Broad versus narrow research questions in evidence synthesis: A parallel to (and plea for) estimands.

There has been a transition from broad to more specific research questions in the practice of network meta-analysis (NMA). Such convergence is also taking place in the context of individual registrational trials, following the recent introduction of the estimand framework, which is impacting the design, data collection strategy, analysis and interpretation of clinical trials. The language of estimands has much to offer to NMA, particularly given the "narrow" perspective of treatments and target populations taken in health technology assessment.

An Indirect Comparison of Basal Insulin Plus Once-Weekly Semaglutide and Fully Optimised Basal-Bolus Insulin in Type 2 Diabetes.

INTRODUCTION: To date, there have been few head-to-head comparisons between semaglutide once-weekly (OW) and short-acting meal-time insulin in participants with type 2 diabetes (T2D) treated with basal insulin and requiring treatment intensification. This indirect comparison evaluated the effects of these regimens on glycated haemoglobin (HbA1c), body weight, hypoglycaemia, and other clinically relevant outcomes. METHODS: A post-hoc, unanchored, individual participant data meta-analysis was conducted on the basis of data from single treatment arms in the SUSTAIN 5 and DUAL 7 trials. Semaglutide 0.5 mg OW and 1.0 mg OW plus basal insulin were compared with an optimised (treat-to-target) basal-bolus regimen of insulin glargine and insulin aspart over 26 weeks, using regression adjustment to account for baseline differences between the trials. RESULTS: Over 26 weeks, semaglutide 1.0 mg OW plus basal insulin reduced mean HbA1c by significantly more than the basal-bolus regimen (treatment difference: - 0.36%; p = 0.003), while semaglutide 0.5 mg OW plus basal insulin was comparable with basal-bolus insulin (treatment difference: 0.08%, p = 0.53). Both doses of semaglutide were associated with significant weight loss relative to insulin intensification (treatment differences: 6.8-9.4 kg; p < 0.001). At both doses, semaglutide intensification required less basal insulin per day than bolus intensification, and more participants on semaglutide met HbA1c targets of < 7.0% and ≤ 6.5% without hypoglycaemia or weight gain (odds ratio [OR] for < 7.0%, 21.9; OR for ≤ 6.5%, 16.2; both p < 0.001). CONCLUSIONS: In T2D uncontrolled by basal insulin, intensification with semaglutide 1.0 mg OW was associated with better glycaemic control, weight loss, and reduced hypoglycaemia versus a basal-bolus regimen, while limiting the treatment burden associated with frequent injections. Clinicians could consider treatment intensification with semaglutide when T2D is uncontrolled by basal insulin, especially when weight management is a priority. Effective glycaemic control coupled with weight management can alleviate the burden of diabetes-associated complications.

Fast tipping point sensitivity analyses in clinical trials with missing continuous outcomes under multiple imputation.

When dealing with missing data in clinical trials, it is often convenient to work under simplifying assumptions, such as missing at random (MAR), and follow up with sensitivity analyses to address unverifiable missing data assumptions. One such sensitivity analysis, routinely requested by regulatory agencies, is the so-called tipping point analysis, in which the treatment effect is re-evaluated after adding a successively more extreme shift parameter to the predicted values among subjects with missing data. If the shift parameter needed to overturn the conclusion is so extreme that it is considered clinically implausible, then this indicates robustness to missing data assumptions. Tipping point analyses are frequently used in the context of continuous outcome data under multiple imputation. While simple to implement, computation can be cumbersome in the two-way setting where both comparator and active arms are shifted, essentially requiring the evaluation of a two-dimensional grid of models. We describe a computationally efficient approach to performing two-way tipping point analysis in the setting of continuous outcome data with multiple imputation. We show how geometric properties can lead to further simplification when exploring the impact of missing data. Lastly, we propose a novel extension to a multi-way setting which yields simple and general sufficient conditions for robustness to missing data assumptions.

Continuous Glucose Monitoring Sensor Glucose Levels and Insulin Pump Infusion Set Wear-Time During Treatment with Fast-Acting Insulin Aspart: A Post Hoc Analysis of Onset 5.

