Ida Ehlers Albertsen

Risk of Stroke or Systemic Embolism in Atrial Fibrillation Patients Treated With Warfarin A Systematic Review and Meta-analysis

Background and Purpose— Although oral anticoagulants (OACs) are highly effective in reducing stroke risk in atrial fibrillation, some patients still sustain stroke despite being on an OAC. Our aim was to identify the risk factors that contribute to stroke risk in atrial fibrillation, although patients were taking OACs in a clinical trial setting. Methods— We identified contemporary clinical trials that investigated OACs in patients with atrial fibrillation. Event rates per year from each study and pooled event rates and relative risks, all with a 95% confidence interval, were calculated. Statistical heterogeneity was assessed using the I2 test. Results— Six trials were included in the meta-analysis, with a total of 58 883 patients randomized. Characteristics associated with a higher relative risk of stroke while on an OAC included age ≥75 years (relative risk, 1.46 [95% confidence interval, 1.25–1.69]), female sex (1.30 [1.15–1.49]), previous stroke/transient ischemic attack (1.85 [1.32–2.60]), vitamin K-antagonist naive status (for vitamin K antagonist experienced, 0.85 [0.74–0.97]), moderate and severe renal impairment (1.54 [1.30–1.81] and 2.22 [1.85–2.66], respectively, compared with normal renal function), previous aspirin use (1.19 [1.04–1.37]), Asian race (1.70 [1.42–2.03]), and a CHADS2 score of ≥3 (1.64 [1.18–2.27]). Conclusions— Stroke rates are higher on OACs with some patient clinical characteristics, that is, older age, female sex, previous stroke/transient ischemic attack, vitamin K-antagonist naive status, renal impairment, previous aspirin use, and higher CHADS2 score. The identified risk factors for stroke while on an OAC could potentially be used to consider a risk assessment tool to flag up high-risk patients while on an OAC (in this case, warfarin). Whether these risk factors apply to novel OACs is uncertain.

The Impact of Smoking on Thromboembolism and Mortality in Patients With Incident Atrial Fibrillation

BACKGROUND Smoking and atrial fibrillation (AF) are major health problems worldwide and are responsible for substantial health-care costs. Our aim was to investigate whether smoking impacts the risk of stroke and death in patients with AF. To test this hypothesis, we analyzed data from a large Danish cohort: the Diet, Cancer, and Health study. METHODS This was a cohort study of 57,053 people (27,178 men; 29,876 women) aged 50 to 64 years. The risk of thromboembolism (ischemic stroke/arterial thromboembolism) or death according to smoking habits among 3,161 patients with incident AF (mean age, 66.9 years; 2,032 men, 1,129 women) was assessed using Cox proportional hazard models after a median follow-up of 4.9 years. RESULTS Of those with AF, 34% were current smokers and 37% former smokers. After adjustment for vitamin K antagonist treatment, the hazard ratios (HRs) (95% CI) of thromboembolism or death were 3.13 (1.72-6.37) and 2.73 (2.02-3.70) among women and men who currently were heavy smokers (> 25 g/d), respectively. The associations remained after adjustment for well-established risk factors with HRs of 3.64 (1.88-7.07) and 2.17 (1.59-2.95) among women and men, respectively. In a sensitivity analysis, smoking was still strongly associated with thromboembolism or death after censoring people with a cancer diagnosis during follow-up. CONCLUSIONS Smoking is associated with a higher risk of thromboembolism or death in patients with AF even after adjusting for well-recognized risk factors used in stroke risk stratification schemes. The associations may be modified by sex, as the associations were strongest among women.BACKGROUND Smoking and atrial fibrillation (AF) are major health problems worldwide and are responsible for substantial health-care costs. Our aim was to investigate whether smoking impacts the risk of stroke and death in patients with AF. To test this hypothesis, we analyzed data from a large Danish cohort: the Diet, Cancer, and Health study. METHODS This was a cohort study of 57,053 people (27,178 men; 29,876 women) aged 50 to 64 years. The risk of thromboembolism (ischemic stroke/arterial thromboembolism) or death according to smoking habits among 3,161 patients with incident AF (mean age, 66.9 years; 2,032 men, 1,129 women) was assessed using Cox proportional hazard models after a median follow-up of 4.9 years. RESULTS Of those with AF, 34% were current smokers and 37% former smokers. After adjustment for vitamin K antagonist treatment, the hazard ratios (HRs) (95% CI) of thromboembolism or death were 3.13 (1.72-6.37) and 2.73 (2.02-3.70) among women and men who currently were heavy smokers (>25 g/d), respectively. The associations remained after adjustment for well-established risk factors with HRs of 3.64 (1.88-7.07) and 2.17 (1.59-2.95) among women and men, respectively. In a sensitivity analysis, smoking was still strongly associated with thromboembolism or death after censoring people with a cancer diagnosis during follow-up. CONCLUSIONS Smoking is associated with a higher risk of thromboembolism or death in patients with AF even after adjusting for well-recognized risk factors used in stroke risk stratification schemes. The associations may be modified by sex, as the associations were strongest among women.

