In the management of atrial fibrillation, the most frequently prescribed oral anticoagulant is apixaban, given at a fixed dose of 5mg BID. Apixaban is predominantly metabolized by cytochrome P4503A4 (CYP3A4) and is also a substrate for the drug efflux transporter P-glycoprotein (P-gp). In nearly 300,000 Medicare patients with AF receiving apixaban, we previously showed that concomitant therapy with drugs that inhibit both CYP3A4 and P-gp, specifically amiodarone or diltiazem, significantly increased serious bleeding that caused hospitalization and/or death. We hypothesized that this adverse effect was mediated by an increase in apixaban plasma concentrations caused by concomitant therapy that reduced drug elimination. Utilizing left-over samples obtained from clinically indicated blood draws that would typically be discarded, the Vanderbilt University Medical Center biobank BioVU contains >353,000 samples linked to de-identified electronic medical records (EMRs), with both DNA and plasma harvested. Of 35 samples drawn from patients taking apixaban 5mg BID, 5 were identified to be drawn from patients concomitantly taking drugs inhibiting both CYP3A4 and P-gp. Using a chromogenic anti-Xa assay, we found that plasma concentrations of apixaban were significantly higher (347±64 ng/mL; mean±SEM) for patients receiving concomitant CYP3A4/P-gp-inhibiting drugs compared to those not treated with these drugs (166±67 ng/mL; P=0.025, Mann Whitney). There were no differences between the 2 patient groups with respect to age, weight, or serum creatinine. The results of this pilot study provide preliminary data to support our hypothesis, and they demonstrate the practicality of obtaining pharmacokinetic data from a large cohort of plasma samples linked to deidentified EMRs. This approach could be used to define the role of apixaban levels in high-risk clinical scenarios and to better understand the relationship between drug levels and bleeding risk.

BACKGROUND AND AIMS:Genetic testing is recommended for select patients with atrial fibrillation (AF). The aims of this study were to define the results of genetic evaluation and its therapeutic impact for patients referred to a dedicated AF precision medicine clinic. METHODS:Patients diagnosed with AF before age 60 were candidates for referral. In addition to standard evaluation with history, physical exam, and electrocardiogram (ECG), genetic evaluation included a three-generation pedigree, cardiac imaging, ambulatory monitoring, and clinical genetic testing with a cardiomyopathy/arrhythmia panel. RESULTS:Overall, 264 participants were referred: the median age was 47 years (Q1, Q3: 38, 55), 77 (29%) were female, and 236 (89%) were White. Median age at AF diagnosis was 39 years (Q1, Q3: 31, 48), and median time from AF diagnosis to evaluation was 3.7 years (Q1, Q3: 0.9, 10). A total of 242 patients (92%) underwent genetic testing, which identified a pathogenic or likely pathogenic variant in 48 (20%). The strongest predictors of positive genetic testing were history of cardiomyopathy, infranodal conduction disease, and elevated T1 or late gadolinium enhancement on cardiac magnetic resonance imaging (all P < .05). The strongest predictors of negative genetic testing were obstructive sleep apnoea and a normal 12-lead ECG (both P < .04). Overall, genetic testing changed clinical management in 52% of patients with positive genetic testing, highlighted by seven new implantable cardioverter-defibrillator placements and initiation of disease-modifying therapy in 16 patients. CONCLUSIONS:Genetic testing was positive in 20% of patients with early-onset AF referred to a dedicated AF precision medicine clinic. Genetic testing results may change clinical management in genotype-positive patients.

