Christopher Labos

Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction

Background: Patients prescribed antiplatelet treatment to prevent recurrent acute myocardial infarction are often also given a selective serotonin reuptake inhibitor (SSRI) to treat coexisting depression. Use of either treatment may increase the risk of bleeding. We assessed the risk of bleeding among patients taking both medications following acute myocardial infarction. Methods: We conducted a retrospective cohort study using hospital discharge abstracts, physician billing information, medication reimbursement claims and demographic data from provincial health services administrative databases. We included patients 50 years of age or older who were discharged from hospital with antiplatelet therapy following acute myocardial infarction between January 1998 and March 2007. Patients were followed until admission to hospital due to a bleeding episode, admission to hospital due to recurrent acute myocardial infarction, death or the end of the study period. Results: The 27 058 patients in the cohort received the following medications at discharge: acetylsalicylic acid (ASA) (n = 14 426); clopidogrel (n = 2467), ASA and clopidogrel (n = 9475); ASA and an SSRI (n = 406); ASA, clopidogrel and an SSRI (n = 239); or clopidogrel and an SSRI (n = 45). Compared with ASA use alone, the combined use of an SSRI with antiplatelet therapy was associated with an increased risk of bleeding (ASA and SSRI: hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.08–1.87; ASA, clopidogrel and SSRI: HR 2.35, 95% CI 1.61–3.42). Compared with dual antiplatelet therapy alone (ASA and clopidogrel), combined use of an SSRI and dual antiplatelet therapy was associated with an increased risk of bleeding (HR 1.57, 95% CI 1.07–2.32). Interpretation: Patients taking an SSRI together with ASA or dual antiplatelet therapy following acute myocardial infarction were at increased risk of bleeding.

A Systematic Review and Meta-analysis of the Association Between Implantable Cardioverter-Defibrillator Shocks and Long-term Mortality

BACKGROUND It is unknown whether implantable cardioverter-defibrillator (ICD) discharges actively contribute to a worse prognosis independent of the underlying arrhythmia. There is considerable variability in the reported risk of mortality after appropriate and inappropriate ICD shocks. The aim of our systematic review was to provide a reliable effect size of the association between ICD shock and mortality for both types of therapies. METHODS On the basis of a systematic literature search, 10 studies were considered eligible for inclusion in the analysis, and data on the hazard ratio (HR) of mortality after ICD shock were extracted from each study. RESULTS On pooled analysis, a substantial difference was detected in the risk for subsequent mortality between appropriate and inappropriate shocks. Among patients receiving an appropriate ICD shock, the HR for cardiac death was 2.95 (95% confidence interval [CI], 2.12-4.11; P < 0.001) compared with an HR of 1.71 (95% CI, 1.45-2.02) for those receiving an inappropriate shock. Clinical variables like ejection fraction, New York Heart Association class, and length of follow-up did not affect the HRs in our meta-regression models. CONCLUSIONS Our analysis showed a significant association between appropriate and inappropriate ICD shocks and mortality, with a stronger association for appropriate shocks. Previous trials of ICD therapy reduction programming have shown a significant reduction of inappropriate shocks. The management of appropriate shocks is more challenging and may be optimized by the assessment and treatment of the underlying ventricular arrhythmias. The role of therapies aimed at modifying the arrhythmic substrate and the potential impact on ICD shocks and mortality requires further investigation.

Traditional risk factors and a Genetic Risk Score are associated with age of first acute coronary syndrome

Objective To examine the association between traditional risk factors (TRF) and a Genetic Risk Score (GRS) with age of first acute coronary syndrome (ACS). Early onset ACS may occur due to a high burden of TRFs or to genetic factors that accelerate atherosclerosis. Whether recently discovered genetic variants for ACS are more prevalent at earlier age of first ACS remains unknown. Methods To construct a multilocus GRS, participants were genotyped for 30 single nucleotide polymorphisms (SNP) identified from prior genome-wide association studies. Linear regression models were fit to estimate the association between TRFs and GRS with age of first ACS. Results We included 460 participants with a first ACS enrolled in the Recurrence and Inflammation in the Acute Coronary Syndromes (RISCA) cohort. Several TRFs were associated (all p<0.05) with earlier age of first ACS: male sex (6.9 years earlier (95% CI 4.1 to 9.7)), current cigarette smoking (8.1 years (95% CI 6.1 to 10.0)), overweight (Body Mass Index, BMI >25) and obesity (BMI>30) (5.2 years (95% CI 2.6 to 7.9)). In women, hormone replacement therapy was also associated with earlier age of first ACS (4.8 years earlier (95% CI 0.3 to 8.4)). After multivariable adjustment for TRFs, a 1 SD increment in the GRS was associated with a 1.0 (95% CI 0.1 to 2.0) year earlier age of first ACS. Conclusions Among individuals with a first ACS, a GRS composed of 30 SNPs is associated with younger age of presentation. Although genetic predisposition modestly contributes to earlier ACS, a heavy burden of TRF is associated with markedly earlier ACS.

