Proprotein convertase subtilisin/kexin 9 inhibitors in reducing cardiovascular outcomes: a systematic review and meta-analysis

Du, Hao; Li, Xiaodan; Su, Naichuan; Li, Ling; Hao, Xiaoting; Gao, Haihui; Kwong, Joey S.W.; Vandvik, Per Olav; Yang, Xueli; Németh, Imola; Mordi, Ify; Li, Qianrui; Zhang, Longhao; Li, Rao; Lang, Chim C.; Li, Jianshu; Tian, Haoming; Li, Sheyu

doi:10.1136/heartjnl-2019-314763

Cited by 22 publications

(23 citation statements)

References 68 publications

(82 reference statements)

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“…Despite the effect of PCSK9 inhibitors on LDL-cholesterol, our review found that these drugs did not improve cardiovascular health. In contrast, previous meta-analyses have presented a statistically significantly reduced risk of major adverse cardiovascular events (MACE) [11,12,15,63]. MACE is a heterogeneously defined composite outcome that often includes interventions and may be susceptible to bias [64,65].…”

Section: Cardiovascular Outcomesmentioning

confidence: 97%

“…Second, prior systematic reviews about PCSK9 inhibitors included non-atherosclerotic types of myocardial infarction (MI) [10][11][12]. Besides spontaneous MI, clinical outcome trials have included MI due to supply-demand imbalance, cardiac death suggestive of MI without increased biomarkers, and MI related to revascularisation procedures [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

Bruggen

Nijhuis

Zuidema

et al. 2020

Expert Review of Clinical Pharmacology

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Background: Previous reviews of PCSK9 inhibitor trials are limited by a focus on composite cardiovascular outcomes. ClinicalTrials.gov provides trial results for individual clinical outcomes. Aim of this systematic review was to assess the effect of PCSK9 inhibitors on the risk of myocardial infarction, stroke/TIA, heart failure, diabetes mellitus, neurocognitive events, all-cause serious adverse events (SAE), and all-cause deaths as registered on ClinicalTrials.gov. Methods: PubMed, regulatory reports, ClinicalTrials.gov, and company websites were used to search studies. Randomized trials comparing PCSK9 inhibitor with placebo in participants with hypercholesterolemia were eligible. Study characteristics, risk of bias, and numbers of participants with the outcomes of interest were collected. Results: We identified 33 lipid-lowering and 4 clinical outcomes trials with results on ClinicalTrials.gov (n = 16,958 and n = 73,836, respectively). Risk of bias was generally high. PCSK9 inhibitors did not affect the risk of any of the investigated outcomes in either type of trial. However, in clinical outcomes studies, alirocumab decreased the risk of all-cause SAE (OR 0.92; 95% CI 0.86-0.98), and evolocumab probably increased the risk of mortality (OR 1.12; 95% CI 1.00-1.25). Conclusions: Our meta-analysis of clinical events registered on ClinicalTrials.gov did not show that PCSK9 inhibitors improve cardiovascular health. Evolocumab increased the risk of all-cause mortality.

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Section: Cardiovascular Outcomesmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

Bruggen

Nijhuis

Zuidema

et al. 2020

Expert Review of Clinical Pharmacology

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“…23 Ezetimibe and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors are two new non-statin lipid-lowering drugs, which were suggested to reduce the cardiovascular events. 14,24 Compared to PCSK9 inhibitors, ezetimibe reduced only borderline risk of cardiovascular diseases (hazard ratio of ezetimibe, 0.936; 95% CI, 0.89 to 0.99 according to IMPROVE-IT trial vs relative risk of PCSK9 inhibitors, 0.84; 95% CI, 0.79 to 0.89 according to recent systematic review). 14,24 However, according to recent costeffectiveness analysis, PCSK9 inhibitors are too costly to be reasonably used in the US health system.…”

Section: Discussionmentioning

confidence: 99%

“…14,24 Compared to PCSK9 inhibitors, ezetimibe reduced only borderline risk of cardiovascular diseases (hazard ratio of ezetimibe, 0.936; 95% CI, 0.89 to 0.99 according to IMPROVE-IT trial vs relative risk of PCSK9 inhibitors, 0.84; 95% CI, 0.79 to 0.89 according to recent systematic review). 14,24 However, according to recent costeffectiveness analysis, PCSK9 inhibitors are too costly to be reasonably used in the US health system. 25 Although the prices of the two major PCSK9 inhibitors (alirocumab and evolocumab) were reduced consequently, they are still beyond the threshold of per capita GDP to be costeffective in most countries.…”