Background: In the onset 5 trial, fast-acting insulin aspart (faster aspart) was noninferior to insulin aspart (IAsp) for change from baseline glycated hemoglobin at 16 weeks, when used in continuous subcutaneous insulin infusion by participants with type 1 diabetes. The aim of this post hoc analysis was to investigate whether infusion set wear-time was associated with changes in sensor glucose, measured using continuous glucose monitoring (CGM). Materials and Methods: This was a post hoc analysis of onset 5 data. Mean infusion set wear-time and duration of CGM-wearing period were assessed. Mean CGM sensor glucose 24 h before and 24 h after were used to calculate the before-after difference (CGM sensor glucose drift). Results: Mean infusion set wear-time was 2.9 and 3.0 days in the faster aspart and IAsp arms, respectively. At 16 weeks, the average duration of the CGM wearing period was 13.7 and 13.8 days, respectively. Mean CGM sensor glucose before versus after an infusion set change, at week 16, was 10.14 versus 9.39 mmol/L with faster aspart and 9.48 versus 9.47 mmol/L with IAsp. The estimated treatment difference in CGM sensor glucose drift at 16 weeks for faster aspart versus IAsp was +0.72 mmol/L (95% confidence interval: 0.48-0.96, P < 0.001). Conclusions: Mean infusion set wear-time and duration of CGM-wearing period were similar for faster aspart and IAsp. A significantly greater upward drift in CGM sensor glucose values measured during an infusion set wearing period was observed with faster aspart versus IAsp. Clinical trial registration: NCT02825251.

An indirect treatment comparison of the efficacy of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg.

AIM: To compare the effects of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg on HbA1c and body weight in patients with type 2 diabetes. MATERIALS AND METHODS: A Bucher indirect comparison was conducted to compare efficacy outcomes of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg using published results from the SUSTAIN 7 and AWARD-11 trials. Sensitivity analyses using individual patient data from SUSTAIN 7 and aggregate data from AWARD-11 were conducted to explore the impact of adjustment for cross-trial imbalances in baseline characteristics. RESULTS: Semaglutide 1.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg, with an estimated treatment difference (ETD) of -0.24%-points (95% confidence interval [CI] -0.43, -0.05), with comparable reductions in HbA1c versus dulaglutide 4.5 mg with an ETD of -0.07%-points (95% CI -0.26, 0.12). Semaglutide 1.0 mg significantly reduced body weight versus dulaglutide 3.0 and 4.5 mg with an ETD of -2.65 kg (95% CI -3.57, -1.73) and -1.95 kg (95% CI -2.87, -1.03), respectively. Sensitivity analyses supported the primary analysis findings. CONCLUSIONS: This indirect comparison showed significantly greater reductions in HbA1c with semaglutide 1.0 mg versus dulaglutide 3.0 mg and comparable HbA1c reductions versus dulaglutide 4.5 mg. Semaglutide 1.0 mg significantly reduced body weight versus both dulaglutide 3.0 and 4.5 mg. With several glucagon-like peptide-1 receptor agonists available, information regarding their comparative efficacy can be valuable to clinicians.

Efficacy and Safety of Fast-Acting Insulin Aspart in People with Type 1 Diabetes Using Carbohydrate Counting: A Post Hoc Analysis of Two Randomised Controlled Trials.

INTRODUCTION: Insulin dosing based on carbohydrate counting is the gold standard for improving glycaemic control in type 1 diabetes (T1D). This post hoc analysis aimed to explore the efficacy and safety of fast-acting insulin aspart (faster aspart) according to bolus dose adjustment method in people with T1D. METHODS: Post hoc analysis of two 26-week, treat-to-target, randomised trials investigating treatment with double-blind mealtime faster aspart, insulin aspart (IAsp), or open-label post-meal faster aspart (onset 1, n = 1143; onset 8, n = 1025). Participants with previous experience continued carbohydrate counting (onset 1, n = 669 [58.5%]; onset 8, n = 428 [41.8%]), while remaining participants used a bolus algorithm. RESULTS: In onset 1, HbA1c reduction was statistically significantly in favour of mealtime faster aspart versus IAsp with carbohydrate counting (estimated treatment difference [ETD 95% CI] - 0.19% [- 0.30; - 0.09]; - 2.08 mmol/mol [- 3.23; - 0.93]). In onset 8, there was no statistically significant difference in HbA1c reduction with either dose adjustment method, although a trend towards improved HbA1c was observed for mealtime faster aspart with carbohydrate counting (ETD - 0.14% [- 0.28; 0.003]; - 1.53 mmol/mol [- 3.10; 0.04]). In both trials, bolus insulin doses and overall rates of severe or blood glucose-confirmed hypoglycaemia were similar between treatments across dose adjustment methods. CONCLUSION: For people with T1D using carbohydrate counting, mealtime faster aspart may offer improved glycaemic control versus IAsp, with similar insulin dose and weight gain and no increased risk of hypoglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01831765 (onset 1) and NCT02500706 (onset 8). FUNDING: Novo Nordisk.

