Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis

Eliano Pio Navarese; Michalina Kołodziejczak; Volker Schulze; Paul A. Gurbel; Udaya Tantry; Yingfeng Lin; Maximilian Brockmeyer; David E. Kandzari; Julia M. Kubica; Ralph B. D'Agostino; Jacek Kubica; Massimo Volpe; Stefan Agewall; Dean J. Kereiakes; Malte Kelm

doi:10.7326/M14-2957

Reviews |7 July 2015

Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis Free

Eliano Pio Navarese, MD, PhD *; Michalina Kołodziejczak, MD *; Volker Schulze, MD; Paul A. Gurbel, MD; Udaya Tantry, PhD; Yingfeng Lin, MD; Maximilian Brockmeyer, MD; David E. Kandzari, MD; Julia M. Kubica, MD; Ralph B. D'Agostino Sr., PhD; Jacek Kubica, MD, PhD; Massimo Volpe, MD; Stefan Agewall, MD; Dean J. Kereiakes, MD; Malte Kelm, MD

Eliano Pio Navarese, MD, PhD

From Heinrich Heine University, Düsseldorf, Germany; Collegium Medicum, Bydgoszcz, and University Nicolaus Copernicus, Toruń, Poland; Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, Maryland; Piedmont Heart Institute, Atlanta, Georgia; Institute of Mathematics and Statistics, Biostatistics, and Epidemiology, Boston University, Boston, Massachusetts; Sapienza University of Rome, Sant'Andrea Hospital, Rome, and IRCCS Neuromed, Pozzilli, Italy; Oslo University Hospital, Ullevål, and Institute of Clinical Sciences, University of Oslo, Oslo, Norway; and Christ Hospital Heart and Vascular Center and Lindner Research Center, Cincinnati, Ohio.

Michalina Kołodziejczak, MD

Volker Schulze, MD

Paul A. Gurbel, MD

Udaya Tantry, PhD

Yingfeng Lin, MD

Maximilian Brockmeyer, MD

David E. Kandzari, MD

Julia M. Kubica, MD

Ralph B. D'Agostino Sr., PhD

Jacek Kubica, MD, PhD

Massimo Volpe, MD

Stefan Agewall, MD

Dean J. Kereiakes, MD

Malte Kelm, MD

Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 28 April 2015.

* Drs. Navarese and Kołodziejczak contributed equally to this work.

From Heinrich Heine University, Düsseldorf, Germany; Collegium Medicum, Bydgoszcz, and University Nicolaus Copernicus, Toruń, Poland; Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, Maryland; Piedmont Heart Institute, Atlanta, Georgia; Institute of Mathematics and Statistics, Biostatistics, and Epidemiology, Boston University, Boston, Massachusetts; Sapienza University of Rome, Sant'Andrea Hospital, Rome, and IRCCS Neuromed, Pozzilli, Italy; Oslo University Hospital, Ullevål, and Institute of Clinical Sciences, University of Oslo, Oslo, Norway; and Christ Hospital Heart and Vascular Center and Lindner Research Center, Cincinnati, Ohio.
Note: The study is a project of Systematic Investigation and Research on Interventions and Outcomes (SIRIO)-MEDICINE, a network of senior scientists and fellows collaborating worldwide to pursue research and innovation in medicine.
Financial Support: In part by CRC 1116 Masterswitches in Myocardial Ischemia, funded by the German Research Council DFG.
Disclosures: Dr. Kereiakes has received modest consulting fees from Sanofi. Authors not named here have no conflicts of interest. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2957.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: Eliano Pio Navarese, MD, PhD, Department of Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany; e-mail, eliano.navarese@med.uni-duesseldorf.de.
Current Author Addresses: Drs. Navarese, Kołodziejczak, Schulze, Lin, Brockmeyer, and Kelm: Department of Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
Drs. Gurbel and Tantry: Cardiac Catheterization Laboratory, Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Baltimore, MD 21215.
Dr. Kandzari: Piedmont Heart Institute, 275 Collier Road NW, Atlanta, GA 30309.
Drs. Julia M. Kubica and Jacek Kubica: Department of Cardiology and Internal Medicine, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Skłodowskiej-Curie Street No. 9, 85-094 Bydgoszcz, Poland.
Dr. D'Agostino: Mathematics and Statistics Department, Boston University, 111 Cummington Mall, Boston, MA 02215.
Dr. Volpe: Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine, University of Rome Sapienza, Sant'Andrea Hospital, Via di Grottarossa, 1035/1039, 00189 Rome, Italy.
Dr. Agewall: Department of Cardiology, Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Kirkeveien 166, Oslo 0407, Norway.
Dr. Kereiakes: Christ Hospital Heart and Vascular Center/Lindner Research Center, 2123 Auburn Avenue, Cincinnati, OH 45219.
Author Contributions: Conception and design: E.P. Navarese.
Analysis and interpretation of the data: E.P. Navarese, M. Kołodziejczak. M. Kelm.
Drafting of the article: E.P. Navarese, M. Kołodziejczak.
Critical revision of the article for important intellectual content: E.P. Navarese, M. Kołodziejczak, V. Schulze, P.A. Gurbel, U. Tantry, Y. Lin, M. Brockmeyer, D. Kandzari, J.M. Kubica, R.B. D'Agostino, J. Kubica, M. Volpe, S. Agewall, D. Kereiakes, M. Kelm.
Final approval of the article: E.P. Navarese, M. Kołodziejczak, V. Schulze, P.A. Gurbel, U. Tantry, Y. Lin, M. Brockmeyer, D. Kandzari, R. D'Agostino, M. Volpe, S. Agewall, D. Kereiakes, M. Kelm.

Abstract

Background:

Guidelines recommend statins as first-line therapy for dyslipidemia. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new lipid-lowering approach.

Purpose:

To assess the efficacy and safety of PCSK9 antibodies in adults with hypercholesterolemia.

Data Sources:

MEDLINE, PubMed Central, and Google Scholar; conference proceedings; and the ClinicalTrials.gov registry through 4 April 2015.

Study Selection:

Phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia.

Data Extraction:

Two investigators independently extracted data on study characteristics and lipid and clinical outcomes, and rated risk of bias of trials. Prespecified primary end points were all-cause and cardiovascular mortality.

Data Synthesis:

Twenty-four RCTs comprising 10 159 patients were included. Compared with no antibody, treatment with PCSK9 antibodies led to marked reductions in low-density lipoprotein cholesterol levels (mean difference, −47.49% [95% CI, −69.64% to −25.35%]; P < 0.001] and other atherogenic lipid fractions, and it reduced all-cause mortality (odds ratio [OR], 0.45 [CI, 0.23 to 0.86]; P = 0.015; heterogeneity P = 0.63; I² = 0%) and cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084; heterogeneity P = 0.78; I² = 0%). The rate of myocardial infarction was significantly reduced with use of PCSK9 antibodies (OR, 0.49 [CI, 0.26 to 0.93]; P = 0.030; heterogeneity P = 0.45; I² = 0%), and increases in the serum creatine kinase level were reduced (OR, 0.72 [CI, 0.54 to 0.96]; P = 0.026; heterogeneity P = 0.65; I² = 0%). Serious adverse events did not increase with administration of PCSK9 antibodies.

