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PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease - PubMed

  • ️Wed Jan 01 2020

Meta-Analysis

PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease

Amand F Schmidt et al. Cochrane Database Syst Rev. 2020.

Abstract

Background: Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL-C and CVD risk.

Objectives: Primary To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention.

Search methods: We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017.

Selection criteria: All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks were eligible.

Data collection and analysis: Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables.

Main results: We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of -2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD -1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD -2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence). Compared to active treatment the alirocumab effects, for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was -1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence). Compared to placebo the evolocumab, for CVD, the RD was -2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was -1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than -1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence). Compared to active treatment, the evolocumab effects, for any CVD event RD was less than -1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke. AUTHORS' CONCLUSIONS: The evidence for the clinical endpoint effects of evolocumab and alirocumab were graded as high. There is a strong evidence base to prescribe PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials. The evidence base of PCSK9 inhibitors compared with active treatment is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies. Related, most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal. Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.

Trial registration: ClinicalTrials.gov NCT01764633 NCT01984424 NCT01813422 NCT02642159 NCT02585778 NCT02107898 NCT02289963 NCT01663402 NCT01854918 NCT02729025 NCT02207634 NCT02392559 NCT01624142 NCT02833844.

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Conflict of interest statement

AFS has received unrelated funding from Servier for the development of a genetically guided drug target validation platform. Servier does not produce a PCSK9 monoclonal antibody drug.

JPLC: none.

LSP: none.

JTW: none.

JPO: none.

AH is a member of the organisation committee of The Genetics of Subsequent Coronary Heart Disease Consortium and the Heart failure Molecular Epidemiology for Therapeutic Targets Consortium (HERMES) each comprising over 20 member cohorts. A number of Pharma companies have provided direct and in‐kind support for these initiatives, but AH is not a direct recipient of any of these funds.

JPC: none.

Figures

1
1

Study flow diagram. RCT: randomised controlled trial.

2
2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3
3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

4
4

A funnel plot of the alirocumab versus placebo cardiovascular disease effects.

5
5

A funnel plot of the alirocumab versus placebo influenza effects.

1.1
1.1. Analysis

Comparison 1: Alirocumab versus placebo, Outcome 1: Any cardiovascular disease

1.2
1.2. Analysis

Comparison 1: Alirocumab versus placebo, Outcome 2: All‐cause mortality

1.3
1.3. Analysis

Comparison 1: Alirocumab versus placebo, Outcome 3: Any myocardial infarction

1.4
1.4. Analysis

Comparison 1: Alirocumab versus placebo, Outcome 4: Any stroke

1.5
1.5. Analysis

Comparison 1: Alirocumab versus placebo, Outcome 5: Influenza

1.6
1.6. Analysis

Comparison 1: Alirocumab versus placebo, Outcome 6: Type 2 diabetes mellitus

1.7
1.7. Analysis

Comparison 1: Alirocumab versus placebo, Outcome 7: Any cancer

1.8
1.8. Analysis

Comparison 1: Alirocumab versus placebo, Outcome 8: Hypertension

2.1
2.1. Analysis

Comparison 2: Evolocumab versus placebo, Outcome 1: Any cardiovascular disease

2.2
2.2. Analysis

Comparison 2: Evolocumab versus placebo, Outcome 2: All‐cause mortality

2.3
2.3. Analysis

Comparison 2: Evolocumab versus placebo, Outcome 3: Any myocardial infarction

2.4
2.4. Analysis

Comparison 2: Evolocumab versus placebo, Outcome 4: Any stroke

2.5
2.5. Analysis

Comparison 2: Evolocumab versus placebo, Outcome 5: Influenza

2.6
2.6. Analysis

Comparison 2: Evolocumab versus placebo, Outcome 6: Type 2 diabetes mellitus

3.1
3.1. Analysis

Comparison 3: Alirocumab versus active therapy, Outcome 1: Any cardiovascular disease

3.2
3.2. Analysis

Comparison 3: Alirocumab versus active therapy, Outcome 2: All‐cause mortality

3.3
3.3. Analysis

Comparison 3: Alirocumab versus active therapy, Outcome 3: Any myocardial infarction

3.4
3.4. Analysis

Comparison 3: Alirocumab versus active therapy, Outcome 4: Any stroke

3.5
3.5. Analysis

Comparison 3: Alirocumab versus active therapy, Outcome 5: Influenza

3.6
3.6. Analysis

Comparison 3: Alirocumab versus active therapy, Outcome 6: Type 2 diabetes mellitus

3.7
3.7. Analysis

Comparison 3: Alirocumab versus active therapy, Outcome 7: Any cancer

3.8
3.8. Analysis

Comparison 3: Alirocumab versus active therapy, Outcome 8: Hypertension

4.1
4.1. Analysis

Comparison 4: Evolocumab versus active therapy, Outcome 1: Any cardiovascular disease

