scholarly journals Cardiovascular and safety events of PCSK9 inhibitors in statin-treated patients with cardiovascular risk: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 23 ◽  
pp. 422-436
Author(s):  
Zinan ZHAO ◽  
Xin HU ◽  
Yatong ZHANG ◽  
Deping LIU
Keyword(s):  
Myocardial Infarction ◽  
Ischemic Stroke ◽  
Cardiovascular Risk ◽  
Injection Site ◽  
Randomized Clinical Trials ◽  
Adverse Drug Events ◽  
Meta Analysis ◽  
Injection Site Reaction ◽  
Nonfatal Myocardial Infarction ◽  
Site Reaction

Objectives: To evaluate whether proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is associated with cardiovascular and safety events in statin-treated patients with cardiovascular risk. Methods: Electronic databases (Pubmed, Cochrane, MEDLINE, EMBASE, ClinicalTrials.gov) were searched through March 31, 2020. Included randomized clinical trials (RCTs) compared PCSK9i use with no PCSK9i in statin treated patients. Two investigators abstracted data and appraised risks of bias. A meta-analysis was performed to calculate risk ratios (RRs) and 95% CIs using fix-effects models. Adjudicated cardiovascular events (CVE) and adverse drug events (ADE) were defined as the primary outcome. Secondary outcomes were cardiovascular (CV) death, all-cause death, nonfatal myocardial infarction, ischemic stroke, serious ADE and injection-site reaction. Results: A total of 10 RCTs 50 053 participants were included. PCSK9i use was associated with signigicant reductions in the CVE (RR, 0.87 [95%CI, 0.83-0.91]; NNT, 54; P<0.00001; I2=0%, heterogeneity P=0.86), nonfatal myocardial infarction (RR, 0.86 [95% CI, 0.78-0.96]; NNT, 95; P=0.005; I2=0%, heterogeneity P=0.88), and ischemic stroke (RR, 0.75 [95%CI 0.64-0.87]; NNT, 244; P=0.00; I2=0%, heterogeneity P=0.82) compared with no PCSK9i in statin-treated patients with CV risk. No significant associations were found between PCSK9i use and no PCSK9i in ADE and serious ADE. PCSK9i use was associated with signigicant increasing in injection-site reaction (RR, 1.55 [95%CI 1.38-1.75]; NNT, 101; P<0.00001; I2=0%, heterogeneity P=0.44). Conclusions: Among statin-treated patients with CV risk, the use of PCSK9i was associated with improving CV outcomes. The use of PCSK9i was well tolerated, but had significantly injection-site reactions.

Indirect comparison of the efficacy and safety of alirocumab and evolocumab: a systematic review and network meta-analysis

2020 ◽  
Author(s):  
Paul Guedeney ◽  
Sabato Sorrentino ◽  
Gennaro Giustino ◽  
Celine Chapelle ◽  
Silvy Laporte ◽  
...  
Keyword(s):  
Systematic Review ◽  
Injection Site ◽  
Meta Analysis ◽  
Injection Site Reaction ◽  
Indirect Comparison ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Efficacy And Safety ◽  
Site Reaction ◽  
Increased Risk

Abstract Aims Although alirocumab and evolocumab have both been associated with improved outcomes in patients with dyslipidaemia or established atherosclerotic cardiovascular disease, data on their respective performances are scarce. This study aimed at providing an indirect comparison of the efficacy and safety of alirocumab vs. evolocumab. Methods and results We conducted a systematic review and network meta-analysis of randomized trials comparing alirocumab or evolocumab to placebo with consistent background lipid-lowering therapy up to November 2018. We estimated the relative risk (RR) and the 95% confidence intervals (CIs) using fixed-effect model in a frequentist pairwise and network meta-analytic approach. A total of 30 trials, enrolling 59 026 patients were included. Eligibility criteria varied significantly across trials evaluating alirocumab and evolocumab. Compared with evolocumab, alirocumab was associated with a significant reduction in all-cause death (RR 0.80, 95% CI 0.66–0.97) but not in cardiovascular death (RR 0.83, 95% CI 0.65–1.05). This study did not find any significant differences in myocardial infarction (RR 1.15, 95% CI 0.99–1.34), stroke (RR 0.96, 95% CI 0.71–1.28), or coronary revascularization (RR 1.13, 95% CI 0.99–1.29) between the two agents. Alirocumab was associated with a 27% increased risk of injection site reaction compared to evolocumab; however, no significant differences were found in terms of treatment discontinuations, systemic allergic reaction, neurocognitive events, ophthalmologic events, or new-onset of or worsening of pre-existing diabetes. Conclusion Alirocumab and evolocumab share a similar safety profile except for injection site reaction. No significant differences were observed across the efficacy endpoints, except for all-cause death, which may be related to the heterogeneity of the studied populations treated with the two drugs.

