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Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.

ABSTRACT: Signals of an increased risk of myocardial infarction (MI) have been identified with dabigatran etexilate in randomized controlled trials (RCTs).We conducted searches of the published literature and a clinical trials registry maintained by the drug manufacturer. Criteria for inclusion in our meta-analysis included all RCTs and the availability of outcome data for MI, other cardiovascular events, major bleeding, and all-cause mortality. Among the 501 unique references identified, 14 RCTs fulfilled the inclusion criteria. Stratification analyses by comparators and doses of dabigatran etexilate were conducted. Peto odds ratio (ORPETO) values using the fixed-effect model (FEM) for MI, other cardiovascular events, major bleeding, and all-cause mortality were 1.34 (95% CI 1.08 to 1.65, P=0.007), 0.93 (95%CI 0.83 to 1.06, P=0.270), 0.88 (95% CI 0.79 to 0.99, P=0.029), and 0.89 (95% CI 0.80 to 1.00, P=0.041). When compared with warfarin, ORPETO values using FEM were 1.41 (95% CI 1.11 to 1.80, P=0.005), 0.94 (95%CI 0.83 to 1.06, P=0.293), 0.85 (95% CI 0.76 to 0.96, P=0.007), and 0.90 (95% CI 0.81 to 1.01, P=0.061), respectively. In RCTs using the 150-mg BID dosage, the ORPETO values using FEM were 1.45 (95% CI 1.11 to 1.91, P=0.007), 0.95 (95% CI 0.82 to 1.09, P=0.423), 0.92 (95% CI 0.81 to 1.05, P=0.228), and 0.88 (95% CI 0.78 to 1.00, P=0.045), respectively. The results of the 110-mg BID dosage were mainly driven by the RE-LY trial.This meta-analysis provides evidence that dabigatran etexilate is associated with a significantly increased risk of MI. This increased risk should be considered taking into account the overall benefit in terms of major bleeding and all-cause mortality.

SUBMITTER: Douxfils J

PROVIDER: S-EPMC4309041 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.

Douxfils Jonathan J Buckinx Fanny F Mullier François F Minet Valentine V Rabenda Véronique V Reginster Jean-Yves JY Hainaut Philippe P Bruyère Olivier O Dogné Jean-Michel JM

Journal of the American Heart Association 20140606 3

<h4>Background</h4>Signals of an increased risk of myocardial infarction (MI) have been identified with dabigatran etexilate in randomized controlled trials (RCTs).<h4>Methods and resules</h4>We conducted searches of the published literature and a clinical trials registry maintained by the drug manufacturer. Criteria for inclusion in our meta-analysis included all RCTs and the availability of outcome data for MI, other cardiovascular events, major bleeding, and all-cause mortality. Among the 501 ...[more]