Limitation:

Results were derived from study-level data rather than patient-level data, and clinical outcome data are rare.

Conclusion:

PCSK9 antibodies seem to be safe and effective for adults with dyslipidemia.

Primary Funding Source:

CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG.

Hypercholesterolemia contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. Current guidelines from the American College of Cardiology and American Heart Association and from the European Society of Cardiology and European Atherosclerosis Society recommend lipid-lowering for patients with known cardiovascular disease; a 10-year cardiovascular disease risk of 7.5% or greater; diabetes and a low-density lipoprotein (LDL) cholesterol level of 1.8 mmol/L or greater (≥70 mg/dL); or an LDL cholesterol level of 5 mmol/L or greater (≥193 mg/dL) (1, 2). Statins are first-line pharmacotherapy, having shown significant reductions in both LDL cholesterol values and cardiovascular events (1, 2). Yet, despite intensive statin regimens to delay atherosclerotic plaque development and lower the risk for cardiovascular complications (3), a sizable proportion of statin-treated patients does not achieve recommended target LDL cholesterol levels, and some discontinue treatment owing to drug-related side effects (4–6).

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that plays an important role in lipid metabolism by modulating the density of LDL cholesterol receptors in multiple organs. The enzyme is synthesized in the nucleus, and after intramolecular autocatalytic cleavage of its N-terminal prosegment in the endoplasmic reticulum, it is secreted from hepatocytes, where it binds to the surrounding LDL cholesterol receptors. The complex is then subject to endocytosis and degradation of its entire structure in lysosomes (7). This physiologic function leads to an inverse relationship between the level of PCSK9 in the blood and the number of LDL receptors; inhibition of PCSK9 prevents LDL receptor degradation within lysosomes and preserves receptor recycling to the hepatocyte surface. Each receptor normally recycles approximately 150 times. Thus, monoclonal antibody binding and inhibition of PCSK9 prevents PCSK9 binding to the LDL cholesterol–LDL receptor complex and subsequent lysosomal degradation of the LDL receptor. The LDL-receptor recycling is preserved, with a consequent increase in receptor density on the hepatocyte surface and LDL cholesterol clearance.

Randomized, controlled trials (RCTs) have shown marked reductions in LDL cholesterol levels when PCSK9 antibodies are administered compared with no administration of PCSK9 antibodies (placebo or ezetimibe) (8–10). The PCSK9 inhibitors are currently undergoing regulatory review on the basis of efficacy and safety data from LDL cholesterol–lowering trials. In 2014, pharmaceutical companies submitted a biologics license application to obtain approval from the U.S. Food and Drug Administration for use of the PCSK9 inhibitor alirocumab (SAR236553/REGN727) and evolocumab (AMG 145) in the treatment of high cholesterol. In this context, we performed a systematic review and meta-analysis of RCTs to investigate the safety and efficacy of treatment with PCSK9 antibodies, particularly with respect to their effect on clinical outcomes.

Methods

We used established methods recommended by the Cochrane guidelines to conduct the meta-analysis and report our findings according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement (11, 12). The review protocol was not registered.

Data Sources and Searches

We searched MEDLINE, the Cochrane Central Register of Controlled Trials, Google Scholar, and Embase; TCTMD (www.tctmd.com), EuroPCR (www.europcr.com), ClinicalTrials.gov, Clinical Trial Results (www.clinicaltrialresults.org), the PCSK9 Education and Research Forum (www.pcsk9forum.org), and the American College of Cardiology Web site (www.cardiosource.com); and major congress proceedings, all until 4 April 2015. The following keywords were used: PCSK9 antibody, evolocumab, alirocumab, bococizumab, randomized controlled trial, and hypercholesterolemia. Citations were screened at the title and abstract level and retrieved as full reports if they were considered relevant.

Study Selection

The main inclusion criterion was a phase 2 or 3 RCT comparing PCSK9 antibodies with no PCSK9 antibody in adults with hypercholesterolemia, with clinical outcomes reported. No restrictions on language, follow-up, or study size were applied. The doses of PCSK9 antibody that had been used in phase 3 RCTs were selected for comparisons; study arms in which doses of PCSK9 antibodies were given that had not been used in phase 3 RCTs were excluded from the analysis.

Primary clinical end points were all-cause mortality and cardiovascular mortality; secondary end points were myocardial infarction, unstable angina, increased serum creatine kinase level, and serious adverse events (as reported in the original trials). Efficacy end points were percent change from baseline in LDL cholesterol and high-density lipoprotein (HDL) cholesterol levels; secondary efficacy end points were changes from baseline in total cholesterol and lipoprotein(a) levels. When LDL cholesterol results were reported by ultracentrifugation and by Friedewald formula calculation, the former was abstracted because we considered it more accurate (13).

Data Extraction and Quality Assessment

Two investigators who were not involved in any of the selected studies independently abstracted data by using prespecified forms. Two investigators then independently appraised the accuracy of the abstractions and resolved any discrepancies by consensus after discussion with a third investigator. Intensive background statin therapy was defined as daily use of atorvastatin, 40 mg or more; rosuvastatin, 20 mg or more (or ≥5 mg for the YUKAWA study, which was defined for a Japanese population); simvastatin, 80 mg or more; or any statin plus ezetimibe at baseline. Other treatment regimens were defined as nonintensive. When patients underwent a statin therapy washout period, the study was classified as “no statin.”

Serious adverse events were defined across trials in accordance with the Medical Dictionary for Regulatory Activities. Serious adverse events were predominantly defined as fatal, life-threatening, requiring or prolonging hospital admission, or causing persistent or substantial disability.

Two unblinded investigators independently appraised the potential risk of bias of the RCTs by using methods described in the Cochrane Collaboration guidelines (11).

Data Synthesis and Statistical Analysis

Data were analyzed according to the intention-to-treat principle. Odds ratios (ORs) for dichotomous data and mean difference (MD) of percent change from baseline for continuous variables, with 95% CIs, were used as summary statistics. For clinical outcomes, a continuity correction in case of rare events was applied. If SDs were not reported, they were calculated from CIs or SEs of the mean, according to formulas in the Cochrane Handbook for Systematic Reviews of Interventions (11).

Heterogeneity was assessed by using the Cochran Q test and the I² statistic (14, 15). If no or low to moderate inconsistency (<50%) was found, pooled ORs were calculated by using a fixed-effects model (11); otherwise, a random-effects model was used. If there were no outcome events, the software automatically applied a treatment-arm continuity correction approach (16).

Additional analyses included one stratified by the comparator arm for clinical outcomes. To account for the potential differences in follow-up, a prespecified analysis was performed with adjusted models by person-years to obtain pooled log rate ratios and CIs. Rates, rather than number of events, were considered the most appropriate outcome for the person-years analyses because they incorporate the follow-up duration of the trials.