Trans fatty acids in adipose tissue and risk of myocardial infarction: A case-cohort study.

BACKGROUND: The risk of coronary heart disease associated with intake of individual trans fatty acids (TFAs) is not clear. Adipose tissue content of TFAs is a biomarker of TFA intake and metabolism. OBJECTIVE: We investigated the rate of myocardial infarction (MI) associated with the adipose tissue content of total 18:1t, isomers of 18:1t (18:1 Δ6-10t and 18:1 Δ11t) and 18:2 Δ9c, 11t. METHODS: A case-cohort study, nested within the Danish Diet, Cancer and Health cohort (n = 57,053), was conducted, which included a random sample (n = 3156) of the total cohort and all incident MI cases (n = 2148) during follow-up (14 years). Information on MI cases was obtained by linkage with nationwide registers and validated. Adipose tissue was taken from the participants buttocks and the fatty acid composition was determined by gas chromatography. RESULTS: Women with higher adipose tissue content of total 18:1t had a 57% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.57; 95% confidence interval, 1.12-2.20; P-trend = 0.011) and women with higher content of 18:1 Δ6-10t had a 76% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.76; 95% confidence interval, 1.23-2.51; P-trend = 0.002). No association between 18:1 Δ11t content and MI rate was observed. In men, no associations between adipose tissue content of total 18:1t and 18:1 Δ6-10t and MI rate were observed. However, men with higher content of 18:1 Δ11t had a 48% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.48; 95% confidence interval, 1.17-1.86; P-trend = 0.003). Adipose tissue content of 18:2 Δ9c, 11t was not associated with MI rate in women or men. CONCLUSIONS: Adipose tissue content of 18:2 Δ9c, 11t was not associated with MI rate in women or men, whereas higher contents of isomers of 18:1t were associated with higher MI rates but the associations for individual 18:1t isomers differed, however, in women and men.

White Matter Hyperintensities Improve Ischemic Stroke Recurrence Prediction.

BACKGROUND: Nearly one in 5 patients with ischemic stroke will invariably experience a second stroke within 5 years. Stroke risk stratification schemes based solely on clinical variables perform only modestly in non-atrial fibrillation (AF) patients and improvement of these schemes will enhance their clinical utility. Cerebral white matter hyperintensities are associated with an increased risk of incident ischemic stroke in the general population, whereas their association with the risk of ischemic stroke recurrence is more ambiguous. In a non-AF stroke cohort, we investigated the association between cerebral white matter hyperintensities and the risk of recurrent ischemic stroke, and we evaluated the predictive performance of the CHA2DS2VASc score and the Essen Stroke Risk Score (clinical scores) when augmented with information on white matter hyperintensities. METHODS: In a registry-based, observational cohort study, we included 832 patients (mean age 59.6 (SD 13.9); 42.0% females) with incident ischemic stroke and no AF. We assessed the severity of white matter hyperintensities using MRI. Hazard ratios stratified by the white matter hyperintensities score and adjusted for the components of the CHA2DS2VASc score were calculated based on the Cox proportional hazards analysis. Recalibrated clinical scores were calculated by adding one point to the score for the presence of moderate to severe white matter hyperintensities. The discriminatory performance of the scores was assessed with the C-statistic. RESULTS: White matter hyperintensities were significantly associated with the risk of recurrent ischemic stroke after adjusting for clinical risk factors. The hazard ratios ranged from 1.65 (95% CI 0.70-3.86) for mild changes to 5.28 (95% CI 1.98-14.07) for the most severe changes. C-statistics for the prediction of recurrent ischemic stroke were 0.59 (95% CI 0.51-0.65) for the CHA2DS2VASc score and 0.60 (95% CI 0.53-0.68) for the Essen Stroke Risk Score. The recalibrated clinical scores showed improved C-statistics: the recalibrated CHA2DS2VASc score 0.62 (95% CI 0.54-0.70; p = 0.024) and the recalibrated Essen Stroke Risk Score 0.63 (95% CI 0.56-0.71; p = 0.031). C-statistics of the white matter hyperintensities score were 0.62 (95% CI 0.52-0.68) to 0.65 (95% CI 0.58-0.73). CONCLUSIONS: An increasing burden of white matter hyperintensities was independently associated with recurrent ischemic stroke in a cohort of non-AF ischemic stroke patients. Recalibration of the CHA2DS2VASc score and the Essen Stroke Risk Score with one point for the presence of moderate to severe white matter hyperintensities led to improved discriminatory performance in ischemic stroke recurrence prediction. Risk scores based on white matter hyperintensities alone were at least as accurate as the established clinical risk scores in the prediction of ischemic stroke recurrence.

