scholarly journals Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics

2020 ◽  
Vol 12 (549) ◽  
pp. eaay6570 ◽  
Author(s):  
Jonas Bovijn ◽  
Kristi Krebs ◽  
Chia-Yen Chen ◽  
Ruth Boxall ◽  
Jenny C. Censin ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Genetic Variants ◽  
Cardiovascular Events ◽  
Coronary Revascularization ◽  
Meta Analysis ◽  
Major Adverse Cardiovascular Events ◽  
Cardiovascular Safety ◽  
Mineral Density ◽  
Increased Risk ◽  
Cardiovascular Outcome Trial

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.

Efficacy and safety of aspirin for cardiovascular risk prevention in younger and older age: an updated systematic review and meta-analysis

2021 ◽  
Author(s):  
Dario Calderone ◽  
Antonio Greco ◽  
Salvatore Ingala ◽  
Federica Agnello ◽  
Antonio Gabriele Franchina ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Major Bleeding ◽  
Cardiovascular Events ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Major Adverse Cardiovascular Events ◽  
Older Individuals ◽  
Efficacy And Safety ◽  
Safety Outcome ◽  
Increased Risk

Aims - The efficacy and safety of aspirin for primary cardiovascular disease (CVD) prevention is controversial. The aim of this study was to investigate the merits of aspirin in subjects with no overt CVD, with a focus on age as a treatment modifier. Methods and results - Randomized trials comparing aspirin use versus no aspirin use or placebo were included. The primary efficacy outcome was all-cause death. The primary safety outcome was major bleeding. Subgroups analyses were conducted to investigate the consistency of the effect sizes in studies including younger and older individuals, using a cut-off of 65 years. A total of 21 randomized trials including 173,810 individuals at a mean follow-up of 5.3 years were included. Compared with control, aspirin did not reduce significantly the risk of all-cause death (risk ratio 0.96, 95% CI 0.92-1.00, p=0.057). Major adverse cardiovascular events were significantly reduced by 11%, paralleled by significant reductions in myocardial infarction and transient ischemic attack. Major bleeding, intracranial hemorrhage, and gastrointestinal bleeding were significantly increased by aspirin. There was a significant age interaction for death (p for interaction=0.007), with aspirin showing a statistically significant 7% relative benefit on all-cause death in studies including younger patients. Conclusions - The use of aspirin in subjects with no overt cardiovascular disease was associated with a neutral effect on all-cause death and a modest lower risk of major cardiovascular events at the price of an increased risk in major bleeding. The benefit of aspirin might be more pronounced in younger individuals.

scholarly journals Febuxostat and Cardiovascular Events: A Systematic Review and Meta-Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
John A. Cuenca ◽  
Javier Balda ◽  
Ana Palacio ◽  
Larry Young ◽  
Michael H. Pillinger ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cardiovascular Disease ◽  
Cardiovascular Events ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
The United States ◽  
Major Adverse Cardiovascular Events ◽  
Control Group ◽  
Embase Database ◽  
Cvd Mortality

Background. Febuxostat is approved in the United States for the management of hyperuricemia in patients with gout. In November 2017 the FDA released a warning alert on a possible link between febuxostat and cardiovascular disease (CVD) reported in a single clinical trial. Objective. To conduct a systematic review and meta-analysis and assess the risk of major adverse cardiovascular events (MACE) in patients receiving febuxostat compared to a control group. Methods. We searched the MEDLINE and EMBASE database for studies published up until March 2018. We included randomized clinical trials (RCTs) that compared febuxostat to control groups including placebo and allopurinol. We calculated the pooled relative risk (RR) of MACE and cardiovascular disease (CVD) mortality with the corresponding 95% confidence intervals (CI). Results. Our search yielded 374 potentially relevant studies. Among the 25 RCTs included in the systematic review, 10 qualified for the meta-analysis. Among the 14,402 subjects included, the median age was 54 years (IQR 52-67) and 90% were male (IQR 82-96); 8602 received febuxostat, 5118 allopurinol, and 643 placebo. The pooled RR of MACE for febuxostat was 0.9; 95% CI 0.6-1.5 (p= 0.96) compared to the control. The RR of CV-related death for febuxostat was 1.29; 95% CI 1.01-1.66 (p=0.03). Conclusions. Compared with other SU-lowering treatments, febuxostat does not increase or decrease the risk of cardiovascular disease but may increase the risk of CVD death. More RCTs measuring cardiovascular safety as a primary outcome are needed to adequately evaluate the risk of CVD with febuxostat.

scholarly journals Antidepressant Use and the Risk of Major Adverse Cardiovascular Events in Patients Without Known Cardiovascular Disease: A Retrospective Cohort Study