Prespecified sensitivity analyses were conducted for efficacy end points by type and dose of PCSK9 antibody. More specifically, separate analyses were performed for alirocumab, 75 mg every 2 weeks; alirocumab, 150 mg every 2 weeks; evolocumab, 140 mg every 2 weeks; and evolocumab, 420 mg every 4 weeks. Another sensitivity analysis was stratified by intensity of background statin therapy. Potential publication bias was examined by constructing funnel plots in which the SE of the log OR was plotted against the OR of the selected binomial outcomes. For continuous outcomes, the SE was plotted against the MD.

For the summary treatment effect estimate, a 2-tailed P value less than 0.05 was considered statistically significant. Analyses were done by using R, version 3.1.3 (R Development Core Team), and Comprehensive Meta-Analysis software, version 2 (Biostat).

Role of the Funding Source

Part of this study was supported by CRC 1116 Masterswitches in Myocardial Ischemia, funded by the German Research Council DFG. The funding source had no role in the study design; collection, extraction, analysis, or interpretation of the data; or the decision to submit the manuscript for publication.

Results

Study Selection and Patient Population

Appendix Figure 1 shows the PRISMA flow chart of study selection. Twenty-four studies comprising a total of 10 159 patients were included in our final analysis (8–10, 17–35). Study characteristics are shown in Appendix Table 1. Eight trials were phase 2, and 16 trials were phase 3.

Appendix Figure 1.

Summary of evidence search and selection.

RCT = randomized, controlled trial.

Appendix Table 1. Study Characteristics

Appendix Table 2 shows patient characteristics. Twelve trials were of patients with familial hypercholesterolemia, 9 were of nonfamilial or unspecified hypercholesterolemia, 2 were of statin-intolerant hypercholesterolemia, and 1 was of mixed familial and nonfamilial hypercholesterolemia. Patients who did not receive a PCSK9 antibody (control groups) were treated with either placebo or ezetimibe. Seventeen trials were less than 6 months in duration, 2 were 6 to 12 months, and 4 were longer than 1 year. The longest follow-up was 104 weeks. To avoid overlapping patient samples, the OSLER trial was excluded, because the enrolled patients were derived from previous RCTs (36). All included trials were funded by industry.

Appendix Table 2. Patient Characteristics

Risk of Bias in the Included Studies

The risks of bias of the included studies are shown in Appendix Table 3. No publication bias was suggested by the funnel plots or the Egger regression test (Appendix Figures 2, 3, 4, 5, 6, 7, 8, and 9 and Appendix Table 4).

Appendix Table 3. Risk of Bias of Individual Randomized, Controlled Trials

Appendix Figure 2.

Funnel plot for all-cause mortality.

Appendix Figure 3.

Funnel plot for cardiovascular mortality.

Appendix Figure 4.

Funnel plot for increase in creatine kinase.

Appendix Figure 5.

Funnel plot for serious adverse events.

Appendix Figure 6.

Funnel plot for low-density lipoprotein cholesterol percentage of change from baseline.

Appendix Figure 7.

Funnel plot for high-density lipoprotein cholesterol percentage of change from baseline.

Appendix Figure 8.

Funnel plot for total cholesterol percentage of change from baseline.

Appendix Figure 9.

Funnel plot for lipoprotein(a) percentage of change from baseline.

Appendix Table 4. Egger Bias Analysis

The RCTs were similar in their risk of bias (Appendix Table 3). All were multicenter trials done according to the intention-to-treat principle. No studies had selective outcome reporting. Risk of bias was considered to be unclear predominantly in studies that were available only as presentation slides rather than full reports (8, 9, 18, 21, 25).

Primary Clinical End Points

All-Cause Mortality

Twenty-four RCTs with a total of 10 159 patients were included in the analysis of all-cause mortality (Figure 1). Overall, there was a statistically significant reduction in mortality with use of PCSK9 antibodies compared with no anti-PCSK9 treatment; the respective mortality rates were 0.31% (19 of 6187 patients) and 0.53% (21 of 3971 patients) (OR, 0.45 [95% CI, 0.23 to 0.86]; P = 0.015; heterogeneity P = 0.63; I² = 0%). No inconsistency was detected across trials (I² = 0%). The analysis that was adjusted for follow-up showed the consistency of the results (OR, 0.48 [CI, 0.27 to 0.85]; P = 0.010; heterogeneity P = 0.68; I² = 0%) (Appendix Figure 10). The sensitivity analysis that was stratified by comparator (placebo or ezetimibe) also supported the results (Appendix Table 5).

Figure 1.

All-cause mortality.

Expanded study abbreviations are as follows: DESCARTES = Durable Effect of PCSK9 Antibody Compared with Placebo Study; GAUSS = Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects; LAPLACE-2 = LDL-C Assessment with PCKS9 Monoclonal Antibody Inhibition Combined With Statin Therapy-2; LAPLACE-TIMI 57 = LDL-C Assessment with PCKS9 Monoclonal Antibody Inhibition Combined With Statin Therapy = Thrombosis in Myocardial Infarction 57; MENDEL = Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy For Easing Lipid Levels; RUTHERFORD = The Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familiar Hypercholesterolemia Disorder; PCSK9 = proprotein convertase subtilisin/kexin type 9; TESLA = Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities; YUKAWA = Study of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibody in Japanese Patients With Advanced Cardiovascular Risk.

Appendix Figure 10.

Analysis of all-cause mortality, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse-variance, fixed-effects model.

Appendix Table 5. Stratified Analysis of Clinical End Points

Cardiovascular Mortality

Twenty-four RCTs comprising 10 159 patients were included in the analysis of cardiovascular mortality (Figure 2). There was a statistically nonsignificant reduction in cardiovascular mortality with use of PCSK9 antibodies compared with no anti-PCSK9 treatment; the respective cardiovascular mortality rates were 0.19% (12 of 6187 patients) and 0.33% (13 of 3972 patients) (OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084; heterogeneity P = 0.78; I² = 0%). The analysis that was adjusted for follow-up showed the consistency of the results (OR, 0.49 [CI, 0.23 to 1.07]; P = 0.070; heterogeneity P = 0.79; I² = 0%) (Appendix Figure 11). The analysis that was stratified by comparator (placebo or ezetimibe) also supported the results (Appendix Table 5).

Figure 2.

Cardiovascular mortality.

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 11.

Analysis of cardiovascular mortality, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse variance, fixed-effects model.

Secondary Safety End Points

Myocardial Infarction and Unstable Angina

Ten RCTs with a total of 5195 patients reported data on myocardial infarction (Figure 3, top). Treatment with PCSK9 antibodies resulted in a statistically significant reduction in myocardial infarction compared with no anti-PCSK9 treatment; rates were 0.58% (19 of 3289 patients) and 1.00% (19 of 1906 patients), respectively (OR, 0.49 [CI, 0.26 to 0.93]; P = 0.030; heterogeneity P = 0.45; I² = 0%). The analysis that was adjusted for follow-up showed the consistency of the results (OR, 0.49 [CI, 0.26 to 0.93]; P = 0.030; heterogeneity P = 0.53; I² = 0%) (Appendix Figure 12). The analysis that was stratified by comparator (placebo) also supported the results (Appendix Table 5).

Figure 3.

Myocardial infarction (top) and unstable angina (bottom).

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 12.

Analysis of myocardial infarction, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse variance, fixed-effects model.