Death and thrombo-embolic risk after ablation of atrial flutter compared with atrial fibrillation: a nationwide cohort study.

AIMS: The aim of this study was to investigate whether there is a similar mortality and thrombo-embolic risk, after an atrial ablation procedure, compared with an atrial fibrillation (AF) procedure. METHODS AND RESULTS: Using data from nationwide Danish health registries, we identified patients aged 18-75 years undergoing a first-time atrial flutter or an AF ablation procedure in the period 2000-13. Cox proportional hazards regression was used to calculate hazard ratios (HRs) after 5 years of follow-up, adjusting for concomitant risk factors. A total of 1096 and 2266 patients underwent an ablation for atrial flutter or AF, respectively. Age distribution was similar in the two, but atrial flutter patients had more co-morbidities. During 5 years of follow-up, we observed 38 and 36 deaths in the atrial flutter and AF groups, corresponding to an almost two-fold higher mortality rate among atrial flutter patients [crude HR 1.92, 95% confidence interval (CI) 1.22-3.03]. The higher mortality rate persisted after adjustment for age, sex, diabetes mellitus, and hypertension (adjusted HR 1.68, 95% CI 1.05-2.69). The rate of thrombo-embolic events was similar in the two groups (crude HR 1.34, 95% CI 0.71-2.56; adjusted HR 1.22, 95% CI 0.62-2.41). CONCLUSION: In this observational study, patients with atrial flutter had a significantly higher all-cause mortality rate compared with those with AF after an ablation procedure, but similar thrombo-embolic event rates. Future studies should elucidate the reason for this difference in mortality.

Rivaroxaban versus warfarin and dabigatran in atrial fibrillation: comparative effectiveness and safety in Danish routine care.

PURPOSE: To evaluate effectiveness and safety of rivaroxaban versus warfarin or dabigatran etexilate in a prospective cohort of routine care non-valvular atrial fibrillation (AF) patients during February 2012 to August 2014. METHODS: We identified in nationwide health registries a cohort of AF patients who were new-users of rivaroxaban 15 mg (R15) or 20 mg (R20); dabigatran 110 mg (D110) or 150 mg (D150); or warfarin. Propensity-adjusted Cox regression was used to compare outcome rates in four settings: 'R15 vs. warfarin'; 'R15 vs. D110'; 'R20 vs. warfarin'; and 'R20 vs. D150'. RESULTS: Rivaroxaban users (R15: n = 776; R20: n = 1629) were older and with more comorbidities than warfarin (n = 11 045) and dabigatran users (D110: n = 3588; D150: n = 5320). Rivaroxaban 15-mg users had the overall highest crude mortality rate. After propensity adjustment, rivaroxaban had lower stroke rates vs. warfarin (R15: hazard ratio [HR] 0.46, 95% confidence interval [CI]: 0.26-0.82; R20 HR: 0.72, 95%CI: 0.51-1.01), and similar stroke rates vs. dabigatran. The bleeding rate was similar to warfarin and moderately higher vs. dabigatran (R15 vs. D110 HR: 1.28, 95%CI: 0.82-2.01; R20 vs. D150 HR: 1.81, 95%CI: 1.25-2.62). The mortality rate was higher vs. dabigatran (R15 vs. D110 HR: 1.43, 95%CI: 1.13-1.81; R20 vs. D150 HR: 1.52, 95%CI: 1.06-2.19). CONCLUSIONS: Rivaroxaban was associated with similar or lower stroke rates, but higher bleeding and mortality rates. Channeling of rivaroxaban towards elderly and less healthy patients may have generated residual confounding. In particular, our findings cannot stand alone when deciding which oral anticoagulant to prescribe. Copyright © 2016 John Wiley & Sons, Ltd.