P5367Indirect comparison of the safety and efficacy of alirocumab and evolocumab: from a comprehensive meta-analysis of 30 randomized controlled trials

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Guedeney ◽  
S Sorrentino ◽  
G Giustino ◽  
C Chapelle ◽  
B Claessen ◽  
...  
Keyword(s):  
Injection Site ◽  
Meta Analysis ◽  
Injection Site Reaction ◽  
Fixed Effect Model ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Site Reaction ◽  
Eligibility Criteria ◽  
Safety And Efficacy ◽  
Increased Risk

Abstract Background Alirocumab and evolocumab, two proprotein convertase subtilisin–kexin type 9 inhibitors, have both been associated with improved outcomes in patients with atherosclerotic cardiovascular disease in addition to standard lipid-lowering therapies. However, their comparative safety and efficacy profiles are unknown. Purpose To compare the safety and efficacy of alirocumab versus evolocumab. Methods We conducted a systematic review and network meta-analysis of placebo-controlled randomized trials available up to November 2018 evaluating the safety and efficacy of alirocumab and evolocumab. We estimated risk ratio and 95% confidence intervals using fixed effect model in a frequentist pairwise and network metanalytic approach. The primary safety endpoints were any adverse events leading to treatment-discontinuation, injection site reaction, systemic allergic reaction, neurocognitive events, ophthalmologic events and new-onset of diabetes mellitus (DM) or worsening of pre-existing DM. The primary efficacy endpoints were all-cause and cardiovascular (CV) death, myocardial infarction (MI) and stroke. This study was registered in PROSPERO (CRD42018090768). Results A total of 30 trials, enrolling 59,026 patients were included in this analysis, of whom 13,607 received alirocumab and 17,931 received evolocumab. Mean weighted follow-up time was 2.5 years, with an exposure time of 144,907 patients-years. Eligibility criteria varied significantly across trials evaluating alirocumab and evolocumab. There were no significant differences between alirocumab and evolocumab in terms of safety endpoints, except for injection site reaction with a 27% increased risk of injection site reaction with alirocumab compared to evolocumab (Figure). Compared with evolocumab, alirocumab was associated with a reduction of all-cause death but not CV death. There were no significant differences in MI or stroke between alirocumab and evolocumab. Conclusion Alirocumab and evolocumab share a similar safety profile. No significant differences were observed across the efficacy endpoints, except for all-cause death, which may be related to heterogeneity of the studied populations between the two drugs.

Primary Prevention of Cardiovascular Events with Aspirin: Toward More Harm than Benefit—A Systematic Review and Meta-Analysis

2019 ◽  
Vol 45 (05) ◽  
pp. 478-489 ◽  
Author(s):  
Mikael Christiansen ◽  
Erik Lerkevang Grove ◽  
Anne-Mette Hvas
Keyword(s):  
Risk Factors ◽  
Myocardial Infarction ◽  
Cardiovascular Risk ◽  
Primary Prevention ◽  
Cardiovascular Risk Factors ◽  
Cardiovascular Events ◽  
Meta Analysis ◽  
Cardiovascular Death ◽  
Nonfatal Myocardial Infarction ◽  
Healthy Individuals

AbstractPrimary prevention of cardiovascular events with aspirin remains controversial, as the risk of bleeding might outweigh the benefits. Recently, new evidence has emerged from the ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events), ASCEND (A Study of Cardiovascular Events in Diabetes), and ASPREE (Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly) trials. The aim of this study was to perform a systematic review and meta-analysis of aspirin's efficacy and safety in the primary prevention of cardiovascular events in healthy individuals and in individuals with cardiovascular risk factors, and separately in those with diabetes. The Medline database was searched, without time restrictions, for relevant human trials published in English up to December 10, 2018, and additional trials were identified from reference lists. Data on efficacy (cardiovascular death and nonfatal myocardial infarction) and safety (major bleeding) were extracted for analysis. In total, 20 randomized trials were identified. Separate meta-analyses were performed on 10 trials including 144,930 individuals, who were healthy or had cardiovascular risk factors, and on 4 trials including 20,326 individuals with diabetes. In healthy individuals and individuals with cardiovascular risk factors, aspirin reduced the risk of nonfatal myocardial infarction by 21% (p < 0.001), but had no effect on cardiovascular death (p = 0.52), and increased the risk of major bleeding by 48% (p < 0.001). In individuals with diabetes, aspirin had no effect on nonfatal myocardial infarction (p = 0.93) or cardiovascular death (p = 0.92) and increased the risk of bleeding by 49% (p = 0.13). This meta-analysis suggests that aspirin should not be used on a routine basis in the primary prevention of cardiovascular events, especially in individuals with diabetes.