4.2
4.2. Analysis

Comparison 4: Evolocumab versus active therapy, Outcome 2: All‐cause mortality

4.3
4.3. Analysis

Comparison 4: Evolocumab versus active therapy, Outcome 3: Any myocardial infarction

4.4
4.4. Analysis

Comparison 4: Evolocumab versus active therapy, Outcome 4: Influenza

4.5
4.5. Analysis

Comparison 4: Evolocumab versus active therapy, Outcome 5: Type 2 diabetes mellitus

4.6
4.6. Analysis

Comparison 4: Evolocumab versus active therapy, Outcome 6: Hypertension

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References

References to studies included in this review

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ODYSSEY DM‐DYSLIPIDEMIA {published data only (unpublished sought but not used)}
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ODYSSEY DM‐INSULIN {published data only (unpublished sought but not used)}
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ODYSSEY FH I {published data only}
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ODYSSEY FH II {published data only}
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ODYSSEY HIGH FH {published data only}
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ODYSSEY JAPAN {published data only (unpublished sought but not used)}
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ODYSSEY KT {published data only (unpublished sought but not used)}
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ODYSSEY MONO {published data only}
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ODYSSEY OPTIONS I {published data only}
    1. Bays H, Gaudet D, Weiss R, Ruiz JL, Watts GF, Gouni-Berthold I, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. Journal of Clinical Endocrinology and Metabolism 2015;100(8):3140-8. - PMC - PubMed
ODYSSEY OPTIONS II {published data only}
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ODYSSEY OUTCOMES {published data only (unpublished sought but not used)}
    1. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner RD, Edelberg JM, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. New England Journal of Medicine 2018;379(22):2097-107. - PubMed
OSLER‐1 {published data only}
    1. Koren M, Sabatine M, Giugliano R, Langslet G, Wiviott S, Ruzza A, et al. Final report of the OSLER-1 study: long-term evolocumab for the treatment of hypercholesterolemia. Journal of Clinical Lipidology 2019;13:e53-e54.
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OSLER‐2 {published and unpublished data}
    1. NCT01854918. Open-label extension study of evolocumab (AMG 145) in adults with hyperlipidemia and mixed dyslipidemia. clinicaltrials.gov/ct2/show/results/NCT01854918 (first received 16 May 2013). [CLINICALTRIALS.GOV: clinicaltrials.gov/ct2/show/results/NCT01854918]
Sugizaki 2019 {published data only}
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References to studies excluded from this review