Vascular Disease and Risk Stratification for Ischemic Stroke and All-Cause Death in Heart Failure Patients without Diagnosed Atrial Fibrillation: A Nationwide Cohort Study.

BACKGROUND: Stroke and mortality risk among heart failure patients previously diagnosed with different manifestations of vascular disease is poorly described. We conducted an observational study to evaluate the stroke and mortality risk among heart failure patients without diagnosed atrial fibrillation and with peripheral artery disease (PAD) or prior myocardial infarction (MI). METHODS: Population-based cohort study of patients diagnosed with incident heart failure during 2000-2012 and without atrial fibrillation, identified by record linkage between nationwide registries in Denmark. Hazard rate ratios of ischemic stroke and all-cause death after 1 year of follow-up were used to compare patients with either: a PAD diagnosis; a prior MI diagnosis; or no vascular disease. RESULTS: 39,357 heart failure patients were included. When compared to heart failure patients with no vascular disease, PAD was associated with a higher 1-year rate of ischemic stroke (adjusted hazard rate ratio [HR]: 1.34, 95% confidence interval [CI]: 1.08-1.65) and all-cause death (adjusted HR: 1.47, 95% CI: 1.35-1.59), whereas prior MI was not (adjusted HR: 1.00, 95% CI: 0.86-1.15 and 0.94, 95% CI: 0.89-1.00, for ischemic stroke and all-cause death, respectively). When comparing patients with PAD to patients with prior MI, PAD was associated with a higher rate of both outcomes. CONCLUSIONS: Among incident heart failure patients without diagnosed atrial fibrillation, a previous diagnosis of PAD was associated with a significantly higher rate of the ischemic stroke and all-cause death compared to patients with no vascular disease or prior MI. Prevention strategies may be particularly relevant among HF patients with PAD.

Diabetes mellitus and risk of ischemic stroke in patients with heart failure and no atrial fibrillation.

OBJECTIVE: The risk of ischemic stroke, systemic thromboembolism, and all-cause death among heart failure patients previously diagnosed with diabetes mellitus is poorly described. We evaluated the risk of these endpoints among heart failure patients without diagnosed atrial fibrillation according to the presence of diabetes mellitus. METHODS: Population-based nationwide cohort study of non-anticoagulated patients diagnosed with incident heart failure during 2000-2012, identified by record linkage between nationwide registries in Denmark. We calculated relative risks after 1year to evaluate the association between diabetes and risk of events in 39,357 heart failure patients, among whom 18.1% had diabetes. Analysis took into account competing risks of death. RESULTS: Absolute risks of all endpoints were higher in patients with diabetes compared to patients without diabetes after 1-year follow-up (ischemic stroke: 4.1% vs. 2.8%; systemic thromboembolism: 11.9% vs. 8.6%; all-cause death: 22.1% vs. 21.4%). Diabetes was significantly associated with an increased risk of ischemic stroke (adjusted relative risk [RR]: 1.27, 95% confidence interval [CI]: 1.07-1.51); systemic thromboembolism (RR: 1.20, 95% CI: 1.11-1.30); and all-cause death (RR: 1.17, 95% CI: 1.11-1.23). Additionally, time since diabetes diagnosis was associated with higher adjusted cumulative incidences of ischemic stroke, systemic thromboembolism, and all-cause death (p for trend, p<0.001). CONCLUSIONS: Among heart failure patients without atrial fibrillation, diabetes was associated with a significantly increased risk of ischemic stroke, systemic thromboembolism, and all-cause death compared to those without diabetes, even after adjustment for concomitant cardiovascular risk factors. Increased focus on secondary prevention in heart failure patients with diabetes may be warranted.

Anticoagulant therapy after venous thromboembolism and 10-year mortality.