Six RCTs including a total of 3894 patients provided data on unstable angina (Figure 3, bottom). The rates were similar between the 2 groups: 0.04% (1 of 2515 patients) who received PCSK9 antibodies and 0.08% (1 of 1379 patients) who did not receive PCSK9 antibodies (OR, 0.61 [CI, 0.06 to 6.14]; P = 0.676; heterogeneity P = 0.34; I² = 0%). The analysis that was adjusted for follow-up showed the consistency of the results (OR, 0.51 [CI, 0.05 to 4.86]; P = 0.56; heterogeneity P = 0.34; I² = 0%) (Appendix Figure 13). The analysis that was stratified by comparator (placebo) also supported the results (Appendix Table 5).

Appendix Figure 13.

Analysis of unstable angina, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse-variance, fixed-effects model.

Serum Creatine Kinase Level

Twenty-four RCTs comprising 10 159 patients provided data on serum creatine kinase levels (Figure 4). Treatment with PCSK9 antibodies resulted in statistically significant reductions compared with no anti-PCSK9 treatment; increased creatine kinase levels were found in 1.96% of patients who received PCSK9 antibodies (121 of 6187) and 2.31% of those who did not receive PCSK9 antibodies (92 of 3972) (OR, 0.72 [CI, 0.54 to 0.96]; P = 0.026; heterogeneity P = 0.65; I² = 0%). The analysis that was adjusted for follow-up showed the consistency of the results (OR, 0.73 [CI, 0.55 to 0.97]; P = 0.030; heterogeneity P = 0.67; I² = 0%) (Appendix Figure 14). The analysis that was stratified by comparator (placebo or ezetimibe) also supported the results (Appendix Table 5).

Figure 4.

Increase in creatine kinase level.

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 14.

Analysis of increase in creatine kinase level, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse-variance, fixed-effects model.

Serious Adverse Events

Twenty-four RCTs comprising all 10 159 patients were included in the analysis of serious adverse events (Figure 5). The overall incidence was 9.26% (573 of 6187) among patients treated with PCSK9 antibodies and 7.73% (307 of 3972) among patients who were not treated with PCSK9 antibodies (OR, 1.01 [CI, 0.87 to 1.18]; P = 0.879; heterogeneity P = 0.98; I² = 0%). Average discontinuation rates were no higher among patients receiving PCSK9 antibodies than among patients receiving placebo or ezetimibe (Appendix Table 6). Adjustment for follow-up showed the consistency of the results (OR, 1.01 [CI, 0.88 to 1.16]; P = 0.89; heterogeneity P = 0.98; I² = 0%) (Appendix Figure 15). The analysis that was stratified by comparator (placebo or ezetimibe) also supported the results (Appendix Table 5).

Figure 5.

Serious adverse events.

See the legend for Figure 1 for abbreviation expansions.

Appendix Table 6. LDL Cholesterol Values and Discontinuation Rates

Appendix Figure 15.

Analysis of serious adverse events, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse-variance, fixed-effects model.

Efficacy End Points

LDL Cholesterol

Twenty-four studies comprising 10 159 patients were included in the analysis of LDL cholesterol (Appendix Figure 16). Overall, a reduction in LDL cholesterol levels of almost 50% was observed with use of PCSK9 antibodies compared with no anti-PCSK9 treatment (MD, −47.49% [CI, −69.64% to −25.35%]; P < 0.001). The reduction in LDL cholesterol with anti-PCSK9 therapy compared with placebo was significantly greater than that compared with ezetimibe (placebo: MD, −58.77% [CI, −61.03% to −56.51%]; P < 0.001; ezetimibe: MD, −36.17% [CI, −39.28% to −33.06%]; P < 0.001). Sensitivity analyses stratified by type and dose of PCSK9 antibody showed consistent results (Appendix Table 7).

Appendix Figure 16.

Low-density lipoprotein cholesterol percentage of change from baseline.

See the legend for Figure 1 for abbreviation expansions.

Appendix Table 7. Sensitivity Analyses for Efficacy

HDL Cholesterol

Fourteen RCTs comprising 4378 patients were included in the analysis of HDL cholesterol (Appendix Figure 17). Overall, the percentage of increase (MD) with use of PCSK9 antibodies versus no treatment with PCSK9 antibodies was 6.30% (CI, 5.58% to 7.02%; P < 0.001). Similar increases in HDL cholesterol levels were observed when PCSK9 antibodies were compared with placebo (MD, 6.14% [CI, 5.31% to 6.97%]; P < 0.001) or ezetimibe (MD, 6.80% [CI, 5.33% to 8.26%]; P < 0.001) (Appendix Table 7). Findings of sensitivity analyses were consistent with the main results.

Appendix Figure 17.

High-density lipoprotein cholesterol percentage of change from baseline.

See the legend for Figure 1 for abbreviation expansions.

Total Cholesterol

Ten studies comprising 5357 patients contributed to the analysis of total cholesterol (Appendix Figure 18). Overall, a 31% reduction was observed when treatment with PCSK9 antibodies was compared with no anti-PCSK9 treatment (MD, −31.49% [CI, −46.35% to −16.64%]; P < 0.001). The reduction in total cholesterol with anti-PCSK9 treatment was greater compared with placebo (MD, −38.99% [CI, −40.72% to −37.26%]; P < 0.001) than with ezetimibe (MD, −23.83% [CI, −27.35% to −20.32%]; P < 0.001). Sensitivity analyses by type and dose of anti-PCSK9 agent showed consistent results (Appendix Table 7).

Appendix Figure 18.

Total cholesterol percentage of change from baseline.

See the legend for Figure 1 for abbreviation expansions.

Lipoprotein(a)

Twelve RCTs including a total of 6566 patients were included in the analysis of lipoprotein(a) (Appendix Figure 19). Overall, a greater than 25% reduction in lipoprotein(a) levels was observed when anti-PCSK9 treatment was compared with no anti-PCSK9 treatment (MD, −26.45% [CI, −30.19% to −22.71%]; P < 0.001). A similar reduction in lipoprotein(a) values was found in placebo-controlled trials (MD, −27.96% [CI, −31.21% to −24.71%]; P < 0.001) and in ezetimibe-controlled trials (MD, −24.05% [CI, −28.94% to −19.16%]; P < 0.001). Sensitivity analyses for type and dose of PCSK9 antibody showed consistency in the direction and magnitude of the results (Appendix Table 7).

Appendix Figure 19.

Lipoprotein(a) percentage of change from baseline.

See the legend for Figure 1 for abbreviation expansions.

Additional Analyses

Analyses that were stratified by the comparator arm (placebo or ezetimibe) and background statin therapy (no statin vs. not intensive vs. intensive) showed directions that were consistent with those of the main results from a larger sample size (Appendix Tables 5 and 7). Additional analyses by agent and dose of antibody showed that neither a different type nor dose of PCSK9 antibody significantly modified the positive effect on lipid profile.

Discussion

Our main findings are that compared with no anti-PCSK9 treatment, use of PCSK9 antibodies is associated with 1) lower odds of all-cause mortality and myocardial infarction and a statistically nonsignificant reduction in cardiovascular mortality; 2) lower increase in the serum creatine kinase level; 3) no increase in serious adverse events; and 4) a marked reduction in atherogenic lipid fractions. Improvements in clinical outcomes were consistent in multiple sensitivity analyses that used different methods of analysis.

