Christel Renoux

Aim: Our international cohort study assessed the comparative effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) among patients with non‐valvular atrial fibrillation (NVAF) using antiarrhythmic drugs. Methods: Using the United Kingdom's (UK's) Clinical Practice Research Datalink Aurum and Québec claims data, we assembled two study cohorts of patients with NVAF who initiated DOACs or VKAs while on antiarrhythmic drugs (2011–2020). Using an as‐treated exposure definition, we assessed the risks of ischemic stroke and major bleeding associated with DOACs vs . VKAs. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after propensity score‐based inverse‐probability‐of‐treatment‐weighting. Site‐specific estimates were pooled together using random‐effects models. Secondary analyses assessed effect measure modification by individual DOAC and type of antiarrhythmic drugs (interacting vs . non‐interacting). Results: The study cohort included 44 435 patients with NVAF initiating DOACs (n = 29 071) or VKAs (n = 15 364) while using antiarrhythmics. Compared to VKAs, DOACs were not associated with the risk of ischemic stroke (UK: HR, 0.90; 95% CI, 0.61–1.32/ Quebec: HR, 0.85; 95% CI, 0.70–1.03/ pooled: HR, 0.86; 95% CI 0.72–1.02; I ² = 0%) but with a decreased risk of major bleeding (UK: HR, 0.90; 95% CI, 0.75–1.08/Quebec: HR, 0.83; 95% CI, 0.76–0.91/pooled: HR 0.84; 95% CI 0.78–0.92; I ² = 0%); the latter was more pronounced with apixaban (pooled HR, 0.71; 95% CI, 0.63–0.81; I ² = 74%). There was no effect modification by type of antiarrhythmic drugs. Conclusions: DOACs were as effective but safer than VKAs among NVAF patients treated with antiarrhythmic drugs.

Background Incretin-based drugs, namely glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP-4) inhibitors, may have neuroprotective effects. Thus, we assessed whether these drugs are associated with a decreased risk of dementia among patients with type 2 diabetes. Methods Using the Clinical Practice Research Datalink from the UK, we formed two new user cohorts of patients at least 50 years of age with type 2 diabetes starting incretin-based drugs or sulfonylureas between 2007 and 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia were estimated separately for GLP-1 RAs and DPP-4 inhibitors using Cox proportional hazards models with propensity score fine-stratification weighting and inverse probability of censoring weights. Results Among 275,144 initiators of DPP-4 inhibitors or sulfonylureas, followed for 750,846 person-years, DPP-4 inhibitors were associated with a reduced dementia risk compared with sulfonylureas (4.4 vs. 5.7 events per 1000 person-years; HR 0.77, 95% CI 0.71–0.85). HRs decreased with increasing cumulative duration of use and dose. Similar associations were observed across dementia subtypes and individual DPP-4 inhibitors molecules. Among 181,215 initiators of GLP-1 RAs or sulfonylureas, followed for 530,415 person-years, GLP-1 RAs were associated with a similar reduction in dementia risk compared with sulfonylureas, although with high uncertainty (2.3 vs. 3.1 events per 1000 person-years; HR 0.74, 95% CI 0.46–1.18). The magnitude of the association increased with cumulative duration of use and dose but with high uncertainty. Conclusions In this population-based study, DPP-4 inhibitors, and possibly GLP-1 RAs, were associated with a reduced dementia risk compared with sulfonylureas.

Aims: Debate remains about the optimal initial treatment strategy for hypertension. Most guidelines recommend first‐line combination therapy for most patients. However, the UK's National Institute for Health and Care Excellence recommends first‐line monotherapy for all patients. It is unknown if first‐line combination therapy use is increasing despite this recommendation. This study aims to assess trends in prescriptions for first‐line antihypertensive monotherapy and combination therapy in UK primary care. Methods: Using the Clinical Practice Research Datalink, we formed a cohort of all patients newly diagnosed with hypertension between 2011 and 2019. We calculated annual proportions of patients newly prescribed first‐line monotherapy and combination therapy within 3 months of diagnosis. We used Kaplan–Meier methods to estimate the median treatment persistence, and the probability of persistence at 6 months and 1 year for mono‐ and combination therapy. Results: Among 535 234 patients with hypertension, 1.7% received first‐line combination therapy, while 85.6% received monotherapy. Rates of initiation varied by age and hypertension stage. Median treatment persistence was 298 (95% confidence interval [CI] 276–318) days on first‐line combination therapy, compared to 398 (95% CI 394–403) days on monotherapy. At 6 months, 58.2% (95% CI 57.2%–59.3%) of combination therapy and 62.2% (95% CI 62.1%–62.4%) of monotherapy initiators remained on first‐line treatment; at 1 year the numbers fell to 46.4% (95% CI 45.4%–47.6%) and 51.2% (95% CI 51.1%–51.4%), respectively. Conclusions: First‐line antihypertensive combination therapy remains exceedingly rare in the UK in accordance with National Institute for Health and Care Excellence guidelines, but in contrast to other international recommendations. Treatment persistence was lower on first‐line combination therapy than monotherapy.