scholarly journals Complete revascularization reduces cardiovascular death in patients with ST-segment elevation myocardial infarction and multivessel disease: systematic review and meta-analysis of randomized clinical trials

2019 ◽  
Vol 41 (42) ◽  
pp. 4103-4110 ◽  
Author(s):  
Rita Pavasini ◽  
Simone Biscaglia ◽  
Emanuele Barbato ◽  
Matteo Tebaldi ◽  
Dariusz Dudek ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Cardiovascular Death ◽  
Multivessel Disease ◽  
Complete Revascularization ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
St Segment

Abstract Aims The aim of this work was to investigate the prognostic impact of revascularization of non-culprit lesions in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease by performing a meta-analysis of available randomized clinical trials (RCTs). Methods and results Data from six RCTs comparing complete vs. culprit-only revascularization in STEMI patients with multivessel disease were analysed with random effect generic inverse variance method meta-analysis. The endpoints were expressed as hazard ratio (HR) with 95% confidence interval (CI). The primary outcome was cardiovascular death. Main secondary outcomes of interest were all-cause death, myocardial infarction (MI), and repeated coronary revascularization. Overall, 6528 patients were included (3139 complete group, 3389 culprit-only group). After a follow-up ranging between 1 and 3 years (median 2 years), cardiovascular death was significantly reduced in the group receiving complete revascularization (HR 0.62, 95% CI 0.39–0.97, I2 = 29%). The number needed to treat to prevent one cardiovascular death was 70 (95% CI 36–150). The secondary endpoints MI and revascularization were also significantly reduced (HR 0.68, 95% CI 0.55–0.84, I2 = 0% and HR 0.29, 95% CI 0.22–0.38, I2 = 36%, respectively). Needed to treats were 45 (95% CI 37–55) for MI and 8 (95% CI 5–13) for revascularization. All-cause death (HR 0.81, 95% CI 0.56–1.16, I2 = 27%) was not affected by the revascularization strategy. Conclusion In a selected study population of STEMI patients with multivessel disease, a complete revascularization strategy is associated with a reduction in cardiovascular death. This reduction is concomitant with that of MI and the need of repeated revascularization.

scholarly journals Ten-year cardiovascular risk in diabetes patients without of coronary artery disease – a Danish cohort study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.K.W Olesen ◽  
M Madsen ◽  
C Gyldenkerne ◽  
P.G Thrane ◽  
T Thim ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery Disease ◽  
Ischemic Stroke ◽  
Cardiovascular Risk ◽  
General Population ◽  
Funding Source ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Artery Disease ◽  
Diabetes Patients

Abstract Background Patients with diabetes without obstructive coronary artery disease (CAD) by coronary angiography (CAG) have a risk of myocardial infarction (MI) similar to that of non-diabetes patients without CAD. Their cardiovascular risk compared to the general population is unknown. Purpose We examined the 10-year risks of myocardial infarction (MI), ischemic stroke, and death in diabetes patients without CAD after CAG compared to the general population. Methods We included all diabetes patients without obstructive CAD examined by CAG from 2003–2016 in Western Denmark and an age and sex matched comparison group, sampled from the general population in Western Denmark without previous history of coronary heart disease. Outcomes were MI, ischemic stroke, and death. The 10-year cumulative incidences were estimated. Adjusted hazard ratios (HRs) were estimated by stratified Cox regression using the general population as the reference group. Results We identified 5,760 diabetes patients without obstructive CAD and 29,139 individuals from the general population. Median follow-up was 7 years with 25% of participants followed for up to 10 years. Diabetes patients without obstructive CAD had an almost similar 10-year risk of MI (3.2% vs 2.9%, adjusted HR 0.91, 95% CI 0.70–1.17, Figure) compared to the general population cohort. Diabetes patients had an increased risk of ischemic stroke (5.2% vs 2.2%, adjusted HR 1.88, 95% CI 1.48–2.39), and death (29.7% vs 17.9%, adjusted HR 1.41, 95% CI 1.29–1.54). The duration of diabetes was associated with increased cardiovascular risk. Conclusions Absence of obstructive CAD by CAG in patients with diabetes ensures a low MI risk similar to the general population, but diabetes patients still have an increased risk of ischemic stroke and all-cause death despite absence of CAD. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Department of Cardiology, Aarhus University Hospital

A phase 1b study of personalized neoantigen vaccine plus pembrolizumab in adults with advanced cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2615-2615
Author(s):  
Aaron Miller ◽  
Zeynep Kosaloglu-Yalcin ◽  
Luise Westernberg ◽  
Leslie Montero ◽  
Milad Bahmanof ◽  
...  
Keyword(s):  
T Cell ◽  
Injection Site ◽  
Cell Function ◽  
Injection Site Reaction ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Patient Specific ◽  
Clinical Activity ◽  
Site Reaction ◽  
Cell Responses

