Jonathan M. Plumb

Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients

Atrial fibrillation (AF) carries an increased risk of ischaemic stroke, and oral anticoagulation with warfarin can reduce this risk. The objective of this study was to evaluate the association between time in therapeutic International Normalised Ratio (INR) range when receiving warfarin and the risk of stroke and mortality. The study cohort included AF patients aged 40 years and older included in the UK General Practice Research Database. For patients treated with warfarin we computed the percentage of follow-up time spent within therapeutic range. Cox regression was used to assess the association between INR and outcomes while controlling for patient demographics, health status and concomitant medication. The study population included 27,458 warfarin-treated (with at least 3 INR measurements) and 10,449 patients not treated with antithrombotic therapy. Overall the warfarin users spent 63% of their time within therapeutic range (TTR). This percentage did not vary substantially by age, sex and CHA2DS2-VASc score. Patients who spent at least 70% of time within therapeutic range had a 79% reduced risk of stroke compared to patients with ≤30% of time in range (adjusted relative rate of 0.21; 95% confidence interval 0.18-0.25). Mortality rates were also significantly lower with at least 70% of time spent within therapeutic range. In conclusion, good anticoagulation control was associated with a reduction in the risk of stroke.

Warfarin treatment in patients with atrial fibrillation: Observing outcomes associated with varying levels of INR control

INTRODUCTION We aimed to determine the level of INR control associated with reduced stroke and mortality. MATERIAL AND METHODS The study used a retrospective cohort design using linked inpatient, haematology and mortality data from Cardiff and the Vale of Glamorgan, UK. Anonymised patients admitted with a diagnosis of non-valvular atrial fibrillation (NVAF) were defined as warfarin or non-warfarin treated by number of repeated International Normalised Ratio (INR) tests. Warfarin treated patients (>5 INR tests) categorised as at moderate or high risk of stroke (CHADS2 score > or = 2) with varying levels of INR control were compared to those who did not receive warfarin treatment using Cox proportional hazards models controlling for age, sex and CHADS2 score. Outcome measures were time to stroke and mortality. RESULTS 6,108 patients with NVAF were identified. 2,235 (36.6%) of these patients had five or more INR readings and of these 486 (21.7%) had CHADS2 score > or = 2. There was significant improvement in time to stroke event in those patients with INR control of greater than 70% of time in therapeutic range (2.0 to 3.0) compared with the non-warfarin treatment group. Overall survival was significantly improved for all warfarin treated groups with INR control of greater than 40% of time in range. CONCLUSIONS Patients with INR control of above 70% of time in range had a significantly reduced risk of stroke. Patient suitability for warfarin treatment should be continuously assessed based on their ability to maintain a consistently therapeutic INR.

Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis?

Summary.  Background: Practice guidelines recommend long‐term stroke prophylaxis in patients with chronic atrial fibrillation (cAF). Objectives: To examine treatment initiation and persistence and factors that influence the choice of cAF treatment. Patients/methods: This study used the General Practice Research Database, including computerized medical records of general practitioners in the UK. Patients aged 40+ years with cAF after 1 January 2000 were included. Cox proportional hazards regression models evaluated initiation and treatment continuation over time of warfarin and aspirin. Treatment discontinuation was defined as no repeat prescription within a three‐month period after the expected end of the treatment course. Results: The study population included 41 910 cAF patients. Elderly patients (aged 85+) were less likely to start warfarin [relative rate (RR) = 0.16, 95% confidence interval (CI) 0.15–0.18] and more likely to start aspirin (RR = 1.66, 95% CI 1.47–1.88) than patients aged 40–64 years. A history of dementia (RR = 0.28, 95% CI 0.17–0.44) and falls (RR = 0.76, 95% CI 0.70–0.83) also reduced the likelihood of warfarin initiation. Adjusting for age and gender, higher stroke risk (CHADS2 score) was not found to be associated with initiation of warfarin or aspirin contrary to current guidelines recommendations. One‐year persistence was 70% for warfarin and 50% for aspirin. Treatment persistence was higher in elderly patients using warfarin and aspirin. A higher CHADS2 score was associated with improved persistence only with warfarin. Conclusions: The low likelihood of patients with cAF in general practice remaining on treatment long‐term indicates that not all benefits as observed in clinical trials may be achieved in usual clinical practice.

Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme

BACKGROUND The aim of the study is to estimate the incidence and prevalence of chronic AF (cAF) in the United Kingdom and test the accuracy of the CHADS2 score for stroke prediction. METHODS The General Practice Research Database was used to identify patients aged 40+ years diagnosed with cAF and control patients. Harrells C-statistic was used to test possible improvements in CHADS2. RESULTS The study population included 51,807 cAF patients. The incidence of cAF increased by age and was higher in men than women. The prevalence of cAF has increased over time. The excess 5-year risk for stroke in cAF patients correlated well with CHADS2 as follows: score 0, 1.9% (95% CI 1.6-2.1); 1, 3.0% (95% CI 2.7-3.3); 2, 4.7% (95% CI 4.3-5.1); 3, 7.2% (95% CI 6.6-7.9); 4, 10.5% (95% CI 9.4-11.5); 5, 13.9% (95% CI 12.2-15.5); and 6, 15.8% (95% CI 13.5-18.1). Adding sex, the extension of age categories and reweighing of established risk factors improved CHADS2 accuracy (C-statistic 0.68-0.72). Applying the reclassification resulted in a substantial number of patients changing stroke risk category. CONCLUSION Atrial fibrillation is a prevalent and growing problem, which significantly increases the risk of ischemic stroke. The CHADS2 score is a good predictor of the stroke risk but could be improved.

Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty - A meta-analysis

Dabigatran etexilate has been investigated in three phase III trials for the prevention of venous thromboembolism (VTE). Health technology assessment agencies increasingly require meta-analyses of all relevant evidence for an intervention, if appropriate. The objective of this study was to perform a meta-analysis of efficacy and safety data for the recommended dose of dabigatran etexilate, 220 mg once daily (od), for VTE prophylaxis after total knee arthroplasty (TKA) and total hip arthroplasty (THA), and discuss the appropriateness of combining the data. Risk ratios (RR) for VTE and bleed end-points were estimated using fixed and random effects meta-analysis. Analyses were performed combining RE-MODEL and RE-NOVATE, which compared dabigatran etexilate with enoxaparin 40 mg od after TKA and THA, respectively, and also including RE-MOBILIZE, which compared dabigatran etexilate with enoxaparin 30 mg twice daily after TKA. Tests for statistical heterogeneity were performed using the Chi-squared statistic. No significant differences were detected between dabigatran etexilate and enoxaparin in any of the end-points analysed, either in the two trial analysis (all p > 0.15), or when all three trials were combined ( all p > 0.30). RRs (random effects) for the composite end-point total VTE and all-cause mortality were 0.95 [95% confidence intervals 0.82 - 1.10] and 1.05 [0.87 - 1.26] in the two and three trial analyses, respectively. Meta-analysis of RE-MODEL and RE-NOVATE supported the conclusions of the individual trials that dabigatran etexilate is non-inferior to enoxaparin 40 mg od, with a similar safety profile. Meta-analysis of all three trials found no significant differences between treatments in any of the end-points analysed. Heterogeneity between the trials cannot be ruled out.

Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation.

Objective To assess the cost-effectiveness of dabigatran etexilate, a new oral anticoagulant, versus warfarin and other alternatives for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation (AF). Methods A Markov model estimated the cost-effectiveness of dabigatran etexilate versus warfarin, aspirin or no therapy. Two patient cohorts with AF (starting age of <80 and ≥80 years) were considered separately, in line with the UK labelled indication. Modelled outcomes over a lifetime horizon included clinical events, quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). Results Patients treated with dabigatran etexilate experienced fewer ischaemic strokes (3.74 dabigatran etexilate vs 3.97 warfarin) and fewer combined intracranial haemorrhages and haemorrhagic strokes (0.43 dabigatran etexilate vs 0.99 warfarin) per 100 patient-years. Larger differences were observed comparing dabigatran etexilate with aspirin or no therapy. For patients initiating treatment at ages <80 and ≥80 years, the ICERs for dabigatran etexilate were £4831 and £7090/QALY gained versus warfarin with a probability of cost-effectiveness at £20 000/QALY gained of 98% and 63%, respectively. For the patient cohort starting treatment at ages <80 years, the ICER versus aspirin was £3457/QALY gained and dabigatran etexilate was dominant (ie, was less costly and more effective) compared with no therapy. These results were robust in sensitivity analyses. Conclusions This economic evaluation suggests that the use of dabigatran etexilate as a first-line treatment for the prevention of stroke and systemic embolism is likely to be cost-effective in eligible UK patients with AF.

Treatments for stroke prevention in atrial fibrillation: A network meta-analysis and indirect comparisons versus dabigatran etexilate

Patients with atrial fibrillation at moderate to high risk of stroke are not always anticoagulated despite a lack of contraindications to vitamin K antagonists (VKAs) like warfarin. These patients are treated with aspirin, aspirin-clopidogrel combination therapy or even receive no thromboprophylaxis. The oral direct thrombin inhibitor, dabigatran etexilate 150 mg BID and 110 mg BID, might represent an alternative for these patients; however, no head-to-head clinical trial data exist versus these alternative treatments. A network meta-analysis (NMA) was performed to indirectly compare dabigatran etexilate with antiplatelets and placebo. Compared with placebo, dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke (ischaemic and haemorrhagic) by 75% (relative risk [RR] 0.25; 95% confidence interval [CI] 0.12-0.51), ischaemic stroke by 77% (RR 0.23; 95% CI 0.14-0.38), systemic embolism by 83% (RR 0.17; 95% CI 0.05-0.50) and mortality by 36% (RR 0.64; 95% CI 0.45-0.91). Dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke compared with aspirin monotherapy by 63% (RR 0.37; 95% CI 0.20-0.69) and aspirin plus clopidogrel by 61% (RR 0.39; 95% CI 0.21-0.72). Trends toward reduced risk with both dabigatran etexilate regimens were found for most clinical outcomes. Relative risk estimates of dabigatran etexilate versus adjusted-dose VKAs within the NMA were consistent with results from the head-to-head randomised trial of these two strategies. Indirect evidence suggests treatment with dabigatran etexilate offers benefit for the prevention of stroke, systemic embolism and mortality over antiplatelets and placebo. There was no indication of increased intracranial or extracranial haemorrhage with dabigatran etexilate compared to antiplatelet agents.