ANITSCHKOW {published data only}
    1. NCT02729025. Effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on arterial wall inflammation study in patients with elevated lipoprotein(a) (Lp(a)). (ANITSCHKOW). clinicaltrials.gov/ct2/show/NCT02729025 (first received 8 March 2016).
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Ballantyne 2015 {published data only (unpublished sought but not used)}
    1. Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, Plowchalk D, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. American Journal of Cardiology 2015;115(9):1212-21. - PubMed
Baruch 2013 {published data only}
    1. Baruch A, Peng K, Leabman M, Budha N, Luca D, Cowan KJ, et al. Effect of RG7652, a mAb against PCSK9, on apolipoprotein B, oxidized LDL, lipoprotein(A) and lipoprotein-associated phospholipase a2 in healthy individuals with elevated LDL-C. Circulation 2013;128:A12009.
Cho 2014 {published data only}
    1. Cho L, Rocco M, Colquhoun D, Sullivan D, Rosenson RS, Dent R, et al. Clinical profile of statin intolerance in the phase 3 GAUSS-2 study. Canadian Journal of Cardiology 2014;30(10, Supplement):S79. - PubMed
Desai 2014 {published data only}
    1. Desai NR, Giugliano RP, Zhou J, Kohli P, Somaratne R, Hoffman E, et al. AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of National Cholesterol Education Program-Adult Treatment Panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonal antibody inhibition combined with statin therapy-thrombolysis in myocardial infarction 57). Journal of the American College of Cardiology 2014;63:430-3. - PubMed
Dias 2012 {published data only}
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Dufour 2012 {published data only}
    1. Dufour R, Moriarty PM, Genestin E, Sasiela WJ, Du Y, Ferrand AC, et al. Effect of REGN727/SAR236553 anti-proprotein convertase subtilisin/kexin type 9 fully human monoclonal antibody in patients with elevated triglycerides/low high-density lipoprotein cholesterol: data from three phase 2 studies (NCT:01266876; 01288469; 01288443). Circulation 2012;126:A16127.
EBBINGHAUS {published data only}
    1. NCT02207634. Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects (EBBINGHAUS). clinicaltrials.gov/ct2/show/NCT02207634 (first received 31 July 2014).
EQUATOR {published data only (unpublished sought but not used)}
    1. Tingley W, Mosesova S, Baruch A, Davis JD, Budha N, Vilimovskij A, et al. Effects of RG7652, a monoclonal antibody against proprotein convertase subtilisin/kexintype 9, on LDL cholesterol in patients with coronary heart disease or high risk: results from the EQUATOR study. European Heart Journal 2014;35:371.
Gaudet 2012 {published data only}
    1. Gaudet D, Kereiakes D, McKenney J, Roth E, Hanotin C, Gipe D, et al. Effect of SAR236553/REGN727 fully human monoclonal anti-proprotein convertase subtilisin/kexin type 9 antibody on plasma lipoprotein(a) concentrations: pooled analysis from three phase 2 studies (NCT:01266876; 01288469; 01288443). Circulation 2012;126:A14725.
Gaudet 2013 {published data only}
    1. Gaudet D, Kereiakes D, McKenney J, Roth E, Hanotin C, Gipe D, et al. Alirocumab, a fully human monoclonal antibody to PCSK9, reduces high plasma lp(a) concentration: pooled analysis of 352 patients from phase 2. Journal of Clinical Lipidology 2013;7(3):283-4.
Gumbiner 2012 {published data only}
    1. Gumbiner B, Udata C, Joh T, Liang H, Wan H, Shelton D, et al. The effects of multiple dose administration of RN316 (PF-04950619), a humanized IgG2a monoclonal antibody binding proprotein convertase snbtilisin kexin type 9, in hypercholesterolemic subjects. Circulation 2012;126:21.
Habibinejad 2016 {published data only}
    1. Habibinejad H, Khosrokhavar F. The effects of alirocumab on LDL cholesterol in patients receiving statins. Canadian Journal of Cardiology 2016;32(10 Suppl 1):S122.
HAUSER‐RCT {published data only}
    1. NCT02392559. Trial assessing efficacy, safety and tolerability of PCSK9 inhibition in paediatric subjects with genetic LDL disorders (HAUSER-RCT). clinicaltrials.gov/ct2/show/NCT02392559 (first received 25 February 2015).
Hopkins 2013 {published data only}
    1. Hopkins PN, Swergold GD, Mellis S, Bruckert E, Luc G, Mendoza J, et al. A randomized placebo-phase clinical trial with the monoclonal antibody alirocumab demonstrates reductions in low-density lipoprotein cholesterol in patients with proprotein convertase subtilisin/kexin type 9 gain-of-function mutations. Circulation 2013;128(22):A17156.
Jones 2015 {published data only}
    1. Jones PH, Bays H, Chaudhari U, Pordy R, Lorenzato C, Miller K, et al. Pooled safety and adverse events in nine randomized, placebo-controlled, phase 2 and 3 clinical trials of alirocumab. Journal of the American College of Cardiology 2015;65(10 Supplement):A1363.
Kastelein 2015 {published data only}
    1. Kastelein J, Nissen S, Rader D, Krueger K, Wang MD. Safety and efficacy of LY 3015014, a new monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK 9) with an inherently longer duration of action, in patients with primary hypercholesterolemia: a randomized, placebo-controlled, dose-ranging, phase 2 study. Journal of the American College of Cardiology 2015;65:A1591.
Kawashiri 2012 {published data only}
    1. Kawashiri MA, Nohara A, Noguchi T, Tada H, Nakanishi C, Mori M, et al. Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia. American Journal of Cardiology 2012;109:364-9. - PubMed
Mabuchi 2015 {published data only}
    1. Mabuchi H, Nohara A. Therapy: PCSK9 inhibitors for treating familial hypercholesterolaemia. Nature Reviews Endocrinology 2015;11(1):8-9. - PubMed
Maxwell 2012 {published data only}
    1. Maxwell KN, Breslow JL. Antibodies to PCSK9: a superior way to lower LDL cholesterol? Circulation Research 2012;111:274-7. - PubMed
Mearns 2014 {published data only}
    1. Mearns BM. Dyslipidaemia: 1-year results from OSLER trial of anti-PCSK9 monoclonal antibody evolocumab. Nature Reviews Cardiology 2014;11:63. - PubMed
Pordy 2013 {published data only}
    1. Pordy R, Lecorps G, Bessac L, Sasiela WJ, Ginsberg H. Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9: therapeutic dosing in phase 3 studies. Journal of Clinical Lipidology 2013;7(3):279.
Raal 2014a {published data only}
    1. Raal F, Giugliano RP, Sabatine MS, Koren MJ, Blom D, Honarpour N, et al. Long-term reduction in lipoprotein(A) with the PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of 3278 patients in phase 2, 3, and open label extension studies. Circulation 2014;130:A15743.
Raal 2014b {published data only}
    1. Raal F, Nelson P, Langslet G, Basart DC, Civeira F, Lopez-Miranda J, et al. Safety, tolerability, and efficacy of long-term administration of monthly AMG 145 in subjects with heterozygous familial hypercholesterolemia. Global Heart 2014;1:e139.
Shaywitz 2012 {published data only}
    1. Shaywitz AJ, Dias C, Smith B, Gao B, Gibbs J, Emery M, et al. AMG 145, a fully human monoclonal antibody against PCSK9, reduces LDL-C in healthy volunteers and patients on stable doses of statins. Journal of Clinical Lipidology 2012;6(3):286-7.
SPIRE 1/2 {published data only}
    1. Ridker PM, Revking J, Amarenco P, Brunell R, Curto M, Civeria F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. New England Journal of Medicine 2017;376:1527-39. - PubMed
SPIRE biomarker trials {published data only}
    1. Ridker PM, Tardif JC, Amarenco P, Duggan W, Glyn RJ, Jukema WJ, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. New England Journal of Medicine 2017;online first:1-10. - PubMed
Stawowy 2014 {published data only}
    1. Stawowy P, Just IA, Kaschina E. Inhibition of PCSK9: a novel approach for the treatment of dyslipidemia. Coronary Artery Disease 2014;25:353-9. - PubMed
Stein 2012 {published data only}
    1. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. New England Journal of Medicine 2012;366:1108-18. - PubMed
Stein 2013 {published data only}
    1. Stein EA, Somaratne R, Schou MB, Civeira F, Sullivan D, Watts GF, et al. Efficacy and tolerability of long-term treatment with AMG 145 in patients with statin intolerance. Circulation 2013;128:A12621.
Swergold 2010 {published data only}
    1. Swergold G, Biedermann S, Renard R, Nadler D, Wu R, Mellis S. Safety, lipid, and lipoprotein effects of REGN727/SAR236553, a fully-human proprotein convertase subtilisin kexin 9 (PCSK9) monoclonal antibody administered intravenously to healthy volunteers. Circulation 2010;122:2.
Swergold 2011 {published data only}
    1. Swergold G, Smith W, Mellis S, Logan D, Webb C, Wu R, et al. Inhibition of proprotein convertase subtilisin/kexin type 9 with a monoclonal antibody REGN727/SAR236553, effectively reduces low-density-lipoprotein cholesterol, as mono or add-on therapy in heterozygous familial and non familial hypercholesterolemia. Circulation 2011;124:2.
TAUSSIG {published data only}
    1. NCT01624142. Trial assessing long term use of PCSK9 inhibition in subjects with genetic LDL disorders (TAUSSIG). clinicaltrials.gov/ct2/show/NCT01624142 (first received 5 June 2012).
    1. Raal FJ, Hoving GK, Blom D, Santos RD, Harada-Shiba M, Bruckert E. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes & Endocrinology 2017;5:280-90. - PubMed
Wan 2013 {published data only}
    1. Wan H, Gumbiner B, Joh T, Udata C, Forgues P, Garzone PD. Effects of RN316 (pf-04950615), a humanized IgG2a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, on lipoprotein particles in hypercholesterolemic subjects. Journal of the American College of Cardiology 2013;31:E1387.

