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Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial.

ABSTRACT: Background There is concern that selective serotonin reuptake inhibitors ( SSRI s) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results We studied 737 patients taking SSRI s in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1:1 to 737 patients not taking SSRI s. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in ROCKET AF . Over a mean 1.6 years of follow-up, the rate of major/ nonmajor clinically relevant bleeding was 18.57 events/100 patient-years for SSRI users versus 16.84 events/100 patient-years for matched comparators, adjusted hazard ratio ( aHR ) of 1.16 (95% confidence interval [CI], 0.95-1.43). The aHR s were similar in patients taking rivaroxaban ( aHR 1.11 [95% CI, 0.82-1.51]) and those taking warfarin ( aHR 1.21 [95% CI, 0.91-1.60]). For the rarer outcome of major bleeding, the aHR for SSRI users versus those not taking SSRI s was 1.13 (95% CI, 0.62-2.06) for rivaroxaban; for warfarin, the aHR was higher, at 1.58 (95% CI , 0.96-2.60) but not statistically significantly elevated. Conclusions We found no significant increase in bleeding risk when SSRI s were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with SSRI s added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that SSRI s can be safely added to anticoagulants in patients with atrial fibrillation . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00403767.

SUBMITTER: Quinn GR

PROVIDER: S-EPMC6201450 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial.

Quinn Gene R GR Hellkamp Anne S AS Hankey Graeme J GJ Becker Richard C RC Berkowitz Scott D SD Breithardt Günter G Fava Maurizio M Fox Keith A A KAA Halperin Jonathan L JL Mahaffey Kenneth W KW Nessel Christopher C CC Patel Manesh R MR Piccini Jonathan P JP Singer Daniel E DE

Journal of the American Heart Association 20180801 15

Background There is concern that selective serotonin reuptake inhibitors ( SSRI s) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results We studied 737 patients taking SSRI s in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with at ...[more]

PMID: 30371223

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Project description:BackgroundAtrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions.Methods and resultsIn the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677).ConclusionsIn a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.Clinical trial registrationURL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

Project description:Background Patients with atrial fibrillation (AF) treated with oral anticoagulants may be exposed to an increased risk of bleeding events. The HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INRs, Elderly, Drugs or alcohol) score is a simple, well-established, clinical bleeding-risk prediction score. Recently, a new algorithm-based score was proposed, the GARFIELD-AF (Global Anticoagulant in the Field-AF) bleeding score. We compared HAS-BLED and GARFIELD-AF scores in predicting adjudicated bleeding events in a clinical trial cohort of patients with AF taking anticoagulants, in the first external comparative validation of both scores. Methods and Results We analyzed patients from the SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor in Patients With AF) III and V trials. All patients assigned to the warfarin arm with information to calculate the scores were considered. Outcomes were major, major/clinically relevant nonmajor, and any bleeding. A total of 3550 warfarin-treated patients were available for analysis. Of these patients, 2519 (71.0%) had a HAS-BLED score ≥3, whereas based on GARFIELD-AF median value, 2056 (57.9%) were categorized as "high score." Both HAS-BLED and GARFIELD-AF C-indexes showed modest predictive value (C-index [95% confidence interval] for major bleeding, 0.58 [0.56-0.60] and 0.56 [0.54-0.57], respectively); however, GARFIELD-AF was not predictive of any bleeding. The GARFIELD-AF bleeding score had a significantly lower sensitivity and a negative reclassification for any bleeding compared with HAS-BLED, assessed by integrated discrimination improvement and net reclassification improvement (both P<0.001). HAS-BLED showed a 5% net benefit for any bleeding occurrence. Conclusions The algorithm-based GARFIELD-AF bleeding score did not show any significant improvement in major and major/clinically relevant nonmajor prediction compared with the simple HAS-BLED score. For clinical usefulness in prediction of any bleeding, the HAS-BLED score showed a significant net benefit compared with the GARFIELD-AF.

Project description:Background The ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) evaluated rivaroxaban (20/15 mg/d) versus warfarin in patients with atrial fibrillation. A separate trial, J-ROCKET AF (Japanese ROCKET AF), compared rivaroxaban (15/10 mg/d) and warfarin in Japanese patients with atrial fibrillation. Data about rivaroxaban following J-ROCKET AF criteria compared with warfarin and ROCKET AF dosage were limited. Methods and Results This retrospective study used medical data from a multicenter healthcare provider in Taiwan that included 3162 patients taking rivaroxaban. Among 2320 patients with an estimated glomerular filtration rate (eGFR) ≥50 mL/min per 1.73 m2, 384 and 1936 patients followed the ROCKET AF (20 mg/d) and J-ROCKET AF (15 mg/d) recommendation, respectively. Among 842 patients with an eGFR <50 mL/min per 1.73 m2, 422 and 420 patients followed the ROCKET AF (15 mg/d) and J-ROCKET AF (10 mg/d) recommendation, respectively. A total of 2053 patients with atrial fibrillation receiving warfarin were identified. Rivaroxaban following either ROCKET AF or J-ROCKET AF dosage criteria was associated with a comparable risk of thromboembolism but a lower risk of bleeding than warfarin. For patients with an eGFR ≥50 mL/min per 1.73 m2, risks of clinical events did not differ significantly between the 2 dosage criteria of rivaroxaban. For patients with an eGFR <50 mL/min per 1.73 m2, the ROCKET AF dosage was associated with a higher risk of major bleeding compared with the J-ROCKET AF dosage (hazard ratio, 2.70; P=0.0445) without significant differences regarding the risk of ischemic events. Conclusions In Asian patients with atrial fibrillation, the J-ROCKET AF dosage was as effective as the ROCKET AF dosage irrespective of renal function. The risk of major bleeding was lower with the J-ROCKET AF dosage in patients with an eGFR <50 mL/min per 1.73 m2. Compared with warfarin, rivaroxaban following either dosage criteria was effective and even safer.