2020 ◽  
Vol 11 ◽  
Author(s):  
Ha Young Jang ◽  
Jae Hyun Kim ◽  
Yun-Kyoung Song ◽  
Ju-Young Shin ◽  
Hae-Young Lee ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Risk Score ◽  
Cardiovascular Events ◽  
Major Adverse Cardiovascular Events ◽  
Cvd Risk ◽  
Hazard Ratios ◽  
Increased Risk ◽  
History Of ◽  
Antidepressant Use ◽  
Cox Proportional Hazard Regression

Aims: Conflicting data exist on whether an association exists between antidepressants and the risk of major adverse cardiovascular events (MACEs) in patients with depression. This may be due to the use of various study designs and residual or unmeasured confounding. We aimed to assess the association between antidepressant use and the risk of MACEs while considering various covariates, including severity of depression and the cardiovascular disease (CVD) risk score.Methods: Patients newly diagnosed with depression with no history of ischemic heart disease and stroke were followed-up from 2009 to 2015. We conducted Cox proportional hazard regression analysis to estimate hazard ratios (HRs) for each antidepressant for MACE risk.Result: We followed-up (median, 4.4 years) 31,830 matched patients with depression (15,915 antidepressant users and 15,915 non-users). In most patients (98.7%), low-dose tricyclic antidepressants (TCAs) were related with a significantly increased risk of MACEs [adjusted HR = 1.20, 95% confidence interval (CI) = 1.03–1.40]. Duration response relationship showed a gradually increasing HR from 1.15 (95% CI = 0.98–1.33; <30 days of use) to 1.84 (95% CI = 1.35–2.51; ≥365 days of use) (p for trend <0.01). High Korean atherosclerotic CVD risk score (≥7.5%) or unfavorable lifestyle factors (smoking, alcohol intake, and exercise) were significantly associated with MACEs.Conclusion: Even at low doses, TCA use was associated with MACEs during primary prevention. Longer duration of TCA use correlated with higher HR. Careful monitoring is needed with TCA use in patients with no known CVD history.

scholarly journals Relation between Age-Related Macular Degeneration and Cardiovascular Events and Mortality: A Systematic Review and Meta-Analysis

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Jie Wang ◽  
Yangjing Xue ◽  
Saroj Thapa ◽  
Luping Wang ◽  
Jifei Tang ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cardiovascular Disease ◽  
Macular Degeneration ◽  
Cardiovascular Events ◽  
Meta Analysis ◽  
Age Related Macular Degeneration ◽  
Relative Risks ◽  
Age Related ◽  
Increased Risk ◽  
All Cause Mortality

Data on the association between age-related macular degeneration (AMD) and cardiovascular disease and mortality are conflicting. The purpose of this report is to conduct a systematic review to better understand the role of AMD as a risk factor for CVD events and mortality. We searched Medline (Ovid) and Embase (Ovid) for trials published from 1980 to 2015. We included 20 cohort studies that reported relative risks with 95% confidence intervals for the association of AMD and cardiovascular events and mortality, involving 29,964,334 participants. In a random-effects model, the adjusted RR (95% confidence interval [CI]) associated with AMD was 1.08 (1.00–1.117) for all-cause mortality (8 studies) and 1.18 (0.98–1.43) for cardiovascular disease mortality (5 studies). The pooled RR (95% CI) was 1.17 (0.94–1.45) for coronary heart disease (CHD; 3 studies) and 1.13 (0.93–1.36) for stroke (8 studies). Findings from this systematic review support that AMD is associated with increased risk of all-cause mortality. The evidence that AMD predicts incident CVD events or CVD mortality remains inclusive and warrants further study in the future.

scholarly journals Gallstone Disease and the Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Observational Studies

2016 ◽  
Vol 106 (1) ◽  
pp. 21-27 ◽  
Author(s):  
S. Upala ◽  
A. Sanguankeo ◽  
V. Jaruvongvanich
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Cardiovascular Disease ◽  
Confidence Interval ◽  
Cardiovascular Events ◽  
Meta Analysis ◽  
Gallstone Disease ◽  
Hazard Ratio ◽  
Cross Sectional ◽  
Increased Risk

