PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease
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 patients who are u...
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| Veröffentlicht in: | Cochrane database of systematic reviews 2017-04, Vol.2017 (4), p.CD011748 |
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| creator | Schmidt, Amand F Pearce, Lucy S Wilkins, John T Overington, John P Hingorani, Aroon D Casas, Juan P Casas, Juan P |
| description | 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 patients 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) may further reduce LDL‐C, potentially reducing CVD risk as well.
Objectives
Primary
To quantify short‐term (24 weeks), medium‐term (one year), and long‐term (five years) effects of PCSK9 inhibitors on lipid parameters and on the incidence of CVD.
Secondary
To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of type 2 diabetes, cognitive function, and cancer. Additionally, to determine if specific patient subgroups were more or less likely to benefit from the use of PCSK9 inhibitors.
Search methods
We identified studies by systematically searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science. We also searched Clinicaltrials.gov and the International Clinical Trials Registry Platform and screened the reference lists of included studies. We identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017.
Selection criteria
All parallel‐group and factorial randomised controlled trials (RCTs) with a follow‐up time of at least 24 weeks were eligible.
Data collection and analysis
Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates.
Main results
We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs).
Compared with placebo, PCSK9 inhibitors decreased LDL‐C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors dec |
| doi_str_mv | 10.1002/14651858.CD011748.pub2 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6478267</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1893545450</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4732-d3de47e89dcb2e8f1c8f53ecf45028aea2564878d4080ea4497ab1c2c4459a33</originalsourceid><addsrcrecordid>eNqFUU1PAyEUJEZjtfoXGo5eWoFlF_ZiovUzNtHEniUU3lrMdqnQ1vjvZdPWVC-GA7zMvJkJg1CPkgElhJ1TXuRU5nIwvCaUCi4H8-WE7aGjFui3yP7Ou4OOY3wnJCtKJg5Rh0meZ1SKI_T6PHx5LPHMN97UvtE11s3CTbx1EHHlA15MAc-Dm-nwlSCLIxjf2HaaB1hBIvsG-wobHazzKx3NstYBWxdBRzhBB5WuI5xu7i4a396Mh_f90dPdw_By1DdcZKxvMwtcgCytmTCQFTWyyjMwFc8Jkxo0ywsuhbScSAKa81LoCTXMcJ6XOsu66GItmz5hBtakWEHXapNbee3Ub6RxU_XmV6rgQrJCJIGzjUDwH0uICzVz0UBd6wb8Mioqyyzn6ZBELdZUE3yMAaofG0pU243adqO23bTmLC32dkP-rG3LSISrNeHT1fCljDfTkPz_0f3j8g1TDKG4</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1893545450</pqid></control><display><type>article</type><title>PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Cochrane Library</source><source>Alma/SFX Local Collection</source><creator>Schmidt, Amand F ; Pearce, Lucy S ; Wilkins, John T ; Overington, John P ; Hingorani, Aroon D ; Casas, Juan P ; Casas, Juan P</creator><creatorcontrib>Schmidt, Amand F ; Pearce, Lucy S ; Wilkins, John T ; Overington, John P ; Hingorani, Aroon D ; Casas, Juan P ; Casas, Juan P</creatorcontrib><description>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 patients 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) may further reduce LDL‐C, potentially reducing CVD risk as well.
Objectives
Primary
To quantify short‐term (24 weeks), medium‐term (one year), and long‐term (five years) effects of PCSK9 inhibitors on lipid parameters and on the incidence of CVD.
Secondary
To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of type 2 diabetes, cognitive function, and cancer. Additionally, to determine if specific patient subgroups were more or less likely to benefit from the use of PCSK9 inhibitors.
Search methods
We identified studies by systematically searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science. We also searched Clinicaltrials.gov and the International Clinical Trials Registry Platform and screened the reference lists of included studies. We identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017.
Selection criteria
All parallel‐group and factorial randomised controlled trials (RCTs) with a follow‐up time of at least 24 weeks were eligible.
Data collection and analysis
Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates.
Main results
We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs).
Compared with placebo, PCSK9 inhibitors decreased LDL‐C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL‐C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL‐C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate).
Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison.