Pregabalin and duloxetine are widely prescribed non-opioid medications for chronic musculoskeletal pain. Pregabalin may increase the risk of heart failure, and duloxetine increases heart rate and blood pressure; however, little is known about their comparative cardiovascular safety. This study compared cardiovascular outcomes between new users of pregabalin and new users of duloxetine among US Veterans with chronic musculoskeletal conditions. We conducted a retrospective cohort study of US Veterans, aged 18-89 years, with chronic non-cancer musculoskeletal pain who started pregabalin or duloxetine between 2015 and 2021. Veterans with serious illnesses were excluded. The primary outcome was a major adverse cardiovascular event (MACE), a composite of acute myocardial infarction (AMI), stroke, heart failure (HF), or cardiovascular death. We identified cardiovascular events through Veterans Affairs and linked Medicare data and mortality data from the National Death Index. We adjusted for confounding through inverse probability of treatment weighting utilizing a propensity score incorporating 158 covariates. Outcomes were analyzed using Cox proportional hazard regression models. This study included 26,684 new users of pregabalin and 152,808 new users of duloxetine (83% male, 69% reported White race, median age = 56 years). During a total follow-up of 141,112 person-years, there were 1,798 total MACE events. The rate of MACE was higher for pregabalin users compared to duloxetine users (unadjusted HR: 1.61 (95% CI: 1.43-1.81), adjusted HR: 1.24 (95% CI: 1.08-1.41)), driven by higher rates of HF and AMI among pregabalin users. These findings present new considerations regarding the comparative cardiovascular safety of therapeutic options for chronic musculoskeletal pain.

Background and Aims:Genetic testing is recommended for select patients with atrial fibrillation (AF). The aims of this study were to define the results of genetic evaluation and its therapeutic impact for patients referred to a dedicated AF precision medicine clinic. Methods:Patients diagnosed with AF before age 60 were candidates for referral. In addition to standard evaluation with history, physical exam, and ECG, genetic evaluation included a 3-generation pedigree, cardiac imaging, ambulatory monitoring, and clinical genetic testing with a cardiomyopathy/arrhythmia panel. Results:264 participants were referred: the median age was 47 years (Q1, Q3: 38, 55), 77 (29%) were female, and 236 (89%) were White. Median age at AF diagnosis was 39 years (Q1, Q3: 31, 48) and median time from AF diagnosis to evaluation was 3.7 years (Q1, Q3: 0.9, 10). 242 patients (92%) underwent genetic testing, which identified a pathogenic or likely pathogenic variant in 48 (20%). The strongest predictors of positive genetic testing were history of cardiomyopathy, infranodal conduction disease, and elevated T1 or late gadolinium enhancement on cardiac MRI (all p<0.05). The strongest predictors of negative genetic testing were obstructive sleep apnea and a normal 12-lead ECG (both p<0.04). Overall, genetic testing changed clinical management in 52% of patients with positive genetic testing, highlighted by 7 new ICD placements and initiation of disease modifying therapy in 16 patients. Conclusions:Genetic testing was positive in 20% of patients with early-onset AF referred to a dedicated AF precision medicine clinic. Genetic testing results changed clinical management in approximately half of genotype-positive patients. STRUCTURED GRAPHICAL ABSTRACT:Key Question: Does genetic evaluation of patients with early-onset atrial fibrillation (AF) change their clinical management?Key Finding: Among 246 participants that completed genetic evaluation in a dedicated AF precision medicine clinic, 20% had positive genetic testing with identification of a pathogenic cardiomyopathy or channelopathy variant. These findings led to changes in clinical management in 52% of patients with positive genetic testing.Take-home Message: Genetic evaluation of patients with early-onset AF consists of detailed phenotyping and genetic testing to identify previously undiagnosed genetic disorders. This facilitates earlier diagnosis and clinical intervention.