References to ongoing studies

ALTAIR {published data only}
    1. Otak H, Sugizaki Y, Toba T, Nagano Y, Tsukiyama Y, Yanaka KI, et al. Efficacy of alirocumab for reducing plaque vulnerability: study protocol for ALTAIR, a randomized controlled trial in Japanese patients with coronary artery disease receiving rosuvastatin. Journal of Cardiology 2019;73:228-32. - PubMed
EVOLVD {published data only}
    1. Broch K, Gustafsson F, Radegran G, Karl LB, Eiskjnr H, Gjesdal G, et al. EVOLVD: cholesterol lowering with EVOLocumab to prevent cardiac allograft vasculopathy in de-novo heart transplant recipients: rationale and design of a randomized, controlled trial. Journal of Heart and Lung Transplantation 2019;38:S279. - PubMed
NCT02833844 {published data only}
    1. NCT02833844. Safety, tolerability & efficacy on LDL-C of evolocumab in subjects with HIV & hyperlipidemia/mixed dyslipidemia. clinicaltrials.gov/ct2/show/NCT02833844 (first received 13 June 2016).
UMIN000034592 {unpublished data only}
    1. NA. Ongoing study. 26 October 2018. Contact author for more information.

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References to other published versions of this review

Schmidt 2017
    1. Schmidt AF, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2017, Issue 4. Art. No: CD011748. [DOI: 10.1002/14651858.CD011748.pub2] - DOI - PMC - PubMed

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