International guidelines to reduce cardiovascular risk have promoted increasingly lower treatment goals for LDL cholesterol (1, 2). Statins are the most prescribed drugs, and evidence shows they reduce cardiovascular risk across all risk factor categories, lending support for widespread use (37). Although statins have acceptable efficacy and safety profiles, more than one half of cardiovascular events are not being prevented by these drugs, owing to either elevated residual cardiovascular risk or statin intolerance. Several reports indicate that up to 40% of patients receiving statins are not able to reach target LDL cholesterol levels with current guideline recommendations (38). Potential reasons are submaximal doses, discontinuation of therapy owing to side effects, pharmacologic interactions, and the limited (about 6%) additional decrease in LDL cholesterol with doubling of the dose (17).

In recent years, novel treatments have actively been sought, and human monoclonal antibodies against PCSK9 have been identified as an innovative lipid-lowering strategy. Several phase 3 studies in different settings showed that use of PCSK9 antibodies combined with statins provided benefits in terms of reducing atherogenic lipid fractions in patients with hyperlipidemia (LAPLACE-2) (29) or heterozygous familial hypercholesterolemia (RUTHERFORD-2) (28), and that PCSK9 antibodies as a stand-alone treatment were beneficial in hyperlipidemia (MENDEL-2) (22).

The DESCARTES trial (17) involved 901 adults with or without coronary heart disease who had an LDL cholesterol level greater than 1.9 mmol/L (>75 mg/dL) despite maximal lipid-lowering therapy. Participants were randomly assigned to receive evolocumab, 420 mg every 4 weeks, or placebo, in addition to background therapy consisting of diet modification alone; atorvastatin, 10 mg, plus diet modification; atorvastatin, 80 mg; or atorvastatin, 80 mg, plus ezetimibe, 10 mg.

In the LAPLACE-2 trial, the efficacy and tolerability of evolocumab were evaluated in addition to either moderate-intensity or high-intensity statin therapy. Evolocumab at dosages of 140 mg every 2 weeks or 420 mg every 4 weeks was found to be efficacious and safe. Evolocumab was also found to lower lipoprotein(a) and apoliprotein B levels, and to increase the HDL cholesterol level.

GAUSS and GAUSS-2 differ from the other trials owing to predominant inclusion of statin-intolerant patients, although a substantial proportion of patients actually received a statin during these trials. In those studies, treatment with evolocumab resulted in a 41% to 51% reduction in the LDL cholesterol level, but it had no statistically significant effect on clinical outcomes compared with placebo. These studies demonstrated marked reductions in LDL cholesterol levels with PCSK9 antibody treatment, consistent with the approximate 50% reduction in LDL cholesterol levels in our meta-analysis (Appendix Table 6).

Our large-scale report is the first to show a benefit in mortality with these novel agents. The finding of lower all-cause mortality, although preliminary, is encouraging and is further corroborated by a similar direction of reduction in the odds of cardiovascular mortality, as well as by recent findings of the open-label OSLER-1 and OSLER-2 extension trials that showed reductions in cardiovascular events with evolocumab compared with standard therapy (36). Of note, no signal for heterogeneity was present across trials in the analysis of all-cause and cardiovascular mortality, and there was stability of the direction and magnitude of results in our sensitivity analyses. Moreover, the sensitivity analyses for type and dose of PCSK9 antibody, and the subgroup analyses stratified by placebo or ezetimibe as the control arm and by background statin therapy, all suggest that the overall effect is robust and justified.

The mechanisms of improved survival in patients treated with PCSK9 antibodies are unclear but may be related to the efficacy of these agents in reducing lipid levels (particularly LDL cholesterol, non-HDL cholesterol, and lipoprotein(a)) and may also be influenced by reduced rates of myocardial infarction due to plaque stabilization. However, this encouraging result, which may play a role in the observed survival benefit, should be interpreted with caution.

Whereas mortality data were frequently reported across studies, fewer studies reported data on myocardial infarction. The most informative study on this outcome—ODYSSEY LONG TERM, which includes the largest patient population studied over 78 weeks of follow-up—demonstrated a reduction in myocardial infarction with PCSK9 antibody therapy (37). Further data from ongoing studies in which the primary end point is cardiovascular events will provide a more definitive answer regarding the effect of profound reduction in LDL cholesterol on myocardial infarction.

The recently presented long-term results of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated the efficacy and safety of ezetimibe plus simvastatin versus simvastatin alone, showed that combination therapy compared with monotherapy not only produced marked reductions in LDL cholesterol but also reduced cardiovascular events in high-risk patients with the acute coronary syndrome (39). IMPROVE-IT reinforces the theory that “lower is better,” in terms of LDL cholesterol levels, by resulting in greater clinical benefits. In IMPROVE-IT, adding ezetimibe to statin therapy reduced the LDL cholesterol level by an average of 0.44 mmol/L (17 mg/dL). However, there was no statistically significant effect on mortality.

No single RCT evaluating PCSK9 antibodies has yet been powered to show an effect on mortality and cardiovascular events, but our meta-analysis of 10 159 patients with a mean follow-up of 44.6 weeks found that treatment with PCSK9 antibodies reduced the odds of all-cause death. The magnitude of LDL cholesterol reduction observed with alirocumab and evolocumab was distinctly greater than that with ezetimibe in IMPROVE-IT and in our meta-analysis (Appendix Table 6), with an average additional 36% reduction in LDL cholesterol from baseline compared with ezetimibe-treated patients. It should be noted, however, that patient populations differ.

IMPROVE-IT evaluated the combination of ezetimibe with statin for secondary prevention of acute coronary syndromes. In contrast, PCSK9 antibodies have been tested predominantly in adults without the acute coronary syndrome who have hypercholesterolemia. According to the quantitative interaction principle, whereby the benefit of treatment is larger among high-risk patients (40, 41), our preliminary findings on anti-PCSK9 therapy in our mortality analysis might be amplified in higher-risk scenarios characterized by higher baseline mortality rates in both the active treatment (anti-PCSK9) and control arms.

The reduction in lipoprotein(a), another lipid fraction that contributes to atherosclerotic plaque formation (42), may also contribute to the benefits of PCSK9 antibodies in terms of mortality and myocardial infarction rates. The average 25% reduction in lipoprotein(a) levels observed in our meta-analysis was of similar magnitude when PCSK9 antibodies were compared with placebo or ezetimibe. This finding suggests a possible mechanism for long-term cardiovascular benefit with the combination of potent PCSK9 inhibition and pleiotropic statins, especially for patients at high cardiovascular risk.