Importance:Both pregabalin and gabapentin are common nonopioid medications used to treat chronic pain, which affects up to 30% of patients. Because pregabalin has greater potency than gabapentin in binding to the α2δ subunit of the L-type calcium channel, pregabalin may be associated with an increased risk for heart failure (HF). Objective:To compare incident hospitalizations and emergency department (ED) visits for HF among new users of pregabalin vs gabapentin among Medicare beneficiaries with noncancer chronic pain. Design, Setting, and Participants:This retrospective cohort study included data collected between January 1, 2015, and December 21, 2018, for Medicare beneficiaries aged 65 to 89 years with chronic noncancer pain and without a history of HF and terminal illnesses. Data were analyzed from March 21 to December 2, 2024. Exposure:New use of pregabalin or gabapentin. Main Outcomes and Measures:The primary outcome was hospital admission or ED visit with a primary discharge diagnosis of HF. Secondary outcomes were incidence of outpatient HF diagnosis and all-cause mortality. Adjusted hazard ratios (AHRs) were calculated using inverse probability of treatment weighting propensity score adjustment accounting for 231 covariates, including demographic, clinical, and health care utilization variables and medication use. Results:The cohort included 246 237 Medicare beneficiaries, of whom 18 622 (7.6%) were new users of pregabalin and 227 615 (92.4%) were new users of gabapentin; the cohort was predominantly female (66.8%), with a median age of 73 years (IQR, 69-78 years). During 114 113 person-years of follow-up, 1470 patients had a hospital admission or ED visit for HF. The rate of HF was 18.2 (95% CI, 15.3-21.6) per 1000 person-years for pregabalin and 12.5 (95% CI, 11.9-13.2) per 1000 person-years for gabapentin (AHR, 1.48 [95% CI, 1.19-1.77]). When restricted to patients with a history of cardiovascular disease, pregabalin was associated with an elevated HF risk compared with gabapentin (AHR, 1.85 [95% CI, 1.38-2.47]). Increased risk of outpatient HF incidence was also noted among patients receiving pregabalin compared with those receiving gabapentin (AHR, 1.27 [95% CI, 1.02-1.58]). All-cause mortality was not significantly different between groups (AHR, 1.26 [95% CI, 0.95-1.76]). Conclusions and Relevance:In this retrospective cohort study of Medicare beneficiaries with chronic noncancer pain, incident HF was increased in new users of pregabalin compared with new users of gabapentin. These findings should be considered, especially in patients with a history of cardiovascular disease.

BACKGROUND:The strongest genetic risk factors for atrial fibrillation (AF) are DNA variants on chromosome 4q25 near the transcription factor gene PITX2 (Pitx2:Paired-like homeodomain transcription factor 2). Mice deficient in Pitx2 (Pitx2+/-) have increased AF susceptibility, although the molecular mechanism(s) remains controversial. Pitx2 encodes a transcription factor that activates an antioxidant response to promote cardiac repair. Increased reactive oxygen species causing oxidation of polyunsaturated fatty acids generates reactive lipid dicarbonyl moieties that adduct to proteins and other macromolecules to promote cellular injury. We tested the hypothesis that oxidative stress, and specifically isolevuglandins, the most reactive lipid dicarbonyls identified, are increased in the setting of Pitx2 deficiency to promote proarrhythmic remodeling and AF.METHODS:Pitx2+/- and Pitx2+/+ wild-type littermate control mice were treated orally with vehicle, the lipid dicarbonyl scavenger 2-hydroxybenzylamine, or an inactive control compound at weaning, until study at age 16 to 18 weeks.RESULTS:Pitx2+/- mice demonstrated increased P wave duration indicative of slowed atrial conduction, as well as increased inducible AF burden and sustained AF, compared with wild type, and these abnormalities were prevented by 2-hydroxybenzylamine. Both reactive oxygen species and isolevuglandin protein adducts were elevated in Pitx2+/- atria with reduced expression of reactive oxygen species-protective genes. High-resolution respirometry demonstrated impaired mitochondrial function in Pitx2+/- atria, with disruption of mitochondrial integrity and cell-cell junctions with connexin lateralization, as well as decreased mitochondrial biogenesis gene expression. Proarrhythmic ionic current remodeling in Pitx2+/- atrial myocytes included elevated resting membrane potential, abbreviated action potential duration, and reduced maximum phase 0 upstroke velocity compared with wild type. Most of these abnormalities were ameliorated or prevented by 2-hydroxybenzylamine.CONCLUSIONS:These results demonstrate a critical role for lipid dicarbonyl mediators of oxidative stress in the proarrhythmic remodeling and AF susceptibility that occurs with Pitx2 deficiency, implying the possibility of genotype-specific therapy to prevent AF.