BACKGROUND: Pulmonary embolism (PE) is associated with a higher long-term mortality than deep vein thrombosis (DVT). This association may be related to inadequate antithrombotic therapy. METHODS: Incident VTE patients during the period 1997-2012 were identified in Danish nationwide registries. Two landmark populations were defined, consisting of patients alive at 30 days (30 d), and at 180 days (180 d) after discharge. Patients were classified according to anticoagulant usage at the landmark (30 d: prescription purchase 0-30 d post-discharge; 180 d: prescription purchase in 0-30 d and 90-180 d). Mortality rates were compared using multivariate Cox regression. RESULTS: The 30 d mortality risk among PE patients was high compared to DVT patients (19.9% vs. 4.4%). In the 30 d-landmark population (n=62695), 34.9% of DVT patients and 21.3% of PE patients had not redeemed a prescription for anticoagulants. There was no material difference in 10-year mortality between anticoagulated PE patients and anticoagulated DVT patients. There was a higher 10-year mortality rate among non-anticoagulated PE patients compared to anticoagulated DVT patients (MRR: 1.26, 95% CI: 1.20-1.33). Findings in the 180 d-landmark population also indicated materially similar 10-year mortality rates between anticoagulated PE patients and anticoagulated DVT patients. CONCLUSIONS: The 10-year mortality rate of patients surviving the initial 30 d critical period following incident PE was not increased compared to patients with incident DVT, as long as patients initiated and persisted with anticoagulant therapy. Increased focus on antithrombotic therapy in PE patients and reasons for early therapy discontinuation may be warranted.

ß-Blockers in Atrial Fibrillation Patients With or Without Heart Failure: Association With Mortality in a Nationwide Cohort Study.

BACKGROUND: Recent data suggest that ß-blockers are associated with prognostic advantages in heart failure (HF) patients without concomitant atrial fibrillation (AF), but not in HF patients with concomitant AF. We aimed to investigate associations between ß-blocker treatment and cardiovascular outcome and mortality in AF patients with and without HF. METHODS AND RESULTS: Three nationwide registries were used to identify patients with nonvalvular AF patients with or without concomitant HF. Patients were stratified into ß-blocker users and ß-blocker nonusers, and according to the presence of a HF diagnosis. We followed the patients ≤ 5 years after baseline. Six different cardiovascular outcomes were investigated, including all-cause mortality and fatal thromboembolic events. Crude event rates were ascertained and propensity-matched Cox regression was used to compare event rates according to ß-blocker usage status. A total of 205,174 patients were included, where 39,741 patients had prevalent HF. In the latter subgroup of patients, the 1-year propensity-matched hazard ratio (HR) for all-cause mortality was 0.75 (95% confidence interval, 0.71-0.79; nontreated used as reference). For patients without concomitant HF, the propensity-matched HR for all-cause mortality was 0.78 (95% confidence interval, 0.71-0.76). CONCLUSIONS: In this large nationwide cohort study, evidence of a lower mortality with ß-blocker therapy in AF patients with concomitant HF was observed. In addition, this association was accompanied with indications that ß-blocker treatment is also associated with a better prognosis in AF patients without concomitant HF.

Assessment of the CHA2DS2-VASc Score in Predicting Ischemic Stroke, Thromboembolism, and Death in Patients With Heart Failure With and Without Atrial Fibrillation.