Section: Discussionmentioning

confidence: 99%

<p>Cost-Effectiveness Analysis of Ezetimibe as the Add-on Treatment to Moderate-Dose Rosuvastatin versus High-Dose Rosuvastatin in the Secondary Prevention of Cardiovascular Diseases in China: A Markov Model Analysis</p>

Yang

Zhou

et al. 2020

DDDT

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Background: For patients with inadequate control of cholesterol using moderate-dose statins in the secondary prevention of cardiovascular diseases (CVD), either doubling the dose of statins or adding ezetimibe should be considered. The cost-effectiveness of them is unknown in the Chinese context. The aim of this study is to compare the cost and effectiveness of the two regimens, and estimate the incremental cost-effectiveness ratio (ICER).Methods: A Markov model of five health statuses were used to estimate long-term costs and quality-adjusted life-years (QALYs) of the two treatment regimens from the healthcare perspective. The effectiveness data used to calculate the transition probability was based on a previously published randomized trial. The utility data was gathered from literature and the costs were gathered from the electronic medical record system of West China Hospital in Chinese Yuan (CNY) in 2017 price. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted. Results: The ICER for ezetimibe plus moderate-dose rosuvastatin was 47,102.99 CNY per QALY for 20 years simulation, which did not reach the threshold of per capita gross domestic product (GDP) of 59,660 CNY per QALY in 2017 in China. Non-CVD-related mortality and CVD-related mortality contributed most to the ICER. Conclusion: Adding ezetimibe to the moderate-dose statin in secondary prevention for CVD is cost-effective, compared with the high-dose statin in the Chinese context whose lowdensity lipoprotein cholesterol (LDL-c) was not inadequately controlled by moderate-dose statin alone.

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“…No differences between groups (PCSK9 inhibitors versus controls) were found for all-cause mortality, cardiovascular deaths, heart failure or unstable angina. 5 Interestingly, PCSK9 inhibitors and statins show similar effects on cardiovascular risk reduction per mg/dL reduction in LDL-C when the same duration of therapy is considered, that is, À14% (0-1 year of treatment), À17% (1-2 years of treatment) and À20% (2-3 years of treatment). 6…”

Section: Introductionmentioning

confidence: 99%

Recent advances in synthetic pharmacotherapies for dyslipidaemias

Sirtori

Yamashita

Greco

et al. 2019

Eur J Prev Cardiolog

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Despite the demonstrated benefits of statins and injectable biologics, there is a need for new and safe oral agents for addressing classical lipid targets, low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). LDL-C is unquestionably causal in the development of atherogenesis and atherosclerotic cardiovascular disease, but new options are required to address triglyceride-rich lipoproteins and lipoprotein(a). For hypercholesterolaemia, pitavastatin provides a very low dose and potent statin that does not adversely affect glucose metabolism; bempedoic acid acts at a biochemical step preceding hydroxymethylglutaryl-CoA reductase and is not associated with muscular side effects. For hypertriglyceridaemia, pemafibrate displays a unique and selective agonist activity on peroxisomal proliferator activated receptor-α that does not elevate homocysteine or creatinine. Although omega-3 fatty acids supplementation is not effective in secondary prevention, high dose eicosapentaenoic ethyl ester can lead to a remarkable fall in first and recurrent events in high risk patients with hypertriglyceridaemia/low HDL-C. Gemcabene, a dicarboxylic acid regulating apolipoprotein B-100, is effective in reducing both cholesterol and triglycerides. Among cholesteryl ester transfer protein antagonists that elevate HDL-C, only anacetrapib reduces cardiovascular events. Probucol stimulates reverse cholesteryl ester transport, lowers LDL-C stabilizing plaques and may lower incidence of cardiovascular events. These agents, which act through novel mechanisms, afford good and potentially safe treatment choices that may increase adherence and the attainment of therapeutic targets.

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Proprotein convertase subtilisin/kexin 9 inhibitors in reducing cardiovascular outcomes: a systematic review and meta-analysis

Cited by 22 publications

References 68 publications

Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

<p>Cost-Effectiveness Analysis of Ezetimibe as the Add-on Treatment to Moderate-Dose Rosuvastatin versus High-Dose Rosuvastatin in the Secondary Prevention of Cardiovascular Diseases in China: A Markov Model Analysis</p>

Recent advances in synthetic pharmacotherapies for dyslipidaemias

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