PMID: 24906369

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Project description:ImportancePatients who survive acute myocardial infarction (AMI) have a high risk of subsequent major cardiovascular events. Efforts to identify risk factors for recurrence have primarily focused on the period immediately following AMI admission.ObjectivesTo identify risk factors and develop and evaluate a risk model that predicts 1-year cardiovascular events after AMI.Design, setting, and participantsProspective cohort study. Patients with AMI (n?=?4227), aged 18 years or older, discharged alive from 53 acute-care hospitals across China from January 1, 2013, to July 17, 2014. Patients were randomly divided into samples: training (50% [2113 patients]), test (25% [1057 patients]), and validation (25% [1057 patients]). Risk factors were identified by a Cox model with Markov chain Monte Carlo simulation and further evaluated by latent class analysis. Analyses were conducted from May 1, 2017, to January 21, 2018.Main outcomes and measuresMajor cardiovascular events, including recurrent AMI, stroke, heart failure, and death, within 1 year after discharge for the index AMI hospitalization.ResultsThe mean (SD) age of the cohort was 60.8 (11.8) years and 994 of 4227 patients (23.5%) were female. Common comorbidities included hypertension (2358 patients [55.8%]), coronary heart disease (1798 patients [42.5%]), and dyslipidemia (1290 patients [30.5%]). One-year event rates were 8.1% (95% CI, 6.91%-9.24%), 9.0% (95% CI, 7.22%-10.70%), and 6.4% (95% CI, 4.89%-7.85%) for the training, test, and validation samples, respectively. Nineteen risk factors comprising 15 unique variables (age, education, prior AMI, prior ventricular tachycardia or fibrillation, hypertension, angina, prearrival medical assistance, >4 hours from onset of symptoms to admission, ejection fraction, renal dysfunction, heart rate, systolic blood pressure, white blood cell count, blood glucose, and in-hospital complications) were identified. In the training, test, and validation samples, respectively, the risk model had C statistics of 0.79 (95% CI, 0.75-0.83), 0.73 (95% CI, 0.68-0.78), and 0.77 (95% CI, 0.70-0.83) and a predictive range of 1.2% to 33.9%, 1.2% to 37.9%, and 1.3% to 34.3%. The C statistic was 0.69 (95% CI, 0.65-0.74) for the latent class model in the training data. The risk model stratified 11.3%, 81.0%, and 7.7% of patients to high-, average-, and low-risk groups, with respective probabilities of 0.32, 0.06, and 0.01 for 1-year events.Conclusions and relevanceNineteen risk factors were identified, and a model was developed and evaluated to predict risk of 1-year cardiovascular events after AMI. This may aid clinicians in identifying high-risk patients who would benefit most from intensive follow-up and aggressive risk factor reduction.

Project description:Background The net clinical benefit of dual antiplatelet therapy (DAPT) reflects the paradoxical effects of an increased risk of bleeding and a reduced risk of major adverse cardiovascular events. A time-constrained approach to DAPT has been recently investigated in 5 multicenter trials including GLOBAL LEADERS, STOPDAPT2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2), SMART-CHOICE, TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention), and TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome). Methods and Results We undertook a pooled analysis of these trials to assess the overall associations between time-constrained P2Y12 inhibitor monotherapy (aspirin-free regimen) for bleeding events, major adverse cardiovascular events, and all-cause mortality as compared to standard care with DAPT for at least 12 months post-percutaneous coronary intervention. We implemented a DerSimonian and Laird random effects meta-analysis using the metafor package in R. 32 361 randomized trial participants, including 16 898 (52.2%) who had a history of acute coronary syndrome, underwent percutaneous coronary intervention, and had outcome data available. P2Y12 inhibitor monotherapy from 1 to 3 months was associated with a reduced risk for bleeding (hazard ratio [HR] 0.60; 95% CI, 0.45-0.81), including in the acute coronary syndrome group in which the magnitude of risk reduction was greatest (HR 0.50; 95% CI, 0.41-0.61). The estimates of the effect of P2Y12 inhibitor monotherapy on the HR were also favorable for major adverse cardiovascular events (0.88; 95% CI, 0.77-1.02) and all-cause mortality (0.85; 95% CI, 0.71-1.03). Conclusions Compared with DAPT for 12 months post-percutaneous coronary intervention, P2Y12 inhibitor monotherapy from 1 to 3 months substantially reduces the risk of major and fatal bleeding and, in addition, confers potentially protective effects, for major adverse cardiovascular events and all-cause mortality. Considering patient safety, the results support a strategy of DAPT for 1 to 3 months followed by aspirin-free P2Y12 inhibitor monotherapy.