Of note, in our analysis, increased creatine kinase values occurred significantly less often with PCSK9 antibodies compared with no anti-PCSK9 treatment. Although the majority of included studies involved patients receiving statin therapy, there was a statistically significant 30% reduction in the odds of increased creatine kinase levels with use of PCSK9 antibodies compared with no anti-PCSK9 treatment; this finding suggests that PCSK9 antibodies may have a muscle-sparing effect even in statin-treated patients, which may attenuate statin intolerance. Notably, the rates of serious adverse events reported in the studies did not statistically significantly differ with versus without anti-PCSK9 treatment, confirming the overall comparative safety of the drug. On the basis of these findings of reduced mortality and muscle complications in patients at lower risk (for example, those without or with stable coronary artery disease), PCSK9 inhibition may be even more useful in higher-risk patients, such as those with the acute coronary syndrome, in whom a high dosage of statin is conventionally recommended.

Currently, 4 large cardiovascular outcomes trials (expected completion by 2018) are testing the ability of PCSK9 antibodies to affect clinical outcomes (Appendix Table 8). The FOURIER study is assessing whether treatment with evolocumab compared with placebo reduces recurrent cardiovascular events in 27 500 adults with established cardiovascular disease (43). The ODYSSEY Outcomes trial is examining the effect of alirocumab on major adverse cardiovascular events in patients who recently experienced an acute coronary syndrome and is expected to enroll 18 000 patients (44). The phase 3 program of study for bococizumab consists of 2 cardiovascular outcome studies, as well as multiple studies of the change in LDL cholesterol in more than 22 000 patients. One of the 2 cardiovascular outcome studies, SPIRE-1, will assess whether lowering LDL cholesterol to levels well below current guideline-recommended targets will lead to further reduction in cardiovascular events.

Appendix Table 8. Randomized, Controlled Trials Comparing Treatment With PCSK9 Antibodies With No Anti-PCSK9 Treatment

Our study has limitations. First, our results are derived from study-level data rather than patient-level data; individual patient data would have improved the accuracy of the analysis by allowing subgroup comparisons. Second, a few studies have only been reported in abstract form or presented at meetings. Third, clinical event outcomes should be interpreted with caution because the data were derived from a small number of events. Fourth, the duration of follow-up in the studies ranged from 2 months to 2 years, but we note that administration of PCSK9 antibodies results in a rapid reduction in lipid subfractions. Finally, the investigated populations represent a broad spectrum of patients with and without known genetic disorders; although our analysis contributes information on the general approach to the management of dyslipidemia, future studies that focus on particular populations will probably refine knowledge about the groups that are most responsive to benefits with small risk for harm.

In conclusion, treatment with PCSK9 antibodies produces profound reductions in LDL cholesterol and lipoprotein(a), with an apparently similar level of safety and an important preliminary signal of survival benefit compared with no anti-PCSK9 treatment. Thus, PCSK9 monoclonal antibody therapy seems to be a safe and effective strategy for patients with dyslipidemia. Ongoing trials should provide further data on the safety of this innovative strategy and on the relationship of lower LDL cholesterol levels and the rate of cardiovascular events (45, 46). In particular, these trials should validate or refute the findings on mortality that, if confirmed, could have a profound effect on public health.

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Appendix Figure 1.

Summary of evidence search and selection.

RCT = randomized, controlled trial.

Appendix Figure 2.

Funnel plot for all-cause mortality.

Appendix Figure 3.

Funnel plot for cardiovascular mortality.

Appendix Figure 4.

Funnel plot for increase in creatine kinase.

Appendix Figure 5.

Funnel plot for serious adverse events.

Appendix Figure 6.

Funnel plot for low-density lipoprotein cholesterol percentage of change from baseline.

Appendix Figure 7.

Funnel plot for high-density lipoprotein cholesterol percentage of change from baseline.

Appendix Figure 8.

Funnel plot for total cholesterol percentage of change from baseline.

Appendix Figure 9.

Funnel plot for lipoprotein(a) percentage of change from baseline.

Figure 1.

All-cause mortality.

Appendix Figure 10.

Analysis of all-cause mortality, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse-variance, fixed-effects model.

Figure 2.

Cardiovascular mortality.

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 11.

Analysis of cardiovascular mortality, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse variance, fixed-effects model.

Figure 3.

Myocardial infarction (top) and unstable angina (bottom).

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 12.

Analysis of myocardial infarction, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse variance, fixed-effects model.

Appendix Figure 13.

Analysis of unstable angina, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse-variance, fixed-effects model.

Figure 4.

Increase in creatine kinase level.

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 14.

Analysis of increase in creatine kinase level, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse-variance, fixed-effects model.

Figure 5.

Serious adverse events.

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 15.

Analysis of serious adverse events, adjusted for follow-up.

See the legend for Figure 1 for abbreviation expansions.

* Inverse-variance, fixed-effects model.

Appendix Figure 16.

Low-density lipoprotein cholesterol percentage of change from baseline.

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 17.

High-density lipoprotein cholesterol percentage of change from baseline.

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 18.

Total cholesterol percentage of change from baseline.

See the legend for Figure 1 for abbreviation expansions.

Appendix Figure 19.

Lipoprotein(a) percentage of change from baseline.

See the legend for Figure 1 for abbreviation expansions.

Appendix Table 1. Study Characteristics

Appendix Table 2. Patient Characteristics

Appendix Table 3. Risk of Bias of Individual Randomized, Controlled Trials

Appendix Table 4. Egger Bias Analysis

Appendix Table 5. Stratified Analysis of Clinical End Points

Appendix Table 6. LDL Cholesterol Values and Discontinuation Rates

Appendix Table 7. Sensitivity Analyses for Efficacy

Appendix Table 8. Randomized, Controlled Trials Comparing Treatment With PCSK9 Antibodies With No Anti-PCSK9 Treatment

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5 Comments

Gauranga Dhar

Bangladesh Institute of Family Medicine and Research

May 2, 2015

Revolution in the prevention of atherosclerotic cardiovascular diseases

If we talk about diabetes, despite lifestyle modification and drug treatment, significant number of patients are not at A1C goal (<7%). In the same way most of the hypercholesterolemic patients remain at cardiovascular event risk in spite of intensive statin therapy. Number of patients who abstain from taking statin therapy due to adverse effects are not small.
Introduction of PCSK9 inhibitors probably is a revolution in the management of hypercholesterolemia and prevention of atherosclerotic cardiovascular morbidity and mortality. Completely by different mode of action, monoclonal antibodies increase LDL receptors causing faster and more effective reduction of LDL lipoprotein particles than statin or statin ezetimibe in combination.
Higher lipoprotein(a) is usually genetically determined but there are studies which show that vegans are at increased risk of high serum level of lipoprotein(a). Lipoprotein(a) plays important role in the development of atherosclerosis and we still have no effective drug to manage high lipoprotein(a). Sustained release niacin at high dose or aspirin found to reduce lipoprotein(a) and obviously associated with higher adverse effects. PCSK9 inhibitors are found to reduce lipoprotein(a) by >24% along with reduction of low density lipoprotein particles and moderate increase of high density lipoprotein without specific adverse effects.
Although alirocumab has been proved to cause neurocognitive disorder, number of PSCK9 inhibitors now is at various stages of development. This group of drugs either as monotherapy or along with statin will start a revolution on the prevention of atherosclerotic cardiovascular diseases.