Aims: To assess whether rivaroxaban is associated with a decreased risk of major adverse limb events (MALE), stroke, systemic embolism (SE), and major bleeding (MB) among patients with non-valvular atrial fibrillation (NVAF) and peripheral artery disease (PAD), compared with apixaban. Methods and results: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. Patients aged ≥45 years with incident NVAF and PAD who initiated rivaroxaban or apixaban between 2013 and 2021 were included. Primary effectiveness outcomes were MALE, and a composite of ischaemic stroke, transient ischaemic attack (TIA), or SE. The primary safety outcome was MB. The risk of major cardiovascular events (MACE) was assessed as a secondary outcome. Confounding was addressed using propensity score fine stratification and weighting. Weighted Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). The cohort included 6170 new users of rivaroxaban and 9990 new users of apixaban (44% female; mean [SD] age 78.5 [9.2] years). Incidence rates were similar for MALE (6.7 vs. 5.6/1000 person-years; adjusted HR (aHR): 1.20; 95% CI 0.87–1.65), stroke/TIA/SE (24.5 vs. 21.3/1000 person-years; aHR: 1.15; 95% CI 0.97–1.36), and MACE (40.1 vs. 35.9 per 1000 person-years; aHR 1.10: 95% CI 0.94–1.28). Major bleeding rates were higher with rivaroxaban (46.1 vs. 29.8/1000 person-years; aHR: 1.55; 95% CI 1.36–1.77). Conclusion: In patients with NVAF and PAD, rivaroxaban was associated with a similar risk of MALE and stroke/TIA/SE, but a higher risk of MB compared with apixaban. These findings support apixaban as a potentially safer anticoagulant in this high-risk population.

Objectives To describe the impact of the COVID-19 pandemic on hypertension diagnosis and management in UK primary care. Design Population-based cohort study. Setting Over 2000 general practices across the UK contributing to the Clinical Practice Research Datalink. Participants A cohort of 23 076 390 patients over 18 years of age and registered with their general practice for at least 1 year between 2011 and 2022, who did not have a previous diagnosis of hypertension. From these patients, a subcohort of 712 461 patients diagnosed with hypertension between 2011 and 2022 was selected. Primary and secondary outcome measures Coprimary outcomes included rates of hypertension diagnosis and rates of antihypertensive treatment initiation, treatment change and blood pressure measurement in patients newly diagnosed with hypertension. Results In April 2020, the first month of lockdown, incident hypertension diagnosis rates fell by 65% (95% CI 64% to 67%) compared with historical trends and remained depressed until November 2021, leading to 51 000 fewer diagnoses than expected by March 2022. However, by March 2022, there were 2.6% fewer diagnoses than expected in Scotland, compared with 20%–30% fewer in other UK Nations. Rates of treatment initiation and change fell by 47% (95% CI 43% to 51%) and 36% (95% CI 33% to 38%), respectively, in April 2020. However, initiation rates rebounded above expectations and remained elevated until March 2022. Blood pressure measurements fell by 69% (95% CI 65% to 72%) in April 2020, recovering in February 2021. Conclusions Hypertension diagnosis and management in UK primary care were significantly disrupted during the COVID-19 pandemic. Future studies should investigate the potential clinical implications for the cardiovascular health of the UK population.

Importance: There is uncertainty as to whether treatment of subclinical hypothyroidism (SCH) is associated with cardiovascular outcomes. Objectives: To determine whether levothyroxine replacement therapy decreases the risk of major adverse cardiovascular events (MACE) among individuals with SCH defined as having a thyrotropin (TSH) level between 5 and 10 mU/L. Design: We conducted a population-based cohort study using a prevalent new-user design. Setting: The study utilized data from the United Kingdom Clinical Practice Research Datalink. Participants: We identified a base cohort of individuals aged ≥18 years with incident SCH defined as having at least two TSH levels between 5 and 10 mU/L within one year between 1998 and 2018. We matched 76,946 levothyroxine treated to 76,946 untreated individuals based on age, sex, calendar time, duration of SCH, and time-conditional propensity score. We compared individuals with SCH treated with levothyroxine with individuals with no treatment. Exposure: Levothyroxine treatment versus no treatment. Main Outcome Measures: The primary outcome, MACE, was defined as a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, and cardiovascular-related mortality. Results: The mean age of the study cohort was 62.8 years, and 76.5% were women. During a median follow-up time of 1.6 years (interquartile range: 0.5–4.2), the incidence rate for MACE among individuals treated with levothyroxine was 12.8 per 1000 person-years; confidence interval (CI): 12.2–13.3 and 13.9 per 1000 person-years; CI: 13.4–14.3 among nontreated individuals. Levothyroxine treatment was associated with a small decreased risk of MACE (hazard ratio: 0.88; CI: 0.83–0.93). Conclusions: Levothyroxine treatment of SCH was associated with a small decreased risk of MACE. However, given the observational nature of the study, residual confounding should be considered in the interpretation of this finding.