (Repatha)
- inclisiran (Leqvio, ALN-PCS)
- monoclonal antibody AMG 145
- monoclonal antibody SAR2365535
Additional terms
References
- ↑ Roth EM et al Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia. N Engl J Med. Oct 31, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23113833 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1201832
- ↑ Giugliano RP et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study The Lancet, Early Online Publication, 6 November 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23141813 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61770-X/abstract
Koren MJ et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study The Lancet, Early Online Publication, 6 November 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23141812 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61771-1/abstract
Tonkin AM and Watts GF Into the future: diversifying lipid management The Lancet, Early Online Publication, 6 November 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23141810 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61888-1/fulltext - ↑ 3.0 3.1 3.2 Fitzgerald K et al Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. The Lancet, Early Online Publication, 3 October 2013 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24094767 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61914-5/abstract
Fitzgerald K, White S, Borodovsky A et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2016 Nov 13 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27959715 <Internet> http://www.nejm.org/doi/10.1056/NEJMoa1609243 - ↑ 4.0 4.1 Krumholz HM More Promising Results for PCSK9 Inhibitors. NEJM Journal Watch. March 15 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
Robinson JG et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015 Mar 15; <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25773378 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1501031
Sabatine MS et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015 Mar 15 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25773607 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1500858
Stone NJ and Lloyd-Jones DM. Lower LDL cholesterol is better, but it matters how you get there, and in whom. N Engl J Med 2015 Mar 15 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25773740 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMe1502192 - ↑ 5.0 5.1 Navarese EP et al Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. Published online 28 April 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25915661 <Internet> http://annals.org/article.aspx?articleid=2279798
Cainzos-Achirica M PCSK9 Inhibitors: A New Era in Lipid-Lowering Treatment? Ann Intern Med. Published online 28 April 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25915768 <Internet> http://annals.org/article.aspx?articleid=2279799 - ↑ Prescriber's Letter 22(8): 2015 PCSK9 Inhibitors for High Cholesterol Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=310813&pb=PRL http://www.prescribersletter.com (subscription needed)
- ↑ 7.0 7.1 7.2 New England Comparative Effectiveness Public Advisory Council (CEPAC) PCSK9 Inhibitors for Treatment of High Cholesterol. http://cepac.icer-review.org/adaptations/cholesterol/
Kazi DS, Moran AE, Coxson PG. Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease. JAMA. 2016;316(7):743-753 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27533159 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=2544639 - ↑ 8.0 8.1 8.2 Khan AR, Bavishi C, Riaz H et al. Increased risk of adverse neurocognitive outcomes with proprotein convertase subtilisin-kexin type 9 inhibitors. Circ Cardiovasc Qual Outcomes 2017 Jan; 10:e003153 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28073851 <Internet> http://circoutcomes.ahajournals.org/content/10/1/e003153
Everett BM Low-Density Lipoprotein Cholesterol and the On-Target Effects of Therapy. How Low Is Too Low? J Am Coll Cardiol 69(5) Feb 2017 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28153103 - ↑ 9.0 9.1 Arrieta A, Hong JC, Khera R et al Updated Cost-effectiveness Assessments of PCSK9 Inhibitors From the Perspectives of the Health System and Private Payers. Insights Derived From the FOURIER Trial. JAMA Cardiol. Published online October 18, 2017. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29049467 https://jamanetwork.com/journals/jamacardiology/article-abstract/2657541
Kazi DS, Lu CY, Lin GA et al Nationwide Coverage and Cost-Sharing for PCSK9 Inhibitors Among Medicare Part D Plans. JAMA Cardiol. 2017;2(10):1164-1166 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28903137 https://jamanetwork.com/journals/jamacardiology/article-abstract/2653354
Mark DB, Richman I, Hlatky MA. Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy
Breakthrough in Low-Density Lipoprotein Cholesterol Lowering, Breakdown in Value. JAMA Cardiol. 2017;2(10):1066-1068 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28832860 https://jamanetwork.com/journals/jamacardiology/article-abstract/2649270
Bonow RO, Harrington RA, Yancy CW Cost-effectiveness of PCSK9 Inhibitors. Proof in the Modeling. JAMA Cardiol. Published online October 18, 2017. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29049827 https://jamanetwork.com/journals/jamacardiology/article-abstract/2657544 - ↑ 10.0 10.1 10.2 Phend C. AHA: Revised Lipid Guide Boosts PCSK9s, Coronary Calcium Scans. New recommendations aim to cut statins in low-risk primary prevention. Med Page Today. Nov 10, 2018 https://www.medpagetoday.com/meetingcoverage/aha/76250
Grundy SM, Stone NJ, Bailey AL et al 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 Nov 8. pii: S0735-1097(18)39034-X. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30423393
Lloyd-Jones DM, Braun LT, Ndumele CE et al Use of risk assessment tools to guide decision-making in the primary prevention of atherosclerotic cardiovascular disease: A special report from the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 2018 Nov 3. pii: S0735-1097(18)39036-3. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30423392
Grundy SM, Stone NJ, Bailey AL et al 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-e1143. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30586774
Grundy SM, Stone NJ, Bailey AL et al 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1046-e1081. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30565953
Forman DE, Stone NJ, Grundy SM. Treating Hypercholesterolemia in Older Adults. JAMA. 2019 Aug 20;322(7):695. No abstract available. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31429891- - ↑ Medical Knowledge Self Assessment Program (MKSAP) 18, American College of Physicians, Philadelphia 2018
- ↑ 12.0 12.1 Kazi DS, Penko J, Coxson PG, et al. Cost-effectiveness of alirocumab: A just-in-time analysis based on the ODYSSEY outcomes trial. Ann Intern Med 2019 Jan 1; PMID: https://www.ncbi.nlm.nih.gov/pubmed/30597485
Hlatky MA. A pound of prevention? Assessing the value of new cholesterol- lowering drugs. Ann Intern Med 2019 Jan 1; PMID: https://www.ncbi.nlm.nih.gov/pubmed/30597487 - ↑ 13.0 13.1 13.2 Carter JP et al. Cochrane corner: PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Heart 2022 Jan; 108:14. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34815331 https://heart.bmj.com/content/108/1/14
- ↑ 14.0 14.1 Ballantyne et al Efficacy and safety of the oral PCSK9 inhibitor MK-0616: a phase 2b randomized controlled trial J Am Coll Cardiol. Mar 06, 2023. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36889610 https://www.jacc.org/doi/10.1016/j.jacc.2023.02.018