Aris Liakos, MD, MSc; Eleni Athanasiadou, MSc; Maria Mainou, MD; Eleni Bekiari, MD, PhD; Anna Bettina Haidich, PhD; Evangelos C. Rizos, MD, PhD and Apostolos Tsapas, MD, PhD, MSc

Clinical Research and Evidence Based Medicine, Second Medical Department and Department of Hygiene and Epidemiology, Aristotle University Thessaloniki, Thessaloniki, Greece; Second Medical Department,

May 17, 2015

Conflict of Interest: ECR has received speaker honoraria, consulting fees, and has taken part in clinical trials with Novartis, Sanofi, NovoNordisk, AstraZeneca/Bristol Myers Squibb, MSD, Pfizer, Vianex, Amgen, Boehringer Ingelheim and Plus Pharmaceutical. AT has received minimal speaker honoraria from Sanofi in the field of diabetes. The remaining authors declare no competing interests. There was no funding source for this work.

Comment

TO THE EDITOR: In their systematic review, Navarese and colleagues conclude that proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK-9i) reduce all-cause mortality (odds ratio [OR], 0.45 [95% CI, 0.23 to 0.86]) and myocardial infarction, and have a favorable, yet not statistically significant, effect on cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]) and unstable angina (1). They claim robustness of their findings based on similar results from several sensitivity analyses.
We would like to question these conclusions in light of a re-analysis of the all-cause mortality data. Navarese et al. excluded zero total events trials and used an inverse variance weighted fixed effects model for pooling of rare events. This model relies on large sample theory and has shown poor performance with rare events in simulation studies (2). We repeated the analysis including all trials, and used a Mantel-Haenszel weighted fixed effects model and treatment-arm continuity correction (most trials had no outcome events for the primary outcomes) as previously described for rosiglitazone studies (3). This reanalysis found that the effect estimate for all-cause mortality is indeed sensitive to the exclusion of zero total events trials (OR, 0.62 [CI, 0.37 to 1.04]). Given the lack of a pre-publicized protocol, we viewstatements in the abstract about reduction of all-cause and cardiovascular mortality as overly positive and incorrect. Given the potential impact of the article on the ongoing decision process for a marketing authorization, it is imperative to highlight this limitation of the reported analysis.
Lack of a pre-publicized protocol also raises concerns about the ad libitum presentation of certain secondary safety end points, given that most studies on PCSK-9i as well as the ongoing cardiovascular outcomes trials, utilize a composite cardiovascular end point (including death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization).
Finally, the clinical relevance of the systematic review is attenuated by the short duration of the majority of the included trials that were designed to assess surrogate endpoints. Findings are dominated by the single largest trial with relatively high discontinuation rates after 78 weeks of treatment (28% for alirocumab and 24% for placebo) (4).
All in all, in our opinion, given the observed vibration of effects for hard cardiovascular end points and pending completion of long term randomized controlled trials, it still remains uncertain whether PCSK-9i confer additional cardiovascular benefits beyond high-intensity statin therapy.

References
1. Navarese EP, Kołodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015. [PMID: 25915661]
2. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23:1351-75. [PMID: 15116347]
3. Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578-81. [PMID: 17679700]

5. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;72:1489-99. [PMID: 25773378]

Alessandro Battaggia, Alberto Donzelli, Maria Font

Infofarma Unità Locale Socio, Azienda Sanitaria Locale di Milano, Infofarma Unità Locale Socio Sanitaria

May 26, 2015

The statistical approach adopted by the authors is not correct, the benefits of PCSK9 inhibitors are probably not statistically significant

To the editor: A recent meta-analysis published in the journal suggested large benefits and death reduction with PCSK9 antibodies in hypercholesterolemic adults.(1) Unfortunately, the section "Data synthesis and Statistical Analysis" omitted detail about the pooling and continuity correction method that was used (namely, the management of zero cells in the OR calculation).
To reach the published results (all-cause mortality OR=0.45, 95% CI 0.23-0.86), the authors probably used a combination of the Wolf fixed effect based method and the 'Treatment Arm' continuity correction suggested for zero-cells (2), excluding the "zero-total event trials". We disagree with the inverse variance Wolf method used for pooling. The meta-analysis of the endpoint 'death' involves 23 trials and 10,159 subjects, but only 19 and 21 of them, in the intervention and control arms respectively, died in a follow-up ranging between 8 and 104 weeks (≤52 weeks in 19/23 trials).

Analysis of rare data poses questions about pooling methods: the Peto OR, golden standard for rare event meta-analyses (3), is useless in the presence of unbalanced arms (as is what occurred in the PCSK9 antibody analysis), and the Wolff method is severely biased in presence of rare events (2, 3). We agree with a published comment criticizing the approaches taken in the meta-analysis (4) Using the less biased conventional meta-analytical approach in presence of rare events, (the Mantel-Haenszel method of pooling), and not excluding the "zero-total event trials", we had independently reached the same conclusion of Liakos et al (4): the results (OR= 0.62; 95% CI 0.37-1.04) loose statistical significance. Instead, excluding as in (1) the "zero-total event trials", applying the same continuity correction, but using the correct Mantel-Haenszel method of pooling, the result is significant, but of smaller magnitude compared to that reported in the meta-analysis (OR= 0.54; 95%CI 0.30-0.96).

The meta-analysis (1) mainly included trials, sponsored by product makers, of short duration that were designed to assess surrogate endpoints. A somewhat similar meta-analyses about DPP-4 inhibitors in diabetic patients showed significant and impressive mortality reductions, whereas a subsequent larger meta-analysis (5), with more trials designed to assess hard endpoints, showed no effect on mortality, and an increased risk of heart failure: RR 1.158 (95% CI 1.011 to 1.326).
In conclusion, more research is needed, recruiting patients with higher baseline death risk in trials with well-balanced arms and adequate duration, before promoting this new costly drug class, of uncertain long-term safety.

1. Navarese EP, Kołodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Effects of proprotein convertase subtilisin/sexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015 Apr 28. [PMID: 25915661] doi: 10.7326/M14-2957

2. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004 May 15;23:1351-75. [PMID: 15116347]

3. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

4. Liakos A, Athanasiadou E, Mainou M, Bekiari E, Haidich AB, Rizos EC, et al. Uncertain effects of proprotein convertase/subtilisin kexin type 9 inhibitors on hard clinical end points. Comment posted on May 17, 2015, about (1).

5. Savarese G, Perrone-Filardi P, D'Amore C, Vitale C, Trimarco B, Pani L, et al. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: A meta-analysis. Int J Cardiol 2015; 181:239-44 [PMID 25528528] doi: 10.1016/j.ijcard.2014.12.017

John Cornell, PhD, Cynthia Mulrow, MD

American College of Physicians

June 9, 2015

Conflict: Editors at Annals and Authors of Editorial

Response for the Editors: Liakos, et al. (1) and Battaggia et al. (2) raise questions about the statistical methods and approach Navarese, et al. (3) used in their meta-analysis of the effects of proprotein convertase subtilisin/Kexin Type 9 (PCSK9) to reduce cardiovascular and all-cause mortality among adults with hypercholesterolemia. Navarese et al. did indeed use the fixed-effects Mantel-Haenszel (MH) method with inverse variance weighting to summarize the data. The treatment arm correction, recommended by Sweeting, et al. (4), was used to compensate for zero events in either the PCSK9 or control arm. Studies reporting zero events in both arms were excluded from the analyses.