Project description:Background:Risk stratification models with incorporation of biochemical markers have received attention recently. In acute myocardial infarction (AMI) one such marker is lipoprotein(a) (Lp(a)). Lp(a) has prothrombotic and proinflammatory properties. High levels of Lp(a) probably contribute to the additional adverse effects in AMI, as it enhances the damaging effect of acute thrombosis. This study aimed to evaluate serum Lp(a) as a predictor of major adverse cardiovascular events (MACE) in hospitalized-acute myocardial infarction patients. Methods:A prospective cohort study was conducted at Sanglah Hospital, Denpasar, during June-August 2018, among 66 people by consecutive sampling. Samples that met the inclusion and exclusion criteria were examined for serum Lp(a) at the time of admission and the occurrence of MACE during hospitalization was observed. Data regarding serum Lp(a), demography, smoking history, dyslipidemia, hypertension, diabetes mellitus, and MACE were collected. Log rank test and Cox proportional hazards regression were conducted with SPSS version 20 for Windows. Results:During observation, MACE occurred in 25 (38%) patients, including cardiogenic shock in 7 (10.6%) patients, heart failure in 20 (30.3%) patients, cardiovascular death in 5 (7, 6%) patients, malignant arrhythmias in 5 (7.6%) patients, and postinfarction angina in 5 (7.6%) patients. After the Log rank test, a significant difference in survival was observed (p = 0.001) between groups of high Lp(a) (survival rate of 60.6 hours; 95% CI 43.3-77.9) and low Lp(a) (average survival of 104.3 hours, 95% CI 91.4-117.2). The hazard ratio of high Lp(a) against MACE was 4.63 (p=0.002), and it increased to 4.69 in multivariate analysis with Cox proportional hazards regression test (p=0.003). Conclusion:The high level of Lp(a) in AMI patients was a risk factor for the occurrence of MACE during hospitalization. Patients with high Lp(a) also had worse survival compared to patients with low Lp(a).

Project description:Importance:Pragmatic clinical trial designs have proposed the use of medical claims data to ascertain clinical events; however, the accuracy of billed diagnoses in identifying potential events is unclear. Objectives:To compare the 1-year cumulative incidences of events when events were identified by medical claims vs by physician adjudication and to assess the accuracy of bill-identified events using physician adjudication as the criterion standard. Design, Setting, and Participants:This post hoc analysis of a clinical trial assessed the medical claims forms and records for all rehospitalizations at 233 US hospitals within 1 year of the index acute myocardial infarction (MI) of 12 365 patients enrolled in the Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study between April 1, 2010, and October 31, 2012. Fourteen patients (0.1%) died during the index hospitalization and were excluded from analysis. Recurrent MI, stroke, and bleeding events were identified per the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and procedural codes in medical bills. These events were independently adjudicated by study physicians through medical record reviews using the prespecified criteria of recurrent MI and stroke and the bleeding definition by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scale. Medical claims were reported on a Uniform Bill-04 claims form; claims were collected from all hospitals visited by patients enrolled in TRANSLATE-ACS. Agreement between medical claims-identified events and physician-adjudicated events over the 12 months after discharge was assessed with the κ statistic. Data were analyzed from January 30, 2015, to March 2, 2017. Main Outcomes and Measures:Event rates within 1 year after MI. Results:Among 12 365 patients with acute MI, 8890 (71.9%) were men and mean (SD) age was 60 (11.6) years. The cumulative 1-year incidence of events identified by medical claims was 4.3% for MI, 0.9% for stroke, and 5.0% for bleeding. Incidence rates based on physician adjudication were 4.7% for MI, 0.9% for stroke, and 5.4% for bleeding. Agreement between medical claims-identified and physician-adjudicated events was modest, with a κ of 0.76 (95% CI, 0.73 to 0.79) for MI and 0.55 (95% CI, 0.41 to 0.68) for stroke events. In contrast, agreement between medical claims-identified and physician-adjudicated bleeding events was poor, with a κ of 0.24 (95% CI, 0.19 to 0.30) for any hospitalized bleeding event and 0.15 (95% CI, 0.11 to 0.20) for moderate or severe bleeding on the GUSTO scale. Conclusions and Relevance:Event rates at 1 year after MI were lower for MI, stroke, and bleeding when medical claims were used to identify events than when adjudicated by physicians. Medical claims diagnoses were only modestly accurate in identifying MI and stroke admissions but had limited accuracy for bleeding events. An alternative approach may be needed to ensure good safety surveillance in cardiovascular studies. Trial Registration:clinicaltrials.gov Identifier: NCT01088503.

Dataset Information

Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.

Publications

Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.

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