Alcohol intake and prognosis of atrial fibrillation

Objective To assess alcohol intake as a risk factor for adverse events among patients with incident atrial fibrillation (AF). Design Prospective cohort study. Setting Population based cohort study and nationwide Danish registries. Patients The Danish Diet, Cancer and Health study included 57 053 participants (27 178 men and 29 875 women) aged between 50 and 64 years. The study population for this study included the 3107 participants (1999 men, 1108 women) who developed incident AF after inclusion. Main outcome measures A composite of thromboembolism or death. Results During a median follow-up of 4.9 years 608 deaths and 211 thromboembolic events occurred. Of those who developed AF, 690 (35%) men and 233 (21%) women had a high intake of alcohol (>20 drinks/week for men and >13 drinks/week for women). After adjustment for use of oral anticoagulation and components of the CHA2DS2-VASc score, men with an intake of >27 drinks/week had a higher risk for thromboembolism or death (hazard ratio (HR) 1.33, 95% CI 1.08 to 1.63) than men with an intake of <14 drinks/week. Women with an intake of >20 drinks/week also had a higher risk (HR 1.23, 95% CI 0.78 to 1.96) than women in the low intake category. The higher risk among men was primarily driven by mortality (HR 1.51, 95% CI 1.20 to 1.89), whereas the risk found among women was driven by thromboembolism (HR 1.71, 95% CI 0.81 to 3.60). Conclusions High alcohol intake predicts thromboembolism or death, even after adjustment for established clinical risk factors, and may help identify high risk AF patients who could be targeted for stroke and cardiovascular prevention strategies.

Duration of Diabetes Mellitus and Risk of Thromboembolism and Bleeding in Atrial Fibrillation Nationwide Cohort Study

Background and Purpose— Guidelines advocate anticoagulant treatment to all patients with atrial fibrillation and concomitant diabetes mellitus. The potential refinement to thromboembolic risk stratification that may spring from subdividing diabetes mellitus is unexplored. The purpose was to investigate duration of diabetes mellitus as a predictor of thromboembolism and anticoagulant-related bleeding in patients with atrial fibrillation. Methods— Using nationwide Danish registries, we identified all patients discharged from hospital with an incident diagnosis of atrial fibrillation from 2000 to 2011. Hazard ratios with 95% confidence intervals for thromboembolism and bleeding according to years of diabetes mellitus duration in categories (0–4, 5–9, 10–14, and ≥15) and as a continuous variable using cubic splines were calculated by Cox regression. Results— The study population comprised 137 222 patients with atrial fibrillation, of which 12.4% had diabetes mellitus. Compared with patients without diabetes mellitus and after adjustment for anticoagulant treatment and CHA2DS2-VASc components (congestive heart failure, hypertension, age, previous stroke, vascular disease, and sex), the risk of thromboembolism was lowest in the 0 to 4 years duration category (hazard ratio, 1.11; 95% confidence interval, 1.03–1.20), and highest in the longest duration category of ≥15 years (hazard ratio, 1.48; 95% confidence interval, 1.29–1.70). When analyzed as a continuous variable, duration of diabetes mellitus was associated with risk of thromboembolism in a dose-response-dependent manner, but not with a higher risk of bleeding during anticoagulant treatment. Conclusions— In patients with atrial fibrillation, longer duration of diabetes mellitus was associated with a higher risk of thromboembolism, but not with a higher risk of anticoagulant-related bleeding. Considering the critical balance between preventing thromboembolism and avoiding bleeding, longer duration of diabetes mellitus may favor initiation of anticoagulant therapy.