Authors' conclusions
Over short‐term to medium‐term follow‐up, PCSK9 inhibitors reduced LDL‐C. Studies with medium‐term follow‐up time (longest median follow‐up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE‐1 and ‐2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow‐up times were short and events were few. Large trials with longer follow‐up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high‐risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%).</description><identifier>ISSN: 1465-1858</identifier><identifier>ISSN: 1469-493X</identifier><identifier>EISSN: 1465-1858</identifier><identifier>EISSN: 1469-493X</identifier><identifier>DOI: 10.1002/14651858.CD011748.pub2</identifier><identifier>PMID: 28453187</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>A. Cardiovascular Disease: Primary Prevention ; A.1 Drugs ; A.1.2 Lipid Lowering ; Antibodies, Monoclonal ; Antibodies, Monoclonal - therapeutic use ; Antibodies, Monoclonal, Humanized ; Antibodies, Monoclonal, Humanized - therapeutic use ; Cardiovascular Diseases ; Cardiovascular Diseases - prevention & control ; Cause of Death ; Cholesterol, LDL ; Cholesterol, LDL - blood ; Cholinergic Antagonists ; Cholinergic Antagonists - therapeutic use ; Drugs ; Ezetimibe ; Ezetimibe - therapeutic use ; Heart & circulation ; Heart disease prevention ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use ; Hydroxymethylglutaryl‐CoA Reductase Inhibitors ; Medicine General & Introductory Medical Sciences ; Middle Aged ; PCSK9 Inhibitors ; Prevention ; Primary Prevention ; Primary Prevention - methods ; Proprotein Convertase 9 ; Randomized Controlled Trials as Topic ; Secondary Prevention ; Secondary Prevention - methods ; Time Factors</subject><ispartof>Cochrane database of systematic reviews, 2017-04, Vol.2017 (4), p.CD011748</ispartof><rights>Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.</rights><rights>Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2017 The Cochrane Collaboration</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4732-d3de47e89dcb2e8f1c8f53ecf45028aea2564878d4080ea4497ab1c2c4459a33</citedby><cites>FETCH-LOGICAL-c4732-d3de47e89dcb2e8f1c8f53ecf45028aea2564878d4080ea4497ab1c2c4459a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27915,27916</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28453187$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schmidt, Amand F</creatorcontrib><creatorcontrib>Pearce, Lucy S</creatorcontrib><creatorcontrib>Wilkins, John T</creatorcontrib><creatorcontrib>Overington, John P</creatorcontrib><creatorcontrib>Hingorani, Aroon D</creatorcontrib><creatorcontrib>Casas, Juan P</creatorcontrib><creatorcontrib>Casas, Juan P</creatorcontrib><title>PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease</title><title>Cochrane database of systematic reviews</title><addtitle>Cochrane Database Syst Rev</addtitle><description>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 patients 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) may further reduce LDL‐C, potentially reducing CVD risk as well.
Objectives
Primary
To quantify short‐term (24 weeks), medium‐term (one year), and long‐term (five years) effects of PCSK9 inhibitors on lipid parameters and on the incidence of CVD.
Secondary
To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of type 2 diabetes, cognitive function, and cancer. Additionally, to determine if specific patient subgroups were more or less likely to benefit from the use of PCSK9 inhibitors.
Search methods
We identified studies by systematically searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science. We also searched Clinicaltrials.gov and the International Clinical Trials Registry Platform and screened the reference lists of included studies. We identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017.
Selection criteria
All parallel‐group and factorial randomised controlled trials (RCTs) with a follow‐up time of at least 24 weeks were eligible.
Data collection and analysis
Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates.
Main results
We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs).
Compared with placebo, PCSK9 inhibitors decreased LDL‐C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL‐C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL‐C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate).
Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison.