Association Between Family History, a Genetic Risk Score, and Severity of Coronary Artery Disease in Patients With Premature Acute Coronary Syndromes

Objective— A genetic risk score (GRS) for coronary artery disease has recently been shown to be independent of family history (FHx) in predicting future cardiovascular events. We sought to determine whether the presence of these risk factors, either individually or together, was associated with a higher burden of angiographic coronary artery disease. Approach and Results— We included 763 patients with premature acute coronary syndrome (median age, 50 [46–53] years; 30.8% women) with at least 1 major epicardial vessel stenosis enrolled in the Gender and Sex Determinants of Cardiovascular Disease From Bench to Beyond in Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, a multicentre prospective cohort study of premature patients with acute coronary syndrome (aged ⩽55 years). The prevalence of multivessel disease (ie, ≥2 vessels with >50% stenosis) in individuals with FHx was 49.7% as compared with 37.9% in those without FHx (P<0.01 for comparison). In adjusted models for age, sex, traditional risk factors, and GRS, FHx was associated with a higher prevalence of 3-vessel disease (odds ratio [OR], 1.42; 95% confidence interval, 0.91–2.21; P=0.12 for 2-vessel disease and OR, 2.26; 95% confidence interval, 1.29–3.95; P=0.005 for 3-vessel disease). Individuals with a high GRS were also more likely to have multivessel disease (OR, 1.41; 95% confidence interval, 1.01–1.99; P=0.047) after adjustment for traditional risk factors, including FHx. Individuals with both a FHx and a high GRS as compared with those with neither had the highest ORs for multivessel disease (adjusted OR, 2.14; 95% confidence interval, 1.24–3.69; P=0.0064). Conclusions— In patients with premature acute coronary syndrome, the presence of either a high GRS or FHx is associated with greater severity of coronary artery disease at angiography. Whether preventive strategies targeted to genetically predisposed individuals will reduce the burden of early acute coronary syndrome warrants further study.

Utility of a genetic risk score to predict recurrent cardiovascular events 1 year after an acute coronary syndrome: A pooled analysis of the RISCA, PRAXY, and TRIUMPH cohorts

BACKGROUND Limited evidence exists regarding the utility of genetic risk scores (GRS) in predicting recurrent cardiovascular events after acute coronary syndrome (ACS). We sought to determine whether a GRS would predict early recurrent cardiovascular events within 1 year of ACS. METHODS & RESULTS Participants admitted with acute coronary syndromes from the RISCA, PRAXY, and TRIUMPH cohorts, were genotyped for 30 single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD) or myocardial infarction (MI) in prior genome wide association studies. A 30 SNP CAD/MI GRS was constructed. The primary endpoint was defined as all-cause mortality, recurrent ACS or cardiac re-hospitalization within 1 year of ACS admission. Results across all cohorts for the 30 SNP CAD/MI GRS were pooled using a random-effects model. There were 1040 patients from the RISCA cohort, 691 patients from the PRAXY cohort, and 1772 patients from the TRIUMPH cohort included in the analysis and 389 occurrences of the primary endpoint of recurrent events at 1-year post-ACS. In unadjusted and fully adjusted analyses, a 30 SNP GRS was not significantly associated with recurrent events (HR per allele 0.97 (95%CI 0.91-1.03) for RISCA, HR 0.99 (95%CI 0.93-1.05) for PRAXY, 0.98 (95%CI 0.94-1.02) for TRIUMPH, and 0.98 (95%CI 0.95-1.01) for the pooled analysis). Addition of this GRS to the GRACE risk model did not significantly improve risk prediction. CONCLUSION The 30 MI SNP GRS was not associated with recurrent events 1-year post ACS in pooled analyses across cohorts and did not improve risk discrimination or reclassification indices. Our results suggest that the genetic etiology of early events post-ACS may differ from later events.

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Background— After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na+ current to inactivate leads to intracellular Ca2+ dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na+ current, on ventricular refibrillation. Methods and Results— Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes. Fibrillating hearts were randomized into 3 groups: treatment with ranolazine, GS-967, or nontreated controls. In the treated groups, hearts were perfused with ranolazine or GS-967 at 2 minutes of VF. In control experiments, perfusion solution was supplemented with isotonic saline in lieu of a drug. Inducibility of refibrillation was assessed after initial long-duration VF by attempting to reinduce VF. Sustained refibrillation was successful in fewer ranolazine-treated (29.17%; P=0.005) or GS-967–treated (45.83%, P=0.035) hearts compared with that in nontreated control hearts (84.85%). In GS-967–treated hearts, significantly more spontaneous termination of initial long-duration VF was observed (66.67%; P=0.01). Ca2+ transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca2+ alternans (P=0.03). Conclusions— Late Na+ current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models.