Prevention of venous thromboembolism with new oral anticoagulants versus standard pharmacological treatment in acute medically ill patients: a systematic review and meta-analysis

AbstractIntroduction: Venous thromboembolism (VTE) is a common and potentially avoidable cause of morbidity and mortality in patients hospitalized for acute medical illness. Objective: Our objective was to conduct a systematic review of studies that assessed the efficacy and safety of new oral anticoagulant (OAC) drugs versus standard pharmacological drugs and/or placebo in prevention of VTE in acute medically ill patients. Methods: PubMed.org and ClinicalTrials.gov databases were searched to identify studies that evaluated the efficacy and safety of a new OAC versus the standard pharmacological treatment and/or placebo in the prevention of VTE in medically ill patients. Relative risks (RR), weighted means and 95% CIs were calculated. Statistical heterogeneity was evaluated using Chi2 and I2 statistics.Two studies were included in the meta-analysis. The primary outcome in both studies was the composite of VTE-related death, symptomatic non-fatal pulmonary embolism (PE), symptomatic deep venous thrombosis (DVT) and asymptomatic proximal DVT. Both studies compared a factor (F)Xa inhibitor with enoxaparin in standard short-term thromboprophylaxis followed by a period where the FXa inhibitor was compared with placebo as prolonged thromboprophylaxis in medically ill patients. The primary major safety outcome in both studies was a composite of treatment-related major bleeding and clinically relevant non-major bleeding. A total of 14 629 patients were randomized. Results: Compared with subjects treated with enoxaparin followed by placebo, the RR of the primary outcome during the prolonged treatment period was 0.79 (95% CI 0.66, 0.94), the RR for the primary outcome during the first short-term treatment period was 1.03 (95% CI 0.81, 1.31). For major bleeding during the prolonged treatment period, the RR was 2.69 (95% CI 1.65, 4.39) for patients treated with an FXa inhibitor compared with enoxaparin/placebo. For major bleeding during the shorter treatment period, the RR was 2.01 (95% CI 1.10, 3.65) in favour of enoxaparin. Conclusion: In acute medically ill patients, prolonged thromboprophylaxis with an oral FXa inhibitor is more protective than regular short-term treatment with enoxaparin. However, treatment with FXa inhibitors is significantly associated with major bleeding, both in long- and short-term treatment compared with enoxaparin.

Female sex as a risk factor for thromboembolism and death in patients with incident atrial fibrillation. The prospective Danish Diet, Cancer and Health study.

Several studies have demonstrated sex differences in risk of thromboembolism and death among patients with atrial fibrillation, but it is unclear to what extent these associations relate to actual physiological differences. To date, no study has investigated sex differences with concomitant control for lifestyle related factors known to influence stroke risk. We used data from the Danish Diet, Cancer and Health study, including 57,053 participants (52% female) aged 50-64 years. The study population for this study included the 2,895 patients (36% female) with incident atrial fibrillation after inclusion. Data were linked to outcomes identified using nationwide registries. Risk of thromboembolism and death according to female sex were analysed using Cox proportional hazards models. After a median follow-up of 5.0 years, 137 men and 62 women suffered a thromboembolic event, and 349 men and 151 women died. In a crude analysis, female sex was associated with a non-significant lower risk of thromboembolism (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.61-1.11). Adjustment for differences in antithrombotic therapy, relevant comorbidities and lifestyle did not change this association (HR 0.77, 95% CI 0.55-1.13). In the final model, female sex was associated with a lower risk of death (HR 0.65, 95% CI 0.51-0.84). The associations were similar in a sensitivity analysis of women not taking hormone replacement therapy, and the effect of hormone replacement therapy use within females was non-significant for both endpoints of thromboembolism and death. In conclusion, in a relatively young population of patients with atrial fibrillation, female sex was associated with a lower risk of thromboembolism and death.