Authors' conclusions
Over short‐term to medium‐term follow‐up, PCSK9 inhibitors reduced LDL‐C. Studies with medium‐term follow‐up time (longest median follow‐up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE‐1 and ‐2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow‐up times were short and events were few. Large trials with longer follow‐up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high‐risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%).</description><subject>A. Cardiovascular Disease: Primary Prevention</subject><subject>A.1 Drugs</subject><subject>A.1.2 Lipid Lowering</subject><subject>Antibodies, Monoclonal</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Antibodies, Monoclonal, Humanized - therapeutic use</subject><subject>Cardiovascular Diseases</subject><subject>Cardiovascular Diseases - prevention & control</subject><subject>Cause of Death</subject><subject>Cholesterol, LDL</subject><subject>Cholesterol, LDL - blood</subject><subject>Cholinergic Antagonists</subject><subject>Cholinergic Antagonists - therapeutic use</subject><subject>Drugs</subject><subject>Ezetimibe</subject><subject>Ezetimibe - therapeutic use</subject><subject>Heart & circulation</subject><subject>Heart disease prevention</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use</subject><subject>Hydroxymethylglutaryl‐CoA Reductase Inhibitors</subject><subject>Medicine General & Introductory Medical Sciences</subject><subject>Middle Aged</subject><subject>PCSK9 Inhibitors</subject><subject>Prevention</subject><subject>Primary Prevention</subject><subject>Primary Prevention - methods</subject><subject>Proprotein Convertase 9</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Secondary Prevention</subject><subject>Secondary Prevention - methods</subject><subject>Time Factors</subject><issn>1465-1858</issn><issn>1469-493X</issn><issn>1465-1858</issn><issn>1469-493X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>RWY</sourceid><sourceid>EIF</sourceid><recordid>eNqFUU1PAyEUJEZjtfoXGo5eWoFlF_ZiovUzNtHEniUU3lrMdqnQ1vjvZdPWVC-GA7zMvJkJg1CPkgElhJ1TXuRU5nIwvCaUCi4H8-WE7aGjFui3yP7Ou4OOY3wnJCtKJg5Rh0meZ1SKI_T6PHx5LPHMN97UvtE11s3CTbx1EHHlA15MAc-Dm-nwlSCLIxjf2HaaB1hBIvsG-wobHazzKx3NstYBWxdBRzhBB5WuI5xu7i4a396Mh_f90dPdw_By1DdcZKxvMwtcgCytmTCQFTWyyjMwFc8Jkxo0ywsuhbScSAKa81LoCTXMcJ6XOsu66GItmz5hBtakWEHXapNbee3Ub6RxU_XmV6rgQrJCJIGzjUDwH0uICzVz0UBd6wb8Mioqyyzn6ZBELdZUE3yMAaofG0pU243adqO23bTmLC32dkP-rG3LSISrNeHT1fCljDfTkPz_0f3j8g1TDKG4</recordid><startdate>20170428</startdate><enddate>20170428</enddate><creator>Schmidt, Amand F</creator><creator>Pearce, Lucy S</creator><creator>Wilkins, John T</creator><creator>Overington, John P</creator><creator>Hingorani, Aroon D</creator><creator>Casas, Juan P</creator><creator>Casas, Juan P</creator><general>John Wiley & Sons, Ltd</general><scope>7PX</scope><scope>RWY</scope><scope>ZYTZH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170428</creationdate><title>PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease</title><author>Schmidt, Amand F ; Pearce, Lucy S ; Wilkins, John T ; Overington, John P ; Hingorani, Aroon D ; Casas, Juan P ; Casas, Juan P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4732-d3de47e89dcb2e8f1c8f53ecf45028aea2564878d4080ea4497ab1c2c4459a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>A. Cardiovascular Disease: Primary Prevention</topic><topic>A.1 Drugs</topic><topic>A.1.2 Lipid Lowering</topic><topic>Antibodies, Monoclonal</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Antibodies, Monoclonal, Humanized</topic><topic>Antibodies, Monoclonal, Humanized - therapeutic use</topic><topic>Cardiovascular Diseases</topic><topic>Cardiovascular Diseases - prevention & control</topic><topic>Cause of Death</topic><topic>Cholesterol, LDL</topic><topic>Cholesterol, LDL - blood</topic><topic>Cholinergic Antagonists</topic><topic>Cholinergic Antagonists - therapeutic use</topic><topic>Drugs</topic><topic>Ezetimibe</topic><topic>Ezetimibe - therapeutic use</topic><topic>Heart & circulation</topic><topic>Heart disease prevention</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use</topic><topic>Hydroxymethylglutaryl‐CoA Reductase Inhibitors</topic><topic>Medicine General & Introductory Medical Sciences</topic><topic>Middle Aged</topic><topic>PCSK9 Inhibitors</topic><topic>Prevention</topic><topic>Primary Prevention</topic><topic>Primary Prevention - methods</topic><topic>Proprotein Convertase 9</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Secondary Prevention</topic><topic>Secondary Prevention - methods</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schmidt, Amand F</creatorcontrib><creatorcontrib>Pearce, Lucy S</creatorcontrib><creatorcontrib>Wilkins, John T</creatorcontrib><creatorcontrib>Overington, John P</creatorcontrib><creatorcontrib>Hingorani, Aroon D</creatorcontrib><creatorcontrib>Casas, Juan P</creatorcontrib><creatorcontrib>Casas, Juan P</creatorcontrib><collection>Wiley-Blackwell Cochrane Library</collection><collection>Cochrane Library</collection><collection>Cochrane Library (Open Aceess)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cochrane database of systematic reviews</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schmidt, Amand F</au><au>Pearce, Lucy S</au><au>Wilkins, John T</au><au>Overington, John P</au><au>Hingorani, Aroon D</au><au>Casas, Juan P</au><au>Casas, Juan P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease</atitle><jtitle>Cochrane database of systematic reviews</jtitle><addtitle>Cochrane Database Syst Rev</addtitle><date>2017-04-28</date><risdate>2017</risdate><volume>2017</volume><issue>4</issue><spage>CD011748</spage><pages>CD011748-</pages><issn>1465-1858</issn><issn>1469-493X</issn><eissn>1465-1858</eissn><eissn>1469-493X</eissn><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 patients 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) may further reduce LDL‐C, potentially reducing CVD risk as well.