Battaggia et al.’s re-analysis using a fixed-effects MH method with the treatment arm correction provides a more conservative estimate for the mortality outcomes: OR = 0.54 (95% CI: 0.30 to 0.96). It could be argued that this a better approach to use when pooling rare events. We could also argue that the exact MH, without treatment arm correction, is a more robust estimator for OR (95% CI) when pooling rare events. The exact MH for all-cause mortality is OR = 0.49 (95% CI: 0.26 to 0.91). Either method provides more conservative estimates with larger confidence intervals for the effects of PSCK9 on all-cause mortality, but the results obtained using either method do not alter the overall conclusion that the PCSK9 may statistically significantly reduce all-cause mortality among adults with hypercholesterolemia.

The issue at stake for Liakos et al. is what to do with the zero event studies. They argue that excluding these trials from the analysis overestimates the beneficial effect of PCSK9 on the mortality outcomes. The practice of excluding trials with zero outcomes for clinical outcomes is common in systematic reviews. Trials with no events in either arm fail to provide sufficient information to judge the relative efficacy of an intervention. Both the intervention and control group share a common exposure, hyperlipidemia in this case. So, both are equally at risk for the event of interest at the start of the trial. The intervention is designed to reduce lipid levels, ultimately reducing the morbid and mortal events associated with elevated lipids. Studies with zero events in both arms preclude the opportunity to make comparative judgements about relative efficacy of the intervention. Such zero event trials are said to be non-informative and should be excluded from the analysis. This is a long-standing position among methodologists that is included in the Cochrane methods guides and Handbook (5).

The actual magnitude of the effect PCSK9 has on cardiovascular and all-cause mortality remains an open question. Navarese et al., and an accompanying editorial (6), point out that none of the trials included in their meta-analysis were of sufficient size and duration to allow us to draw definitive conclusions about the effects of PCSK9 on these important clinical outcomes. Caution is always needed when interpreting summary estimates based on small studies reporting rare clinical outcomes. The definitive effects of PCSK9 on cardiovascular morbid and mortal events can only be addressed in large clinical trials of sufficient duration that are specifically designed and powered to assess these clinical outcomes. We clearly need to await the results from 4 large clinical trials, currently underway before we know with certainty what effect PCSK9 has on cardiovascular morbidity and mortality.

John Cornell and Cynthia Mulrow

Reference
1. Liakos A, Athanasiadou E, Mainou M, Bekiari E, Haidish AB, Rioz EC, Tsapas A. Uncertain effects of propotein covertase/subtilisin kexin type 9 inhibitors on hard clinical end points. Ann Intern Med (17 May 2015)
2. Battaggia A, Donzelli A, Font M. The statistical approach dopted byt eh authors is not correct, the benefits of PCSK9 inhibitors are probably not statistically significant. Ann Intern Med (26 May 2015)
3. Navarese PO, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D’Agostino RB Sr., Kubica J, Volpe M, Agewall S, Kereiakes DJ, Kelm M. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: A systematic review and meta-analysis. Ann Intern Med. 2015; doi10.7326/M14-2957.
4. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity correction in meta-analysis of sparse data. Statist Med. 2004; 23: 1351-1375.
5. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
6. Cainzos-Achirica M, Martin SS, Cornell JE, Mulrow CD, Guallar E Eliseo Guallar. PCSK9-Inhibitors: A New Era in Lipid-Lowering Treatment? Ann Intern Med 2015
28 April 2015 doi:10.7326/M15-0920

Helen O'Donnell (1), Laura McCullagh (2), Cathal Walsh (3), Michael Barry (1).

(1) National Centre for Pharmacoeconomics, Dublin, Ireland; (2) Trinity College Dublin, Ireland; (3) University of Limerick, Ireland.

January 10, 2017

Coronary Heart Disease Mortality versus Cardiovascular Mortality

We wish to point that in the meta-analysis conducted by Navarese et al. (1), the second primary clinical endpoint analysed and presented in figure 2 is labelled as cardiovascular mortality. However for 2 of the 24 trials analysed (ODYSSEY LONG TERM (2) and ODYSSEY COMBO I (3)), the authors inputted the number of deaths due to coronary heart disease (CHD) for each arm rather than the number of deaths due to cardiovascular disease (CVD). The definition of CHD is much narrower than that of CVD which also encompasses stroke and other causes of vascular disease such as deep vein thrombosis in addition to CHD. The Cholesterol Treatment Trialists Collaboration (CTTC) meta-analysis indicates that CHD mortality accounts for less than 50% of the total number of cardiovascular deaths. Therefore, it is a concern that a number of cardiovascular deaths are not accounted for in the event counts in both arms of these two trials. (4)
We believe that, since the total numbers of cardiovascular deaths are not reported or computable from the published trial results referenced, these two trials should not have been included in the analysis of this endpoint. Although the meta-analysis included 24 trials, 49.2% of this endpoint was weighted to the results of these two trials alone. Therefore their inappropriate inclusion has an impact on the results of this analysis. We calculate an odds ratio (OR) of 0.77 (95% CI 0.26 to 2.35) when these trials are excluded compared to an OR 0.50 (95% CI: 0.23 to 1.10) reported in the Navarese et al analysis. (1) We conclude that the potential beneficial effect of PCSK9 inhibitor therapy on cardiovascular mortality is overestimated given the data available at the time of the analysis. Different treatment effects sizes based on varying classifications of cardiovascular mortality would not be unexpected. The CTTC estimated a rate ratio per 1 mmol/L reduction in LDL-C of 0.80 for CHD death versus 0.88 for any cardiovascular death. (4)
The treatment effect of PCSK9 inhibitors on cardiovascular morbidity and mortality has yet to be determined and will be confirmed by outcomes trials whose results are expected in 2017. In the interim, this meta-analysis has been used to inform cost effectiveness evaluations submitted to national HTA agencies. (5, 6) Given the number of people suffering with cardiovascular disease, the clinical and economic importance of the treatment of hypercholesterolemia and the current uncertainty surrounding the magnitude of clinical benefit, accurate and unbiased data concerning the potential treatment benefit is paramount.

1. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163(1):40-51.
2. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-99.
3. Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015;169(6):906-15 e13.
4. Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes E, et al. Cholesterol Treatment Trialists’(CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-90.
5. National Institute for Health and Care Excellence. Alirocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia (technology appraisal guidance 393). Published June 2016. Accessed at https://www.nice.org.uk/guidance/ta393/resources/alirocumab-for-treating-primary-hypercholesterolaemia-and-mixed-dyslipidaemia-82602908493253 on 3 January 2017.
6. Scottish Medicines Consortium. Alirocumab 75mg and 150mg solution for injection in prefilled pen (Praluent®) SMC No. (1147/16). Published July 2016. Accessed at https://www.scottishmedicines.org.uk/files/advice/alirocumab_Praluent_FINAL_July_2016_Amended_04.08.16_for_website.pdf on 3 January 2017.

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2015 American College of Physicians