Balancing bleeding and thrombotic risk with new oral anticoagulants in patients with atrial fibrillation

Atrial fibrillation (AF) markedly increases the risk of stroke. Warfarin is highly effective for the prevention of stroke in such patients, but it is difficult to use and causes bleeding. Three new oral anticoagulants have been approved for stroke prevention in AF patients, and are at least as effective as warfarin with better bleeding profiles. These new agents have changed and simplified our approach to stroke prevention, as the threshold for initiation of oral anticoagulation is lower. All patients with AF should be risk assessed using the CHA2DS2-VASc score, and all patients with a score of 1 or above (except women with female sex as their only risk factor on the CHA2DS2-VASc score) should be considered for oral anticoagulation with one of the new agents. Formal bleeding risk assessment is essential, and can be done by using the well-validated HAS-BLED score.

Smoking, atrial fibrillation, and ischemic stroke: a confluence of epidemics

Purpose of review Smoking and atrial fibrillation are major contemporary health concerns. They commonly coexist and are frequent causes of ischemic stroke. The purpose of this article is to describe recent scientific investigations about smoking, atrial fibrillation, and ischemic stroke, with a primary focus on prevention. Recent findings Smoking predisposes to atrial fibrillation and is useful for the prediction of future atrial fibrillation. Several recent risk prediction models for adverse events associated with atrial fibrillation include smoking as a component. Smoking status identifies patients at high risk of incident atrial fibrillation, adverse events in an emergency ward after admission with atrial fibrillation, thromboembolic events following a diagnosis of atrial fibrillation, and potentially poor control of vitamin K antagonist treatment. Summary From multiple perspectives of atrial fibrillation, patients who smoke represent a high-risk population. Appropriate preventive measures targeting this endangered population are paramount. These include smoking cessation, appropriate care in the emergency ward, and careful selection of the optimal antithrombotic strategy to reduce the major burden of ischemic stroke attributed to the confluence of the epidemics of smoking and atrial fibrillation.

Risk of Recurrent Venous Thromboembolism: A Danish Nationwide Cohort Study

PURPOSE In this study, we aimed to estimate recurrence risk after incident venous thromboembolism, stratified according to unprovoked, provoked, and cancer-related venous thromboembolism in a prospective cohort of inpatients and outpatients receiving routine care. METHODS We linked nationwide Danish health registries to identify all patients with incident venous thromboembolism from January 2000 through December 2015. Rates of recurrence were calculated and Cox regression was used to compute hazard ratios (HRs) with 95% confidence intervals (CIs) by incident venous thromboembolism type after adjusting for coexisting risk factors. RESULTS The study included 73,993 patients with incident venous thromboembolism (54.1% females; mean age, 62.3 years). At 6-month follow-up, rates per 100 person-years were 6.80, 6.92, and 9.06 for provoked, unprovoked, and cancer-related venous thromboembolism, respectively. At 10-year follow-up, corresponding rates were 2.22, 2.84, and 3.70, respectively. Additionally, at 6-month follow-up, hazard rates of recurrence were comparable for patients with unprovoked venous thromboembolism 1.01 (95% CI, 0.92-1.11) and provoked. At 10-year follow-up, unprovoked venous thromboembolism (HR, 1.17; 95% CI, 1.12-1.23) and cancer-related venous thromboembolism (HR, 1.21; 95% CI, 1.12-1.32) were associated with higher risk of recurrence compared with that found in provoked venous thromboembolism. CONCLUSIONS In this nationwide cohort, patients with cancer-related venous thromboembolism had the highest risk of recurrence. At 6-month follow-up, there were similar risks of recurrence for patients with unprovoked and provoked venous thromboembolism. At 10-year follow-up, recurrence risks were similar for patients with unprovoked venous thromboembolism and patients with cancer-related venous thromboembolism. High recurrence risks in all categories indicate that further research is needed to optimize duration of extended anticoagulation for these patients.