Objectives
Primary
To quantify short‐term (24 weeks), medium‐term (one year), and long‐term (five years) effects of PCSK9 inhibitors on lipid parameters and on the incidence of CVD.
Secondary
To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of type 2 diabetes, cognitive function, and cancer. Additionally, to determine if specific patient subgroups were more or less likely to benefit from the use of PCSK9 inhibitors.
Search methods
We identified studies by systematically searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science. We also searched Clinicaltrials.gov and the International Clinical Trials Registry Platform and screened the reference lists of included studies. We identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017.
Selection criteria
All parallel‐group and factorial randomised controlled trials (RCTs) with a follow‐up time of at least 24 weeks were eligible.
Data collection and analysis
Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates.
Main results
We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs).
Compared with placebo, PCSK9 inhibitors decreased LDL‐C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL‐C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL‐C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate).
Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison.
Authors' conclusions
Over short‐term to medium‐term follow‐up, PCSK9 inhibitors reduced LDL‐C. Studies with medium‐term follow‐up time (longest median follow‐up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE‐1 and ‐2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow‐up times were short and events were few. Large trials with longer follow‐up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high‐risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%).</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>28453187</pmid><doi>10.1002/14651858.CD011748.pub2</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-1858 |
| ispartof | Cochrane database of systematic reviews, 2017-04, Vol.2017 (4), p.CD011748 |
| issn | 1465-1858 1469-493X 1465-1858 1469-493X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6478267 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Cochrane Library; Alma/SFX Local Collection |
| subjects | A. Cardiovascular Disease: Primary Prevention A.1 Drugs A.1.2 Lipid Lowering Antibodies, Monoclonal Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Humanized Antibodies, Monoclonal, Humanized - therapeutic use Cardiovascular Diseases Cardiovascular Diseases - prevention & control Cause of Death Cholesterol, LDL Cholesterol, LDL - blood Cholinergic Antagonists Cholinergic Antagonists - therapeutic use Drugs Ezetimibe Ezetimibe - therapeutic use Heart & circulation Heart disease prevention Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use Hydroxymethylglutaryl‐CoA Reductase Inhibitors Medicine General & Introductory Medical Sciences Middle Aged PCSK9 Inhibitors Prevention Primary Prevention Primary Prevention - methods Proprotein Convertase 9 Randomized Controlled Trials as Topic Secondary Prevention Secondary Prevention - methods Time Factors |
| title | PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T04%3A22%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=PCSK9%20monoclonal%20antibodies%20for%20the%20primary%20and%20secondary%20prevention%20of%20cardiovascular%20disease&rft.jtitle=Cochrane%20database%20of%20systematic%20reviews&rft.au=Schmidt,%20Amand%20F&rft.date=2017-04-28&rft.volume=2017&rft.issue=4&rft.spage=CD011748&rft.pages=CD011748-&rft.issn=1465-1858&rft.eissn=1465-1858&rft_id=info:doi/10.1002/14651858.CD011748.pub2&rft_dat=%3Cproquest_pubme%3E1893545450%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1893545450&rft_id=info:pmid/28453187&rfr_iscdi=true |