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Meta-Analysis
. 2017 Apr 28;4(4):CD011748.
doi: 10.1002/14651858.CD011748.pub2.

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

Amand F Schmidt  1 , Lucy S Pearce  2 , John T Wilkins  3 , John P Overington  4 , Aroon D Hingorani  1 , Juan P Casas  5
Affiliations
Meta-Analysis

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

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

Update in

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%).

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Conflict of interest statement

Amand F Schmidt: none known.

Lucy S Pearce: none known.

John T Wilkins: none known.

John P Overington: none known.

Aroon Hingorani 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.

Juan P Casas: none known.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figure 4
Figure 4
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in LDL‐C at six months.
Figure 5
Figure 5
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in LDL‐C at six months.
Figure 6
Figure 6
Association of PCSK9 inhibitors compared with ezetimibe with mean percentage change from baseline in LDL‐C at six months.
Figure 7
Figure 7
Sensitivity analyses grouping RCTs by PCSK9 dose compared with placebo on 6 months LDL‐C mean percentage change from baseline.
Figure 8
Figure 8
Sensitivity analyses grouping RCTs by PCSK9 dose compared with placebo on 6 months apolipoprotein B mean percentage change from baseline.
Figure 9
Figure 9
Subgroup and interaction effects of six months mean percentage change in LDL‐C for PCSK9 trials using a placebo comparison arm.
Figure 10
Figure 10
Subgroup and interaction effects of six months mean percentage change in LDL‐C for PCSK9 trials using a ezetimibe comparison arm.
Figure 11
Figure 11
Meta‐regression of PCSK9 mAbs compared with placebo at six months mean percentage change in LDL‐C. The long dashed line represents the fixed effect, the long‐short dashed line random effects, circle diameter is proportionate to the inverse of the variance (i.e. equal to study precision).
Figure 12
Figure 12
Association of PCSK9 inhibitors compared with placebo with the incidence of any CVD.
Figure 13
Figure 13
Association of PCSK9 inhibitors compared with placebo with the incidence of any adverse events.
Figure 14
Figure 14
Association of PCSK9 inhibitors compared with ezetimibe and statins with the incidence of any CVD.
Figure 15
Figure 15
Association of PCSK9 inhibitors compared with ezetimibe and statins with the incidence of any adverse events.
Figure 16
Figure 16
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in HDL‐C at six months.
Figure 17
Figure 17
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in triglycerides at six months.
Figure 18
Figure 18
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in total cholesterol at six months.
Figure 19
Figure 19
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in apolipoprotein A1 at six months.
Figure 20
Figure 20
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in apolipoprotein B at six months.
Figure 21
Figure 21
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in lipoprotein(a) at six months.
Figure 22
Figure 22
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in non‐HDL‐C at six months.
Figure 23
Figure 23
Association of PCSK9 inhibitors compared with placebo with mean absolute change from baseline in HbA1c at six months.
Figure 24
Figure 24
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in HDL‐C at six months.
Figure 25
Figure 25
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in triglycerides at six months.
Figure 26
Figure 26
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in apolipoprotein B at six months.
Figure 27
Figure 27
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in lipoprotein(a) at six months.
Figure 28
Figure 28
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in non‐HDL‐C at six months.
Figure 29
Figure 29
Association of PCSK9 inhibitors compared with ezetimibe with mean percentage change from baseline in HDL‐C at six months.
Figure 30
Figure 30
Association of PCSK9 inhibitors compared with ezetimibe with mean percentage change from baseline in triglycerides at six months.
Figure 31
Figure 31
Association of PCSK9 inhibitors compared with ezetimibe with mean percentage change from baseline in total cholesterol at six months.
Figure 32
Figure 32
Association of PCSK9 inhibitors compared with ezetimibe with mean percentage change from baseline in apolipoprotein A1 at six months.
Figure 33
Figure 33
Association of PCSK9 inhibitors compared with ezetimibe with mean percentage change from baseline in apolipoprotein B at six months.
Figure 34
Figure 34
Association of PCSK9 inhibitors compared with ezetimibe with mean percentage change from baseline in lipoprotein(a) at six months.
Figure 35
Figure 35
Association of PCSK9 inhibitors compared with ezetimibe with mean percentage change from baseline in non‐HDL‐C at six months.
Figure 36
Figure 36
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in LDL‐C at 12 months.
Figure 37
Figure 37
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in HDL‐C at 12 months.
Figure 38
Figure 38
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in triglycerides at 12 months.
Figure 39
Figure 39
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in total cholesterol at 12 months.
Figure 40
Figure 40
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in apolipoprotein A1 at 12 months.
Figure 41
Figure 41
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in apolipoprotein B at 12 months.
Figure 42
Figure 42
Association of PCSK9 inhibitors compared with placebo with mean percentage change from baseline in non‐HDL‐C at 12 months.
Figure 43
Figure 43
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in LDL‐C at 12 months.
Figure 44
Figure 44
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in HDL‐C at 12 months.
Figure 45
Figure 45
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in triglycerides at 12 months.
Figure 46
Figure 46
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in apolipoprotein A1 at 12 months.
Figure 47
Figure 47
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in apolipoprotein B at 12 months.
Figure 48
Figure 48
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in lipoprotein(a) at 12 months.
Figure 49
Figure 49
Association of PCSK9 inhibitors compared with ezetimibe and statins with mean percentage change from baseline in non‐HDL‐C at 12 months.
Figure 50
Figure 50
Association of PCSK9 inhibitors compared with placebo with the incidence of all‐cause mortality.
Figure 51
Figure 51
Association of PCSK9 inhibitors compared with placebo with the incidence of any MI.
Figure 52
Figure 52
Association of PCSK9 inhibitors compared with placebo with the incidence of any stroke.
Figure 53
Figure 53
Association of PCSK9 inhibitors compared with placebo with the incidence of myalgia.
Figure 54
Figure 54
Association of PCSK9 inhibitors compared with placebo with the incidence of influenza.
Figure 55
Figure 55
Association of PCSK9 inhibitors compared with placebo with the incidence of hypertension.
Figure 56
Figure 56
Association of PCSK9 inhibitors compared with placebo with the incidence of any cancer diagnosis.
Figure 57
Figure 57
Association of PCSK9 inhibitors compared with placebo with the incidence of type 2 diabetes.
Figure 58
Figure 58
Association of PCSK9 inhibitors compared with placebo with the incidence of elevated creatine.
Figure 59
Figure 59
Association of PCSK9 inhibitors compared with placebo with the incidence of neurological events.
Figure 60
Figure 60
Association of PCSK9 inhibitors compared with ezetimibe and statins with the incidence of myalgia.
Figure 61
Figure 61
Association of PCSK9 inhibitors compared with ezetimibe and statins with the incidence of influenza.
Figure 62
Figure 62
Association of PCSK9 inhibitors compared with ezetimibe and statins with the incidence of hypertension.
Figure 63
Figure 63
Association of PCSK9 inhibitors compared with ezetimibe and statins with the incidence of type 2 diabetes.
Figure 64
Figure 64
Association of PCSK9 inhibitors compared with ezetimibe and statins with the incidence of elevated creatinine.
Figure 65
Figure 65
Association of PCSK9 inhibitors compared with ezetimibe and statins with the incidence neurological events
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References

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