Leif Friberg

Net Clinical Benefit of Warfarin in Patients With Atrial Fibrillation A Report From the Swedish Atrial Fibrillation Cohort Study

Background— Known risk factors for bleeding during anticoagulant treatment are largely the same as those predicting thromboembolic events in patients with atrial fibrillation (AF). Our objective was to investigate how to maximize the likelihood of avoiding both stroke and bleeding. Methods and Results— All 182 678 subjects with atrial fibrillation in the Swedish Hospital Discharge Register were studied for an average of 1.5 years (260 000 patient-years at risk). Patients were stratified according to risk scores with the use of historic International Classification of Disease diagnostic codes in the register. Information about medication was obtained from the Swedish Drug Registry. Our primary end point was net benefit defined as number of avoided ischemic strokes with anticoagulation minus the number of excess intracranial bleedings with a weight of 1.5 to compensate for the generally more severe outcome with intracranial bleedings. The adjusted net clinical benefit favored anticoagulation for almost all atrial fibrillation patients. The exceptions were patients at very low risk of ischemic stroke with a CHA2DS2-VASc score of 0 and moderately elevated bleeding risk (−1.7%/y). The results were broadly similar with CHADS2, except for patients with very low embolic risk; the CHA2DS2-VASc was able to identify those patients (n=6205, 3.9% of all patients) who had no net clinical benefit or even some disadvantage from anticoagulant treatment. Conclusions— In almost all patients with atrial fibrillation, the risk of ischemic stroke without anticoagulant treatment is higher than the risk of intracranial bleeding with anticoagulant treatment. Analysis of the net benefit indicates that more patients may benefit from anticoagulant treatment. # CLINICAL PERSPECTIVE {#article-title-39}Background— Known risk factors for bleeding during anticoagulant treatment are largely the same as those predicting thromboembolic events in patients with atrial fibrillation (AF). Our objective was to investigate how to maximize the likelihood of avoiding both stroke and bleeding. Methods and Results— All 182 678 subjects with atrial fibrillation in the Swedish Hospital Discharge Register were studied for an average of 1.5 years (260 000 patient-years at risk). Patients were stratified according to risk scores with the use of historic International Classification of Disease diagnostic codes in the register. Information about medication was obtained from the Swedish Drug Registry. Our primary end point was net benefit defined as number of avoided ischemic strokes with anticoagulation minus the number of excess intracranial bleedings with a weight of 1.5 to compensate for the generally more severe outcome with intracranial bleedings. The adjusted net clinical benefit favored anticoagulation for almost all atrial fibrillation patients. The exceptions were patients at very low risk of ischemic stroke with a CHA2DS2-VASc score of 0 and moderately elevated bleeding risk (−1.7%/y). The results were broadly similar with CHADS2, except for patients with very low embolic risk; the CHA2DS2-VASc was able to identify those patients (n=6205, 3.9% of all patients) who had no net clinical benefit or even some disadvantage from anticoagulant treatment. Conclusions— In almost all patients with atrial fibrillation, the risk of ischemic stroke without anticoagulant treatment is higher than the risk of intracranial bleeding with anticoagulant treatment. Analysis of the net benefit indicates that more patients may benefit from anticoagulant treatment.

Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation

AIMS Knowledge about stroke risk in paroxysmal atrial fibrillation (PxAF) is limited. Although current guideline recommendations advocate the same treatment as in permanent atrial fibrillation (PermAF), most patients with PxAF do not receive prophylactic anticoagulation. The aim of this study is to investigate whether there are differences in stroke risk between PxAF and PermAF. METHODS AND RESULTS All patients with PxAF (n = 855) and PermAF (n = 1126) treated for atrial fibrillation (AF) during 2002 at one of Scandinavias largest hospitals were followed-up for 3.6 years regarding incidence of stroke. Information about type of AF, comorbidity, medication, and clinical events during follow-up was acquired from medical records and the National Register of Hospital Discharges. The incidence of ischaemic stroke was similar in PxAF and PermAF (26 vs. 29 events/1000 patient years). The multivariable-adjusted hazard ratio (HR) for ischaemic stroke in PxAF compared with PermAF was 1.07 (95% CI 0.71-1.61) in subjects without prior stroke. The corresponding HR for any stroke, ischaemic or haemorrhagic, was 0.89 (95% CI 0.61-1.30). Compared with the general population, ischaemic stroke was twice as common as expected in PxAF after standardization for age and sex (standardized incidence ratio 2.12, 95% CI 1.52-2.71). PxAF patients who took warfarin had approximately half as many ischaemic strokes as those who did not take warfarin (HR 0.44, 95% CI 0.30-0.65). CONCLUSION Ischaemic stroke is about as common in PxAF as in PermAF, and about twice as common as in the general population. Yet, PxAF patients do not receive protective anticoagulant treatment as often as patients with PermAF do. It is therefore important to increase the use of anticoagulants among PxAF patients in accordance with current guideline recommendations.

Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options-a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference

While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.

Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.