Aims The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are the major components of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice.Methods and results Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared with WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, pro-arrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for Complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-alpha prevented electrical remodelling and AF susceptibility, while IL-1 beta inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke.Conclusion These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling. Graphical Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet the cellular and molecular mechanisms underlying the AF substrate remain unclear. Isolevuglandins (IsoLGs) are highly reactive lipid dicarbonyl products that mediate oxidative stress-related injury. In murine hypertension, the lipid dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) reduced IsoLGs and AF susceptibility. We hypothesized that IsoLGs mediate detrimental pathophysiologic effects in atrial cardiomyocytes that promote the AF substrate. Using Seahorse XFp extracellular flux analysis and a luminescence assay, IsoLG exposure suppressed intracellular ATP production in atrial HL-1 cardiomyocytes. IsoLGs caused mitochondrial dysfunction, with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) with protein carbonylation, and mitochondrial DNA damage. Moreover, they generated cytosolic preamyloid oligomers previously shown to cause similar detrimental effects in atrial cells. In mouse atrial and HL-1 cells, patch clamp experiments demonstrated that IsoLGs rapidly altered action potentials (AP), implying a direct effect independent of oligomer formation by reducing the maximum Phase 0 upstroke slope and shortening AP duration due to ionic current modifications. IsoLG-mediated mitochondrial and electrophysiologic abnormalities were blunted or totally prevented by 2-HOBA. These findings identify IsoLGs as novel mediators of oxidative stress-dependent atrial pathophysiology and support the investigation of dicarbonyl scavengers as a novel therapeutic approach to prevent AF.

AIMS:The concept of "atrial cardiomyopathy" (AtCM) had been percolating through the literature since its first mention in 1972. Since then, publications using the term were sporadic until the decision was made to convene an expert working group with representation from four multinational arrhythmia organizations to prepare a consensus document on atrial cardiomyopathy in 2016 (EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication). Subsequently, publications on AtCM have increased progressively. METHODS AND RESULTS:The present consensus document elaborates the 2016 AtCM document further to implement a simple AtCM staging system (AtCM stages 1-3) by integrating biomarkers, atrial geometry, and electrophysiological changes. However, the proposed AtCM staging needs clinical validation. Importantly, it is clearly stated that the presence of AtCM might serve as a substrate for the development of atrial fibrillation (AF) and AF may accelerates AtCM substantially, but AtCM per se needs to be viewed as a separate entity. CONCLUSION:Thus, the present document serves as a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) to contribute to the evolution of the AtCM concept.

Importance Diltiazem, a commonly prescribed ventricular rate–control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation. Objective To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol. Design, Setting, and Participants This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024. Exposures Diltiazem and metoprolol. Main Outcomes and Measures The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting. Results The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26). Conclusions and Relevance In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Objective: The incidence of neuroleptic malignant syndrome (NMS), a rare, potentially fatal adverse effect of antipsychotics, among children and youth is unknown. This cohort study estimated NMS incidence in antipsychotic users age 5-24 years and described its variation according to patient and antipsychotic characteristics. Methods: We used national Medicaid data (2004-2013) to identify patients beginning antipsychotic treatment and calculated the incidence of NMS during antipsychotic current use. Adjusted hazard ratios (HRs) assessed the independent contribution of patient and antipsychotic characteristics to NMS risk. Results: The 1,032,084 patients had 131 NMS cases during 1,472,558 person-years of antipsychotic current use, or 8.9 per 100,000 person-years. The following five factors independently predicted increased incidence: age 18-24 years (HR [95% CI] = 2.45 [1.65-3.63]), schizophrenia spectrum and other psychotic disorders (HR = 5.86 [3.16-10.88]), neurodevelopmental disorders (HR = 7.11 [4.02-12.56]), antipsychotic dose >200mg chlorpromazine-equivalents (HR = 1.71 [1.15-2.54]), and first-generation antipsychotics (HR = 4.32 [2.74-6.82]). NMS incidence per 100,000 person-years increased from 1.8 (1.1-3.0) for those with none of these factors to 198.1 (132.8-295.6) for those with 4 or 5 factors. Findings were essentially unchanged in sensitivity analyses that restricted the study data to second-generation antipsychotics, children age 5-17 years, and the 5 most recent calendar years. Conclusion: In children and youth treated with antipsychotics, five factors independently identified patients with increased NMS incidence: age 18-24 years, schizophrenia spectrum and other psychotic disorders, neurodevelopmental disorders, first-generation drugs, and antipsychotic doses greater than 200 mg chlorpromazine-equivalents. Patients with 4 or 5 of these factors had more than 100 times the incidence of those with none. These findings could improve early identification of children and youth with elevated NMS risk, potentially leading to earlier detection and improved outcomes.