Searching for High-Risk Venous Thromboembolism Patients Using Risk Scores: Adding to the Heap or Closing a Gap?

Venous thromboembolism (VTE) is a serious complication following orthopaedic surgery.1 However, VTE is largely preventable if patients receive appropriate thromboprophylaxis before major orthopaedic procedures. Anti-coagulation reduces the risk of VTE, but the protective effect must be weighed against the riskof bleeding. In addition, orthopaedic surgery covers a wide range of procedures with varying associated thrombotic and thromboembolic risks. Knee arthroscopy is a frequently performed orthopaedic procedure, but concomitant thromboembolic prophylaxis is controversial. Arthroscopy is often done as short, outpatient procedures in a relatively young patient population. In fact, current guidelines suggest no thromboprophylaxis for patients undergoing arthroscopy.1 This is supported by the randomized controlled trial ‘The Prevention of Thrombosis after Knee ArthroscopyTrial’ (POT-KAST), comparing thromboprophylaxis with lowmolecularweight heparinversusno treatment following knee arthroscopic in 1,451 patients2; no efficacywas found for thromboprophylaxis, as the risk of VTE was similar in the treated and untreated groups. However, risk prediction and tailored thromboprophylactic strategies for high-risk patients should be a topic for further research in patients undergoing knee arthroscopy. Accordingly, guidelines acknowledge that some high-risk patients may benefit from thromboprophylaxis—particularly those with prior VTE.1 Hence, to optimize decision-making of anti-coagulant treatment, a plethora of epidemiological studies investigating predisposing factors, along with risk stratification schemes, have been published.3,4 In this issue of the Journal, Nemeth et al aimed to identify highrisk arthroscopy patients by developing three different VTE risk prediction models, one of which is transformed into the L-TRiP (ascopy) score.2 A rigorous approach is necessary when developing and validating prediction models.5 Important aspects are (increasing) accuracy of outcome predictions, minimizing risk of over-fitting and optimism in predictions and general applicability of the clinical prediction model. Some of these steps are factored into the development and validation of the three proposed scores by Nemeth et al. Of note, two distinct populations are used: one for model derivation (the ‘MEGA’ study) and one for model validation (the ‘THE VTE’ study). The authors assessed the internal validity using bootstrapping procedures, and subsequently examined the performance of the derived model using the ‘THE VTE’ data. Comparable c-statistics were obtained in the derivation and validation cohorts, indicating similar prediction performance in other cohort settings. Despite the acceptable c-statistic of 0.77 for the L-TRiP(ascopy) score, the data applied hold a clear limitation. In the derivation cohort, only 107 cases and 26 controls had an arthroscopy done, respectively. Where in the validation cohort, only 30 cases and 3 controls had the procedure performed. c-Statistics is an appropriate measure to compare discriminative abilities of different models, because it is independent of the prevalence of the outcome.5 However, clinical utility of a prediction model is not captured by the c-statistics, but should instead be measured by (for example) the positive predictive value or negative predictive value. Such measures, on the other hand, are highly influenced by the prevalence of the outcome in a population. Consequently, accurate estimates of outcome prevalence are needed to examine clinical utility of a prediction model. Therefore, we agree with Nemeth et al that the optimal model cut-off point for predicting high-risk patients in need of thromboprophylaxis is lacking. Thus, the clinical utility of the L-TRiP(ascopy) score is currently unknown and warrants further investigation before being implemented into clinical practice.