IMPORTANCE: The CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is used clinically for stroke risk stratification in atrial fibrillation (AF). Its usefulness in a population of patients with heart failure (HF) is unclear. OBJECTIVE: To investigate whether CHA2DS2-VASc predicts ischemic stroke, thromboembolism, and death in a cohort of patients with HF with and without AF. DESIGN, SETTING, AND POPULATION: Nationwide prospective cohort study using Danish registries, including 42 987 patients (21.9% with concomitant AF) not receiving anticoagulation who were diagnosed as having incident HF during 2000-2012. End of follow-up was December 31, 2012. EXPOSURES: Levels of the CHA2DS2-VASc score (based on 10 possible points, with higher scores indicating higher risk), stratified by concomitant AF at baseline. Analyses took into account the competing risk of death. MAIN OUTCOMES AND MEASURES: Ischemic stroke, thromboembolism, and death within 1 year after HF diagnosis. RESULTS: In patients without AF, the risks of ischemic stroke, thromboembolism, and death were 3.1% (n = 977), 9.9% (n = 3187), and 21.8% (n = 6956), respectively; risks were greater with increasing CHA2DS2-VASc scores as follows, for scores of 1 through 6, respectively: (1) ischemic stroke with concomitant AF: 4.5%, 3.7%, 3.2%, 4.3%, 5.6%, and 8.4%; without concomitant AF: 1.5%, 1.5%, 2.0%, 3.0%, 3.7%, and 7% and (2) all-cause death with concomitant AF: 19.8%, 19.5%, 26.1%, 35.1%, 37.7%, and 45.5%; without concomitant AF: 7.6%, 8.3%, 17.8%, 25.6%, 27.9%, and 35.0%. At high CHA2DS2-VASc scores (≥4), the absolute risk of thromboembolism was high regardless of presence of AF (for a score of 4, 9.7% vs 8.2% for patients without and with concomitant AF, respectively; overall P<.001 for interaction). C statistics and negative predictive values indicate that the CHA2DS2-VASc score performed modestly in this HF population with and without AF (for ischemic stroke, 1-year C statistics, 0.67 [95% CI, 0.65-0.68] and 0.64 [95% CI, 0.61-0.67], respectively; 1-year negative predictive values, 92% [95% CI, 91%-93%] and 91% [95% CI, 88%-95%], respectively). CONCLUSIONS AND RELEVANCE: Among patients with incident HF with or without AF, the CHA2DS2-VASc score was associated with risk of ischemic stroke, thromboembolism, and death. The absolute risk of thromboembolic complications was higher among patients without AF compared with patients with concomitant AF at high CHA2DS2-VASc scores. However, predictive accuracy was modest, and the clinical utility of the CHA2DS2-VASc score in patients with HF remains to be determined.

Recurrent Stroke: The Value of the CHA2DS2VASc Score and the Essen Stroke Risk Score in a Nationwide Stroke Cohort.

BACKGROUND AND PURPOSE: The CHA2DS2VASc score and the Essen Stroke Risk Score are respectively used for risk stratification in patients with atrial fibrillation and in patients with cerebrovascular incidents. We aimed to test the ability of the 2 scores to predict stroke recurrence, death, and cardiovascular events (stroke, transient ischemic attack, myocardial infarction, or arterial thromboembolism) in a nationwide Danish cohort study, among patients with incident ischemic stroke and no atrial fibrillation. METHODS: We conducted a registry-based study in patients with incident ischemic stroke and no atrial fibrillation. Patients were stratified according to the CHA2DS2VASc score and the Essen Stroke Risk Score and were followed up until stroke recurrence or death. We estimated stratified incidence rates and hazard ratios and calculated the cumulative risks. RESULTS: 42 182 patients with incident ischemic stroke with median age 70.1 years were included. The overall 1-year incidence rates of recurrent stroke, death, and cardiovascular events were 3.6%, 10.5%, and 6.7%, respectively. The incidence rates, the hazard ratios, and the cumulative risk of all outcomes increased with increasing risk scores. C-statistics for both risk scores were around 0.55 for 1-year stroke recurrence and cardiovascular events and correspondingly for death around 0.67 for both scores. CONCLUSIONS: In this cohort of non-atrial fibrillation patients with incident ischemic stroke, increasing CHA2DS2VASc score and Essen Stroke Risk Score was associated with increasing risk of recurrent stroke, death, and cardiovascular events. Their discriminatory performance was modest and further refinements are required for clinical application.

Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding: A Nationwide Cohort Study.