Objectives: Gallstone disease shares certain risk factors with cardiovascular disease, particularly metabolic risk factors. Patients with gallstone disease may be at increased risk of cardiovascular disease. Several recent studies exploring the effect of gallstone disease on cardiovascular disease outcomes demonstrated inconsistent results. Design: We conducted a systematic review and meta-analysis of cohort, case–control, and cross-sectional studies that compared the risk of developing cardiovascular disease events in patients with gallstone disease versus non-gallstone disease controls. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate the pooled hazard ratio, odd ratio, and 95% confidence interval. Results: Data were extracted from six studies involving 176,734 cases and 803,714 controls. The pooled hazard ratio of cardiovascular events in patients with gallstone disease was 1.28 (95% confidence interval: 1.23–1.33, I2 = 42%). The pooled odd ratio of cardiovascular events in patients with gallstone disease was 1.82 (95% confidence interval: 1.47–2.24, I2 = 68%). Conclusions: Our study demonstrated a statistically significant increase in the risk of cardiovascular disease among patients with gallstone disease.

scholarly journals Lipoprotein(a)

2021 ◽  
Author(s):  
Florian Kronenberg
Keyword(s):  
Cardiovascular Disease ◽  
Genetic Variants ◽  
Cardiovascular Events ◽  
Ldl Cholesterol ◽  
Single Gene ◽  
Genetic Regulation ◽  
Plasma Concentrations ◽  
Lipoprotein A ◽  
Increased Risk ◽  
Peripheral Arterial

AbstractLipoprotein(a) [Lp(a)] is an atherogenic lipoprotein with a strong genetic regulation. Up to 90% of the concentrations are explained by a single gene, the LPA gene. The concentrations show a several-hundred-fold interindividual variability ranging from less than 0.1 mg/dL to more than 300 mg/dL. Lp(a) plasma concentrations above 30 mg/dL and even more above 50 mg/dL are associated with an increased risk for cardiovascular disease including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and all-cause mortality. Since concentrations above 50 mg/dL are observed in roughly 20% of the Caucasian population and in an even higher frequency in African-American and Asian-Indian ethnicities, it can be assumed that Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease.Carriers of genetic variants that are associated with high Lp(a) concentrations have a markedly increased risk for cardiovascular events. Studies that used these genetic variants as a genetic instrument to support a causal role for Lp(a) as a cardiovascular risk factor are called Mendelian randomization studies. The principle of this type of studies has been introduced and tested for the first time ever with Lp(a) and its genetic determinants.There are currently no approved pharmacologic therapies that specifically target Lp(a) concentrations. However, some therapies that target primarily LDL cholesterol have also an influence on Lp(a) concentrations. These are mainly PCSK9 inhibitors that lower LDL cholesterol by 60% and Lp(a) by 25–30%. Furthermore, lipoprotein apheresis lowers both, Lp(a) and LDL cholesterol, by about 60–70%. Some sophisticated study designs and statistical analyses provided support that lowering Lp(a) by these therapies also lowers cardiovascular events on top of the effect caused by lowering LDL cholesterol, although this was not the main target of the therapy. Currently, new therapies targeting RNA such as antisense oligonucleotides (ASO) or small interfering RNA (siRNA) against apolipoprotein(a), the main protein of the Lp(a) particle, are under examination and lower Lp(a) concentrations up to 90%. Since these therapies specifically lower Lp(a) concentrations without influencing other lipoproteins, they will serve the last piece of the puzzle whether a decrease of Lp(a) results also in a decrease of cardiovascular events.

scholarly journals Low fasting glucose and future risks of major adverse outcomes in people without baseline diabetes or cardiovascular disease: a systematic review and meta-analysis

BMJ Open ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. e026010 ◽  
Author(s):  
Hung-Wei Liao ◽  
Jeffrey Saver ◽  
Hsin-Chieh Yeh ◽  
Chi-Hsin Sally Chen ◽  
Yi-Ling Wu ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Events ◽  
Fasting Glucose ◽  
Meta Analysis ◽  
Fasting Blood Glucose ◽  
Glucose Levels ◽  
Major Cardiovascular Events ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Normal Fasting Glucose

ObjectiveTo investigate the link between low fasting blood glucose levels and all-cause mortality and cardiovascular outcomes among people without baseline diabetes or cardiovascular disease.DesignSystematic review and meta-analysis.Data sourcesPubMed and Embase (1966–February 2019).Selection criteriaProspective cohort studies were included for meta-analysis if they reported adjusted HRs with 95% CIs for associations between risk of all-cause mortality, stroke, major cardiovascular events, coronary heart disease and low fasting glucose levels (<4.6 mmol/L and/or 4.0 mmol/L, respectively) versus normal fasting glucose levels.Data extraction and statistical analysisTwo independent reviewers extracted data from eligible studies. Heterogeneity was assessed by p value of χ2tests and I2. We assessed four characteristics for each included study based on items developed by the US Preventive Task Force, as well as the modified checklist used in previous studies.ResultsEleven articles (consisting of 129 prospective cohort studies) with 2 674 882 participants without diabetes and cardiovascular disease at baseline were included in this meta-analysis. Pooled results from the random effects model showed increased risks of all-cause mortality (HR: 1.56; 95% CI 1.09 to 2.23), total stroke (HR: 1.08, 95% CI 1.03 to 1.13) and ischaemic stroke (HR: 1.06, 95% CI 1.01 to 1.10), and major cardiovascular events (HR: 1.05, 95% CI 1.03 to 1.07) among people with a fasting glucose <4.0 mmol/L, as compared with people with normal fasting glucose. The less stringent low fasting glucose level, <4.6 mmol/L, was not associated with increased risk of any endpoints.Discussion and conclusionsAmong people without baseline diabetes or cardiovascular disease, a fasting blood glucose level of <4.0 mmol/L is associated with increased risk of all-cause mortality, major cardiovascular events and stroke.