How effective are dose-adjusted warfarin and aspirin for the prevention of stroke in patients with chronic atrial fibrillation? An analysis of the UK General Practice Research Database.

The objective of this study was to evaluate the rate of stroke associated with aspirin and warfarin in routine clinical practice. The study included patients aged 40+ with chronic atrial fibrillation (cAF) registered in the UK General Practice Research Database. The outcome was the rate of stroke during current, past and no use of aspirin and warfarin. The study included 51,807 cAF patients. There was no difference in the rate of stroke between current and past use of aspirin (relative rate [RR] = 1.04 [95% confidence interval (CI) 0.94 - 1.15]), while the rate of stroke was reduced during current warfarin use compared to past use (RR = 0.62 [95% CI 0.54 - 0.71]). For warfarin, a pattern of lower rates of stroke during current exposure and higher rates with past exposure was seen only in patients treated for at least 6-12 months. For aspirin, no changes in the rates of stroke were observed with discontinuation of aspirin. The effectiveness of warfarin was dependent on the level of anticoagulation, with optimal risk reduction occurring within the recommended international normalised ratio (INR) range of 2.0 to 3.0. The proportion of patients achieving a stable INR within the target therapeutic range was at its lowest during the first three months of warfarin treatment. In conclusion, the results of this study support the effectiveness of warfarin treatment to reduce the rate of stroke in cAF patients in the general clinical practice setting, however the risk reduction is lower than that reported in clinical trials.

Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism in patients aged over 75 years or with moderate renal impairment undergoing total knee or hip replacement.

Oral dabigatran etexilate is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement or total hip replacement. We investigated the cost-effectiveness of the 150 mg once daily (od) dose recommended for patients aged over 75 or with moderate renal impairment, from a United Kingdom National Health Service perspective. Dabigatran etexilate was compared with subcutaneous enoxaparin 40 mg od, using a decision model. Risks for VTE and bleeding were derived from subgroup analyses of the phase III trials. Dabigatran etexilate was less costly than enoxaparin; cost savings varied from pound62 to pound274 (base-case analyses) and were primarily due to differences in administration costs. Results were robust across a range of sensitivity analyses. Dabigatran etexilate 150 mg od is cost saving compared with enoxaparin 40 mg od in patients aged over 75years and in patients with moderate renal impairment, with comparable efficacy and safety.

Annual Cost of Erectile Dysfunction to UK Society

AbstractObjective: The objective of this study was to estimate the annual socioeconomic burden imposed by erectile dysfunction (ED) on UK society. Design and Setting: Health service resource use attributable to ED during 1997/1998 was obtained from appropriate databases and a panel of 22 hospital specialists comprising urologists, genito-urinary physicians, diabetologists and sexual health physicians. National unit resource costs at 1996/1997 prices were applied to the resource use data to estimate the annual National Health Service (NHS) cost of managing ED.A structured questionnaire pertaining to direct costs and absenteeism from work attributable to ED was mailed to a randomly selected sample of 5000 individuals who experience ED. Main outcome measures and results: During 1997/1998, the annual NHS cost was estimated to be £43.8 million for managing 113 600 men with ED. Outpatient visits were the major cost driver, accounting for 65% of the annual cost. Drugs prescribed by general practitioners (GPs) accounted for a further 25%. GP consultations and penile prosthetic surgery each accounted for 4%. Tests initiated by GPs accounted for 2%, while other resources accounted for less than 1%. The annual cost was sensitive to the number of outpatient visits and, to a lesser extent, to the number of prescriptions for ED treatments, but insensitive to changes in use of the other resources.Completed questionnaires were received from 23% (n = 1141) of the sample of individuals who experience ED. From the survey, it was estimated that the NHS managed 35% of individuals with ED in the last year. Assuming this to be representative, the total potential population of individuals with ED in the UK was estimated to be approximately 324 600 men.The total population of individuals with ED (n = 324 600 men) was estimated to incur £7.0 million annually in direct costs attributable to ED and to lose 19 630 days a year from work as a result of their ED, costing society £2.2 million in lost gross domestic product. Conclusions: ED imposes a relatively small burden on UK society — £53 million. Of this, 83% is borne by the NHS and 13% by patients. Indirect costs to society due to lost productivity account for the remaining 4%. The total NHS cost is strongly influenced by the number of hospital outpatient visits. Therefore, the future burden will depend largely on patients’ eligibility to receive ED treatments on the NHS.