Genetic Risk Prediction for Primary and Secondary Prevention of Atherosclerotic Cardiovascular Disease: an Update

Purpose of ReviewThis review aims to summarize the research on genetic risk scores and their ability to improve risk prediction in both a primary and a secondary prevention population.Recent FindingsSeveral groups have examined the role of genetic scores in different patient populations. Recent studies have capitalized on the growing number of identified genetic variants to construct polygenic risk scores that include hundreds and sometimes thousands of SNPs. Also, recent studies have demonstrated that individuals with high genetic risk scores can attenuate their risk with lifestyle modifications and with statins, for which the benefit of treatment may be greater in those at highest genetic risk.SummaryGenetic risk scores when added to existing clinical models appear to improve risk prediction, particularly in the setting of incident cardiovascular disease and may provide actionable information to optimize prevention early in life. Future research will need to establish how to best use this genetic risk information either as a means to further individualize treatment decisions or to better identify high-risk populations.

WHAT FACTORS INFLUENCE THE CHOICE OF APIXABAN, RIVAROXABAN, OR DABIGATRAN FOR STROKE PREVENTION AMONG ATRIAL FIBRILLATION PATIENTS IN REAL-WORLD CLINICAL PRACTICE? INSIGHTS FROM THE PROSPECTIVE SPRINT-AF REGISTRY

Non-vitamin K oral anticoagulants (NOAC) are commonly prescribed to prevent stroke for patients with atrial fibrillation (AF). We sought to assess factors which might influence the selection of a particular NOAC agent in real-world clinical practice. The Stroke Prevention and Rhythm INTerventions

Long term outcomes among adults post transcatheter atrial septal defect closure: Systematic review and meta-analysis

BACKGROUND Transcatheter Closure (TC) has become the main stay therapy for many secundum atrial septal defects (ASD) based on short and intermediate term outcome data. Long-term safety and efficacy of this approach among adult patients however, is not well established. METHODS AND RESULTS A comprehensive search of major electronic databases for studies reporting the long-term (≥5 year) outcomes post TC among adults yielded 114 studies, 9 of which had met the inclusion criteria. This included 1015 patients with a mean age of 45 years ± 5.5 years, two third were female with a mean follow up duration 6.4 years ± 2.7 years. The weighted proportions of long-term mortality and stroke with 95% confidence intervals (CI) were 2.4% (95%CI 0.9%-6.1%) and 2.1% (95%CI 0.7%-5.7%) respectively. Atrial arrhythmia occurred in 6.5% (95%CI 3.5%-11.7%) and atrial fibrillation in 4.9% (95%CI 1.9%-11.7%). ASD related re-interventions were encountered in 2.3% (95%CI 1.0%-5.4%) and residual shunt in 4.2% (95% CI 1.3%-12.4%), with 1 case of suspected device erosion 0.9% (95%CI 0.4-2.2%). Frame fractures and late migrations were observed at 4.2% (95%CI 1.5%-11.5%) and 1.2% (95%CI 0.3%-4%) respectively. No cases of occluder endocarditis or thrombosis were reported. IN CONCLUSION This is the first study that systematically analyzes the long-term outcomes after TC providing important estimates for various clinical and occluder related outcomes. The analysis suggests preserved long-term safety post TC; however, this is limited due to the variable quality of available evidence and requires further assessment by larger studies with more comprehensive follow-up data.

Beta-blockers Associated with a Mortality Benefit in Patients with Systolic Dysfunction and Elevated Serum Bilirubin

Background: Hyperbilirubinemia is associated with increased mortality in heart failure (HF) patients. We evaluated the impact of evidence-based medical therapy, in particular beta-blocker on the survival of patients with HF and hyperbilirubinemia. Methods and Results: We reviewed the charts of all patients followed at our tertiary care heart failure clinic. Hyperbilirubinemia was defined as total bilirubin >30 µmol/L (1.5 times the upper limit of our laboratory value). The primary endpoint was all-cause mortality. The secondary endpoint was a composite of death, cardiac transplant or ventricular assistance device implantation (VAD). Of 1035 HF patients, 121 patients (11.7%) had hyperbilirubinemia. Median follow-up was 556 days. Hyperbilirubinemia was associated with an eight-fold increase in all-cause mortality, hazard ratio (HR): 8.78[95% Confidence Intervals (CI): 5.89-13.06]. Beta-blocker use was associated with approximately 60% reduction in all-cause mortality (HR: 0.38, 95% CI:0.15-0.94) and 70% reduction in the composite secondary endpoint (HR:0.31, 95% CI:0.13-0.71) in patients with hyperbilirubinemia. Conclusion: HF patients with hyperbilirubinemia have increased early mortality, need for cardiac transplantation or VAD. Beta-blocker use was associated with early survival benefit in these patients. Bilirubin levels should be monitored in patients with HF and early initiation of beta-blockers in patients with hyperbilirubinemia should be considered.