Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease : A Population-Based Cohort Study.

BACKGROUND: North American and European health agencies recently warned of severe breathing problems associated with gabapentinoids, including in patients with chronic obstructive pulmonary disease (COPD), although supporting evidence is limited. OBJECTIVE: To assess whether gabapentinoid use is associated with severe exacerbation in patients with COPD. DESIGN: Time-conditional propensity score-matched, new-user cohort study. SETTING: Health insurance databases from the Régie de l'assurance maladie du Québec in Canada. PATIENTS: Within a base cohort of patients with COPD between 1994 and 2015, patients initiating gabapentinoid therapy with an indication (epilepsy, neuropathic pain, or other chronic pain) were matched 1:1 with nonusers on COPD duration, indication for gabapentinoids, age, sex, calendar year, and time-conditional propensity score. MEASUREMENTS: The primary outcome was severe COPD exacerbation requiring hospitalization. Hazard ratios (HRs) associated with gabapentinoid use were estimated in subcohorts according to gabapentinoid indication and in the overall cohort. RESULTS: The cohort included 356 gabapentinoid users with epilepsy, 9411 with neuropathic pain, and 3737 with other chronic pain, matched 1:1 to nonusers. Compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation across the indications of epilepsy (HR, 1.58 [95% CI, 1.08 to 2.30]), neuropathic pain (HR, 1.35 [CI, 1.24 to 1.48]), and other chronic pain (HR, 1.49 [CI, 1.27 to 1.73]) and overall (HR, 1.39 [CI, 1.29 to 1.50]). LIMITATION: Residual confounding, including from lack of smoking information. CONCLUSION: In patients with COPD, gabapentinoid use was associated with increased risk for severe exacerbation. This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research and Canadian Lung Association.

Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding.

Importance: Selective 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. Objectives: To 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 Participants: A 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. Exposures: Concomitant use of SSRIs and OACs (direct OACs and vitamin K antagonists [VKAs]) compared with OAC use alone. Main Outcomes and Measures: The main outcome was incidence rate ratios (IRRs) of hospitalization for bleeding or death due to bleeding. Results: There 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 Relevance: This 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.

Concomitant Use of Selective Serotonin Reuptake Inhibitors and Oral Anticoagulants and Risk of Major Bleeding: A Systematic Review and Meta-analysis.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants, are associated with a modestly increased risk of major bleeding. However, in patients treated with both SSRIs and oral anticoagulants (OACs), the risk of major bleeding may be substantial. OBJECTIVE: To assess the risk of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone. METHODS: We searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials (from inception to December 1, 2021) for clinical trials and observational studies assessing the association between concomitant use of SSRIs and OACs and the risk of major bleeding. Given sufficient homogeneity of studies, we conducted a random-effects meta-analysis to estimate a pooled hazard ratio (HR) of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone. RESULTS: The review comprised 14 studies, including 7 cohort and 7 nested case-control studies. Following assessment of clinical and methodological heterogeneity, eight studies with a total of 98,070 patients were eligible for the meta-analysis. The pooled HR of major bleeding associated with concomitant use of SSRIs and OACs was 1.35 (95% confidence interval [CI]: 1.14-1.58). In secondary analyses, the pooled HR for concomitant use of SSRIs and direct OACs was 1.47 (95% CI: 1.03-2.10). CONCLUSION: Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding. Overall, our findings suggest that physicians may need to tailor treatment according to individual patient risk factors for bleeding when prescribing SSRIs to patients using OACs.

Oral Anticoagulants and the Risk of Dementia in Patients With Nonvalvular Atrial Fibrillation: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: Nonvalvular atrial fibrillation (NVAF) is associated with an increased risk of dementia. Oral anticoagulants (OACs) are essential for stroke prevention in NVAF, and studies have shown a possible protective effect on dementia. However, findings have been inconsistent and hampered by methodological limitations. Thus, we assessed whether the use of OACs is associated with a decreased incidence of dementia in patients with NVAF. In addition, we explored the impact of the cumulative duration of OAC use on the incidence of dementia. METHODS: Using the UK Clinical Practice Research Datalink, we formed a cohort of all patients aged 50 years or older with an incident diagnosis of NVAF between 1988 and 2017 and no prior OAC use, with a follow-up until 2019. Patients were considered unexposed until 6 months after their first OAC prescription for latency considerations and exposed thereafter until the end of follow-up. We used time-dependent Cox regression models to estimate hazard ratios (HRs), adjusted for 54 covariates, with 95% CIs for dementia associated with OAC use, compared with nonuse. We also assessed whether the risk varied with the cumulative duration of OAC use, compared with nonuse, by comparing prespecified exposure categories defined in a time-varying manner and by modeling the HR using a restricted cubic spline. RESULTS: The cohort included 142,227 patients with NVAF, with 8,023 cases of dementia over 662,667 person-years of follow-up (incidence rate 12.1, 95% CI 11.9-12.4 per 1,000 person-years). OAC use was associated with a decreased risk of dementia (HR 0.88, 95% CI 0.84-0.92) compared with nonuse. A restricted cubic spline also indicated a decreased risk of dementia, reaching a low at approximately 1.5 years of cumulative OAC use and stabilizing thereafter. Moreover, OAC use decreased the risk in patients aged 75 years and older (HR 0.84, 95% CI 0.80-0.89), but not in younger patients (HR 0.99, 95% CI 0.90-1.10). DISCUSSION: In patients with incident NVAF, OACs were associated with a decreased risk of dementia, particularly in elderly individuals. This warrants consideration when weighing the risks and benefits of anticoagulation in this population. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with NVAF, OAC use (vs nonuse) is associated with a decreased risk of dementia.