Importance:Dose-related effects of antipsychotic medications may increase mortality in children and young adults. Objective:To compare mortality for patients aged 5 to 24 years beginning treatment with antipsychotic vs control psychiatric medications. Design, Setting, and Participants:This was a US national retrospective cohort study of Medicaid patients with no severe somatic illness or schizophrenia or related psychoses who initiated study medication treatment. Study data were analyzed from November 2022 to September 2023. Exposures:Current use of second-generation antipsychotic agents in daily doses of less than or equal to 100-mg chlorpromazine equivalents or greater than 100-mg chlorpromazine equivalents vs that for control medications (α agonists, atomoxetine, antidepressants, and mood stabilizers). Main Outcome and Measures:Total mortality, classified by underlying cause of death. Rate differences (RDs) and hazard ratios (HRs) adjusted for potential confounders with propensity score-based overlap weights. Results:The 2 067 507 patients (mean [SD] age, 13.1 [5.3] years; 1 060 194 male [51.3%]) beginning study medication treatment filled 21 749 825 prescriptions during follow-up with 5 415 054 for antipsychotic doses of 100 mg or less, 2 813 796 for doses greater than 100 mg, and 13 520 975 for control medications. Mortality was not associated with antipsychotic doses of 100 mg or less (RD, 3.3; 95% CI, -5.1 to 11.7 per 100 000 person-years; HR, 1.08; 95% CI, 0.89-1.32) but was associated with doses greater than 100 mg (RD, 22.4; 95% CI, 6.6-38.2; HR, 1.37; 95% CI, 1.11-1.70). For higher doses, antipsychotic treatment was significantly associated with overdose deaths (RD, 8.3; 95% CI, 0-16.6; HR, 1.57; 95% CI, 1.02-2.42) and other unintentional injury deaths (RD, 12.3; 95% CI, 2.4-22.2; HR, 1.57; 95% CI, 1.12-2.22) but was not associated with nonoverdose suicide deaths or cardiovascular/metabolic deaths. Mortality for children aged 5 to 17 years was not significantly associated with either antipsychotic dose, whereas young adults aged 18 to 24 years had increased risk for doses greater than 100 mg (RD, 127.5; 95% CI, 44.8-210.2; HR, 1.68; 95% CI, 1.23-2.29). Conclusions and Relevance:In this cohort study of more than 2 million children and young adults without severe somatic disease or diagnosed psychosis, antipsychotic treatment in doses of 100 mg or less of chlorpromazine equivalents or in children aged 5 to 17 years was not associated with increased risk of death. For doses greater than 100 mg, young adults aged 18 to 24 years had significantly increased risk of death, with 127.5 additional deaths per 100 000 person-years.