scholarly journals The Cardiovascular Risks of Fostamatinib in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuehong Chen ◽  
Huan Liu ◽  
Yupeng Huang ◽  
Sang Lin ◽  
Geng Yin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systematic Review ◽  
Sensitivity Analysis ◽  
Heart Disease ◽  
Publication Bias ◽  
Cardiovascular Events ◽  
Meta Analysis ◽  
Major Adverse Cardiovascular Events ◽  
Cochrane Central Register ◽  
Increased Risk

Objective: This systematic review and meta-analysis is aimed at assessing the risks of cardiovascular adverse events in patients with rheumatoid arthritis (RA) who have been treated with fostamatinib.Methods: The electronic databases of OVID Medline, OVID EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science were searched to identify studies that reported cardiovascular events or hypertension in RA patients treated with fostamatinib. Two reviewers separately and simultaneously screened the retrieved studies based on study selection criteria, collected data and performed methodological quality assessments. The effect size of meta-analysis was estimated by the Peto odds ratio (OR) or relative risk (RR) with 95% confidence intervals (95%CI). Funnel plot was used to estimate publication bias and sensitivity analysis was performed to test the robustness of the results.Results: A total of 12 trials composed of 5,618 participants with low to moderate risk of bias were included. In comparison to the placebo, the use of fostamatinib was found to elevate the risk of hypertension (RR=3.82, 95%CI 2.88–5.05) but was not associated with the risks of all-cause death (Peto OR=0.16, 95%CI 0.02–1.24), major adverse cardiovascular events (Peto OR=1.24, 95%CI 0.26–5.97), pulmonary heart disease and disease of pulmonary circulation (Peto OR=1.23, 95%CI 0.13–11.87), in addition to other forms of heart disease (Peto OR=1.96, 95%CI 0.72–5.38). Furthermore, sensitivity analysis showed no significant change in effective trends and no publication bias was found.Conclusion: Fostamatinib is associated with increased risk of hypertension; however, no increased risks of cardiovascular events were observed. Further well-planned cohort studies with large study populations and longer follow-up times are needed to elucidate the outcomes.Systematic Review Registration: [PROSPERO], identifier [CRD42020198217].

scholarly journals Urate, blood pressure and cardiovascular disease: updated evidence from Mendelian randomization and meta-analysis of clinical trials

2019 ◽  
Author(s):  
Dipender Gill ◽  
Alan C. Cameron ◽  
Stephen Burgess ◽  
Xue Li ◽  
Daniel J. Doherty ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Serum Urate ◽  
Favorable Effect ◽  
Major Adverse Cardiovascular Events ◽  
Cvd Risk ◽  
Standard Deviation Increase ◽  
Increased Risk

AbstractAimsTo investigate the effect of serum urate on blood pressure and cardiovascular disease (CVD) risk by updating evidence from Mendelian randomization (MR) analysis and meta-analysis of randomized controlled trials (RCTs).Methods and ResultsUsing recently available data from the Million Veterans Program and UK Biobank, the main MR analyses showed that every 1-standard deviation increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio 1.19, 95% confidence interval 1.10-1.30, P=4×10−5), peripheral artery disease (1.12, 95%CI 1.03 to 1.21, P=9×10−3), and stroke (1.11, 95%CI 1.05 to 1.18, P=2×10−4). In MR mediation analyses, SBP was estimated to mediate approximately one third the effect of urate on CVD risk. Systematic review and meta-analysis of RCTs showed a favorable effect of urate-lowering treatment on SBP (mean difference -2.55mmHg, 95%CI -4.06 to -1.05, P=1×10−3) and major adverse cardiovascular events (MACE) in those with previous CVD (OR 0.40, 95%CI 0.22 to 0.73, P=3×10−3), but no significant effect on MACE in all individuals (OR 0.73, 95%CI 0.48 to 1.09, P=0.12).ConclusionMR and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on CVD risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate-lowering may be of cardiovascular benefit.

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