Project description:ImportanceSelective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants associated with a small increased risk of major bleeding. However, the risk of bleeding associated with the concomitant use of SSRIs and oral anticoagulants (OACs) has not been well characterized.ObjectivesTo assess whether concomitant use of SSRIs with OACs is associated with an increased risk of major bleeding compared with OAC use alone, describe how the risk varies with duration of use, and identify key clinical characteristics modifying this risk.Design, setting, and participantsA population-based, nested case-control study was conducted among patients with atrial fibrillation initiating OACs between January 2, 1998, and March 29, 2021. Patients were from approximately 2000 general practices in the UK contributing to the Clinical Practice Research Datalink. With the use of risk-set sampling, for each case of major bleeding during follow-up, up to 30 controls were selected from risk sets defined by the case and matched on age, sex, cohort entry date, and follow-up duration.ExposuresConcomitant use of SSRIs and OACs (direct OACs and vitamin K antagonists [VKAs]) compared with OAC use alone.Main outcomes and measuresThe main outcome was incidence rate ratios (IRRs) of hospitalization for bleeding or death due to bleeding.ResultsThere were 42 190 patients with major bleeding (mean [SD] age, 74.2 [9.3] years; 59.8% men) matched to 1 156 641 controls (mean [SD] age, 74.2 [9.3] years; 59.8% men). Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OACs alone (IRR, 1.33; 95% CI, 1.24-1.42). The risk peaked during the initial months of treatment (first 30 days of use: IRR, 1.74; 95% CI, 1.37-2.22) and persisted for up to 6 months. The risk did not vary with age, sex, history of bleeding, chronic kidney disease, and potency of SSRIs. An association was present both with concomitant use of SSRIs and direct OACs compared with direct OAC use alone (IRR, 1.25; 95% CI, 1.12-1.40) and concomitant use of SSRIs and VKAs compared with VKA use alone (IRR, 1.36; 95% CI, 1.25-1.47).Conclusions and relevanceThis study suggests that among patients with atrial fibrillation, concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OAC use alone, requiring close monitoring and management of risk factors for bleeding, particularly in the first few months of use.

Project description:ObjectivesWe identified factors associated with thromboembolic and bleeding events in two contemporary cohorts of anticoagulated patients with atrial fibrillation (AF), treated with either vitamin K antagonists (VKA) or non-VKA oral anticoagulants (NOACs).DesignProspective, multicentre observational study.Setting461 centres in seven European countries.Participants5310 patients receiving a VKA (PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF), derivation cohort) and 3156 patients receiving a NOAC (PREFER in AF Prolongation, validation cohort) for stroke prevention in AF.Outcome measuresRisk factors for thromboembolic events (ischaemic stroke, systemic embolism) and major bleeding (gastrointestinal bleeding, intracerebral haemorrhage and other life-threatening bleeding).ResultsThe mean age of patients enrolled in the PREFER in AF registry was 72±10 years, 40% were female and the mean CHA2DS2-VASc Score was 3.5±1.7. The incidence of thromboembolic and major bleeding events was 2.34% (95% CI 1.93% to 2.74%) and 2.84% (95% CI 2.41% to 3.33%) after 1-year of follow-up, respectively.Abnormal liver function, prior stroke or transient ischaemic attack, labile international normalised ratio (INR), concomitant therapy with antiplatelet or non-steroidal anti-inflammatory drugs, heart failure and older age (≥75 years) were independently associated with both thromboembolic and major bleeding events.With the exception of unstable INR values, these risk factors were validated in patients treated with NOACs (PREFER in AF Prolongation Study, 72±9 years, 40% female, CHA2DS2-VASc 3.3±1.6). For each single point decrease on a modifiable bleeding risk scale we observed a 30% lower risk for major bleeding events (OR 0.70, 95% CI 0.64 to 0.76, p<0.01) and a 28% lower rate of thromboembolic events (OR 0.72, 95% CI 0.66 to 0.82, p<0.01).ConclusionAttending to modifiable risk factors is an important treatment target in anticoagulated AF patients to reduce thromboembolic and bleeding events. Initiation of anticoagulation in those at risk of stroke should not be prevented by elevated bleeding risk scores.

Dataset Information

Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial.

Publications

Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial.

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