BACKGROUND: Intracranial hemorrhage is the most feared complication of oral anticoagulant treatment. The optimal treatment option for patients with atrial fibrillation who survive an intracranial hemorrhage remains unknown. We hypothesized that restarting oral anticoagulant treatment was associated with a lower risk of stroke and mortality in comparison with not restarting. METHODS AND RESULTS: Linkage of 3 Danish nationwide registries in the period between 1997 and 2013 identified patients with atrial fibrillation on oral anticoagulant treatment with incident intracranial hemorrhage. Patients were stratified by treatment regimens (no treatment, oral anticoagulant treatment, or antiplatelet therapy) after the intracranial hemorrhage. Event rates were assessed 6 weeks after hospital discharge and compared with Cox proportional hazard models. In 1752 patients (1 year of follow-up), the rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for patients treated with oral anticoagulants was 13.6, in comparison with 27.3 for nontreated patients and 25.7 for patients receiving antiplatelet therapy. The rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for recurrent intracranial hemorrhage, the rate of ischemic stroke/systemic embolism, and all-cause mortality (per 100 person-years) patients treated with oral anticoagulants was 8.0, in comparison with 8.6 for nontreated patients and 5.3 for patients receiving antiplatelet therapy. The adjusted hazard ratio of ischemic stroke/systemic embolism and all-cause mortality was 0.55 (95% confidence interval, 0.39-0.78) in patients on oral anticoagulant treatment in comparison with no treatment. For ischemic stroke/systemic embolism and for all-cause mortality, hazard ratios were 0.59 (95% confidence interval, 0.33-1.03) and 0.55 (95% confidence interval, 0.37-0.82), respectively. CONCLUSIONS: Oral anticoagulant treatment was associated with a significant reduction in ischemic stroke/all-cause mortality rates, supporting oral anticoagulant treatment reintroduction after intracranial hemorrhage as feasible. Future trials are encouraged to guide clinical practice in these patients.

Female sex is associated with a lower risk of stroke in patients with heart failure.

BACKGROUND: Stroke in patients with heart failure is associated with poor outcomes. Risk stratification schemes may improve clinical decision making in this patient population. This study investigated whether female sex is a risk factor for stroke in patients with heart failure in sinus rhythm. METHODS: This is a population-based cohort study of patients diagnosed with heart failure during 2000 to 2012, identified by record linkage between nationwide Danish registries. Our primary outcome was stroke, and secondary outcome was thromboembolic event. We used relative risks (RRs) after 1 and 5 years to compare males with females within each of the following age groups: 50 to 59 years, 60 to 69 years, 70 to 79 years, 80 to 89 years, and 90+ years. Analyses took into account the competing risks of death. RESULTS: During the study period, 84,142 patients were diagnosed with heart failure, of which 39,946 (47.5%) were females. At 5-year follow-up, female sex was associated with a lower risk of stroke compared with males (adjusted overall hazard ratio 0.91, 95% CI 0.85-0.96). The observed lower risks of stroke in females were not present in the older age groups, where the competing risk of death was substantial among males in particular. When considering a more broadly defined thromboembolic end point, a decreased risk among females persisted across nearly all age groups after 5-year follow-up (adjusted overall hazard ratio 0.93, 95% CI 0.91-0.96). CONCLUSIONS: We found an association between female sex and decreased stroke risk in patients with heart failure, which persisted after adjustment for concomitant cardiovascular risk factors. The association was attenuated with increasing age, possibly because of competing risks of death.

Use of psychotropic drugs following venous thromboembolism in youth. A nationwide cohort study.

INTRODUCTION: The mental health prognosis following a venous thromboembolism in youth has not been investigated comprehensively. Using psychotropic drug purchase as a proxy for mental health status, we investigated this issue in a large cohort of young incident venous thromboembolism patients. METHODS: Using Danish nationwide administrative registries from the period 1997-2010, we identified 4,132 patients aged 13-33 years with a first-time venous thromboembolism diagnosis and no history of psychotropic drug usage. We sampled comparison cohort of random general population controls, matched individually in a 1:5 ratio based on sex and birth year. Participants were followed in prescription purchase registries for their first psychotropic drug purchase. RESULTS: Among young venous thromboembolism case cases, the 1-year risk of psychotropic drug purchase was 7.1% (95% confidence interval [CI] 6.3, 7.9) and the 5-year risk 22.1% (95% CI 20.7, 23.5). This was substantially higher than among population controls, with 1- and 5-year risk differences relative to the controls of 4.7% (95% CI 3.9, 5.5), and 10.8% (95% CI 9.4, 12.3), respectively. Adjustment for the effects of recent pregnancy or somatic provocations attenuated risk differences to 4.1% (95% CI 3.5, 5.1) after 1 year and 9.6% (95% CI 8.3, 11.2) after 5 years. CONCLUSIONS: A venous thromboembolism diagnosis in youth is associated with a poorer mental health prognosis: one in five patients are prescribed psychotropic medication within the first 5 year after diagnosis.