BACKGROUND:Amiodarone, the most effective antiarrhythmic drug in atrial fibrillation, inhibits apixaban and rivaroxaban elimination, thus possibly increasing anticoagulant-related risk for bleeding.OBJECTIVE:For patients receiving apixaban or rivaroxaban, to compare risk for bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol, antiarrhythmic drugs that do not inhibit these anticoagulants' elimination.DESIGN:Retrospective cohort study.SETTING:U.S. Medicare beneficiaries aged 65 years or older.PATIENTS:Patients with atrial fibrillation began anticoagulant use between 1 January 2012 and 30 November 2018 and subsequently initiated treatment with study antiarrhythmic drugs.MEASUREMENTS:Time to event for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (past 30 days) evidence of bleeding (secondary outcomes), adjusted with propensity score overlap weighting.RESULTS:There were 91 590 patients (mean age, 76.3 years; 52.5% female) initiating use of study anticoagulants and antiarrhythmic drugs, 54 977 with amiodarone and 36 613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use (rate difference [RD], 17.5 events [95% CI, 12.0 to 23.0 events] per 1000 person-years; hazard ratio [HR], 1.44 [CI, 1.27 to 1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, -2.1 events [CI, -4.7 to 0.4 events] per 1000 person-years; HR, 0.80 [CI, 0.62 to 1.03]). The risk for death with recent evidence of bleeding (RD, 9.1 events [CI, 5.8 to 12.3 events] per 1000 person-years; HR, 1.66 [CI, 1.35 to 2.03]) was greater than that for other deaths (RD, 5.6 events [CI, 0.5 to 10.6 events] per 1000 person-years; HR, 1.15 [CI, 1.00 to 1.31]) (HR comparison: P = 0.003). The increased incidence of bleeding-related hospitalizations for rivaroxaban (RD, 28.0 events [CI, 18.4 to 37.6 events] per 1000 person-years) was greater than that for apixaban (RD, 9.1 events [CI, 2.8 to 15.3 events] per 1000 person-years) (P = 0.001).LIMITATION:Possible residual confounding.CONCLUSION:In this retrospective cohort study, patients aged 65 years or older with atrial fibrillation treated with amiodarone during apixaban or rivaroxaban use had greater risk for bleeding-related hospitalizations than those treated with flecainide or sotalol.PRIMARY FUNDING SOURCE:National Heart, Lung, and Blood Institute.

Gabapentin is prescribed for pain and is perceived as safe generally. However, gabapentin can cause respiratory depression, exacerbated by concomitant central nervous system depressants (e.g., opioids), a concern for vulnerable populations. We compared mortality rates among new users of either gabapentin or duloxetine with or without concurrent opioids in the 20% Medicare sample. We conducted a new‐user design retrospective cohort study, in Medicare enrollees ages 65–89 years with noncancer chronic pain and no severe illness who filled prescriptions between 2015 and 2018 for gabapentin ( n = 233,060) or duloxetine ( n = 34,009). Daily opioid doses, estimated in morphine milligram equivalents (MMEs), were classified into none, low (0 < MME < 50), and high (≥ 50 MME), based on Centers for Disease Control and Prevention (CDC) recommendations. The outcomes were all‐cause mortality (primary) and out‐of‐hospital mortality (secondary). We used inverse probability of treatment weighting to adjust for differences between gabapentin and duloxetine users. During 116,707 person‐years of follow‐up, 1,379 patients died. All‐cause mortality rate in gabapentin users was 12.16 per 1,000 person‐years vs. 9.94 per 1,000 in duloxetine users. Risks were similar for users with no concurrent opioids (adjusted hazard ratio (aHR) = 1.03, 95% confidence interval (CI): 0.80–1.31) or low‐dose daily opioids (aHR = 1.06, 95% CI: 0.63–1.76). However, gabapentin users receiving concurrent high‐dose daily opioids had an increased rate of all‐cause mortality compared with duloxetine users on high‐dose opioids (aHR = 2.03, 95% CI: 1.19–3.46). Out‐of‐hospital mortality yielded similar results. In this retrospective cohort study of Medicare beneficiaries, concurrent use of high‐dose opioids and gabapentin was associated with a higher all‐cause mortality risk than that for concurrent use of high‐dose opioids and duloxetine.