2615 Background: Neoantigens (NeoAg) are key targets for personalized immunotherapy but efficient methods for their systematic identification and therapeutic targeting remain elusive. We developed a methodology to reliably identify and verify somatic alteration-derived neoantigens based on natural T cell responses against them which formed the basis of an individualized therapeutic vaccine strategy. Methods: This is a phase Ib study to assess the immunogenicity, safety and early clinical activity of personalized synthetic long peptides (PSLP) cancer vaccines in combination with pembrolizumab for patients with treatment refractory metastatic solid tumors or PSLP vaccine alone as an adjuvant treatment with patients with no evidence of disease (NED) that incorporates patient-specific NeoAg identified by an HLA-agnostic, functional T-cell assay (see table). Results: At the time of data cutoff, a total of 5 patients had been treated on ARM-A, 5 patients on ARM-C and 2 patients on ARM-D. AES possibly attributed to personalized vaccine (PSLP), or pembrolizumab, or both include: Grade 1: Arthralgia (1); Diarrhea (1); Fever (4); Fatigue (7); Generalized muscle weakness (1); Headache (2); Nausea (1); Confusion (1); Injection site reaction (5); Rash maculo-papular (3); Flu like symptoms (5); Myalgia (1); and Grade 2: Diarrhea (1); Fatigue (1); Hyperhidrosis (1); Hypothyroidism (1); Injection site reaction (1); Proteinuria (1); Renal and Urinary – other (1); and Grade 3: Colitis (1). For the 9 patients with at least 1 radiographic assessment at the time of analysis 6 had a best response of stable disease (SD) and 3 had progressive disease (PD). Immune monitoring of peripheral blood specimens consistently demonstrated that NeoAg-specific T cell responses were enhanced following administration of PSLP vaccine. On-treatment biopsies demonstrated immune-editing with the variant allele frequency of targeted mutations decreasing following administration of the PSLP vaccine. Conclusions: Taken together, these data meet the trial primary endpoint by demonstrating PSLP vaccines targeting NeoAg identified using the HLA-agnostic pipeline augment effector T cell function against these targets. Clinical trial information: NCT02287428. [Table: see text]

scholarly journals Cilostazol Mono and Combination Treatments in Ischemic Stroke

Stroke ◽  
2019 ◽  
Vol 50 (12) ◽  
pp. 3503-3511 ◽  
Author(s):  
Seung Min Kim ◽  
Jin-Man Jung ◽  
Bum Joon Kim ◽  
Ji-Sung Lee ◽  
Sun U. Kwon
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Ischemic Stroke ◽  
Hemorrhagic Stroke ◽  
Recurrent Stroke ◽  
Meta Analysis ◽  
Significant Heterogeneity ◽  
Randomized Controlled ◽  
Combination Treatments ◽  
Composite Outcomes

Background and Purpose— We performed a systematic review and meta-analysis to explore the efficacy and safety of cilostazol as a mono or combination (plus aspirin or clopidogrel) treatments compared to conventional single antiplatelet therapy (SAPT, mainly aspirin) for secondary stroke prevention. Methods— Randomized controlled trial studies were searched across multiple comprehensive databases (MEDLINE, EMBASE, and Cochrane) for review. The primary outcome was recurrent stroke comprising ischemic and hemorrhagic stroke. Secondary outcomes included ischemic stroke, hemorrhagic stroke, myocardial infarction, and composite outcomes. We performed an updated systematic review and meta-analysis of the identified reports, including 2 recently published randomized controlled trials. In addition, network meta-analysis was performed to compare the relative effects of mono versus combination cilostazol treatments. Results— Ten studies were included in this review, 5 of which were assigned to the cilostazol mono group (n=5429) and the other 5 to the combination group (n=2456). The relative risks of recurrent stroke, ischemic stroke, and composite outcomes with cilostazol mono as well as combination treatments were significantly lower than with SAPT without any significant heterogeneity. An indirect comparison of these 3 outcomes revealed the cilostazol combination approach to be superior. The cilostazol mono treatment diminished hemorrhagic stroke more significantly than SAPT and the cilostazol combination did not increase hemorrhagic stroke compared to SAPT. The outcomes from the 2 cilostazol regimens were comparable to SAPT in the case of myocardial infarction. Conclusions— Cilostazol is a more effective and safer treatment option than SAPT approaches using mainly aspirin. Cilostazol regimens can also be modified to clinical situations as this drug reduces recurrent and ischemic stroke more efficiently as a combination therapy but is more beneficial for hemorrhagic stroke as a monotherapy.

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