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
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, firstname.lastname@example.org.
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.
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;163:40-51. doi: 10.7326/M14-2957
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Published: Ann Intern Med. 2015;163(1):40-51.
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.
To assess the efficacy and safety of PCSK9 antibodies in adults with hypercholesterolemia.
MEDLINE, PubMed Central, and Google Scholar; conference proceedings; and the ClinicalTrials.gov registry through 4 April 2015.
Phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia.
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.
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.
Results were derived from study-level data rather than patient-level data, and clinical outcome data are rare.
PCSK9 antibodies seem to be safe and effective for adults with dyslipidemia.
CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG.
Summary of evidence search and selection.
RCT = randomized, controlled trial.
Appendix Table 1. Study Characteristics
Appendix Table 2. Patient Characteristics
Appendix Table 3. Risk of Bias of Individual Randomized, Controlled Trials
Funnel plot for all-cause mortality.
Funnel plot for cardiovascular mortality.
Funnel plot for increase in creatine kinase.
Funnel plot for serious adverse events.
Funnel plot for low-density lipoprotein cholesterol percentage of change from baseline.
Funnel plot for high-density lipoprotein cholesterol percentage of change from baseline.
Funnel plot for total cholesterol percentage of change from baseline.
Funnel plot for lipoprotein(a) percentage of change from baseline.
Appendix Table 4. Egger Bias Analysis
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.
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
Analysis of cardiovascular mortality, adjusted for follow-up.
* Inverse variance, fixed-effects model.
Myocardial infarction (top) and unstable angina (bottom).
Analysis of myocardial infarction, adjusted for follow-up.
Analysis of unstable angina, adjusted for follow-up.
Increase in creatine kinase level.
Analysis of increase in creatine kinase level, adjusted for follow-up.
Serious adverse events.
Appendix Table 6. LDL Cholesterol Values and Discontinuation Rates
Analysis of serious adverse events, adjusted for follow-up.
Low-density lipoprotein cholesterol percentage of change from baseline.
Appendix Table 7. Sensitivity Analyses for Efficacy
High-density lipoprotein cholesterol percentage of change from baseline.
Total cholesterol percentage of change from baseline.
Lipoprotein(a) percentage of change from baseline.
Appendix Table 8. Randomized, Controlled Trials Comparing Treatment With PCSK9 Antibodies With No Anti-PCSK9 Treatment
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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.
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.
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
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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