Objective To determine whether women with atrial fibrillation have a higher risk of stroke than men. Design Nationwide retrospective cohort study. Setting Patients with a diagnosis of atrial fibrillation in the Swedish hospital discharge register between 1 July 2005 and 31 December 2008. Information about drug treatment taken from the Swedish drug register. Participants 100 802 patients with atrial fibrillation at any Swedish hospital or hospital affiliated outpatient clinic with a total follow-up of 139 504 years at risk (median 1.2 years). We excluded patients with warfarin at baseline, mitral stenosis, previous valvular surgery, or who died within 14 days from baseline. Main outcome measure Incidence of ischaemic stroke. Results Ischaemic strokes were more common in women than in men (6.2% v 4.2% per year, P<0.0001). The univariable hazard ratio for women compared with men was 1.47 (95% confidence 1.40 to 1.54), indicating a 47% higher incidence of ischaemic stroke in women than in men. Stratification according to the CHADS2 scheme showed increased stroke rates for women in all strata. After multivariable adjustment for 35 cofactors for stroke, an increased risk of stroke in women remained (1.18, 1.12 to 1.24). Among patients with “lone atrial fibrillation” (age <65 years and no vascular disease), the annual stroke rate tended to be higher in women than in men, although this difference was not significant (0.7% v 0.5%, P=0.09). When low risk patients with CHADS2 scores of 0-1 were stratified according to their CHA2DS2-VASc scores, women did not have higher stroke incidence than men at CHA2DS2-VASc scores of 2 or less. Conclusion Women with atrial fibrillation have a moderately increased risk of stroke compared with men, and thus, female sex should be considered when making decisions about anticoagulation treatment. However, women younger than 65 years and without other risk factors have a low risk for stroke, and do not need anticoagulant treatment.

Mass Screening for Untreated Atrial Fibrillation The STROKESTOP Study

Background— The aims of the present study were to define the prevalence of untreated atrial fibrillation (AF) in a systematic screening program using intermittent ECG recordings among 75- to 76-year-old individuals and to study the feasibility of initiating protective oral anticoagulant (OAC) treatment. Methods and Results— Half of the 75- to 76-year-old population in 2 Swedish regions were invited to a screening program for AF. Participants without a previous diagnosis of AF underwent intermittent ECG recordings over 2 weeks. If AF was detected, participants were offered OAC. During the 28-month inclusion period, 13 331 inhabitants were invited. Of these, 7173 (53.8%) participated. Of the participants, 218 (3.0%; 95% confidence interval [CI], 2.7–3.5) were found to have previously unknown AF, and of these, AF was found in 37 (0.5% of the screened population) on their first ECG. The use of intermittent ECGs increased new AF detection 4-fold. A previous diagnosis of AF was known in 9.3% (n=666; 95% CI, 8.6–10.0). Total AF prevalence in the screened population was 12.3%. Of participants with known AF, 149 (2.1%; 95% CI, 1.8–2.4) had no OAC treatment. In total, 5.1% (95% CI, 4.6–5.7) of the screened population had untreated AF; screening resulted in initiation of OAC treatment in 3.7% (95% CI, 3.3–4.2) of the screened population. More than 90% of the participants with previously undiagnosed AF accepted initiation of OAC treatment. Conclusions— Mass screening for AF in a 75- to 76-year-old population identifies a significant proportion of participants with untreated AF. Initiation of stroke prophylactic treatment was highly successful in individuals with newly diagnosed AF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01593553.

Atrial fibrillation prevalence revisited

The estimate of 0.4–1.0% prevalence of atrial fibrillation in the most recent American guidelines is based mainly on studies including patients with permanent atrial fibrillation (AF), although recent evidence shows that the stroke risk is similar with paroxysmal and persistent AF. Our objective was to determine the prevalence of AF in Sweden, irrespective of type and to what extent patients with AF receive adequate stroke prophylaxis.

Atrial Fibrillation, Stroke Risk, and Warfarin Therapy Revisited A Population-Based Study

Background and Purpose— Atrial fibrillation (AF) is a major risk factor for ischemic stroke. This study aims to update the knowledge about AF and associated stroke risk and benefits of anticoagulation. Methods— We extracted data from the hospital, specialized outpatient, and primary healthcare and drug registries in a Swedish region with 1.56 million residents. We identified all individuals who had received an AF diagnosis during the previous 5 years; all stroke events during 2010; and patients with AF aged ≥50 years who had received warfarin during 2009. Results— AF had been diagnosed in 38 446 subjects who were alive at the beginning of 2010 (prevalence of 3.2% in the adult [≥20 years] population); ≈46% received warfarin therapy. In 2010, there were 4565 ischemic stroke events and 861 intracranial hemorrhages. AF had been diagnosed in 38% of ischemic events (≥50% among those aged ≥80 years) and in 23% of intracranial hemorrhages. An AF diagnosis was often lacking in hospital discharge records after stroke events. Warfarin therapy was associated with an odds ratio of 0.50 (confidence interval, 0.43–0.57) for ischemic stroke and, despite an increased risk of intracranial hemorrhage, an odds ratio of 0.57 (confidence interval, 0.50–0.64) for the overall risk for stroke. Conclusions— AF is more common than present guidelines suggest. The attributable risk of AF for ischemic stroke increases with age and is close to that of hypertension in individuals aged ≥80 years. Because a majority of patients with AF with increased risk for stroke had not received anticoagulation therapy, there is a large potential for improvement.

High Prevalence of Atrial Fibrillation Among Patients With Ischemic Stroke

Background and Purpose— Atrial fibrillation (AF) is a common cause of devastating but potentially preventable stroke. Estimates of the prevalence of AF among patients with stroke vary considerably because of difficulties in detection of intermittent, silent AF. Better recognition of AF in this patient group may help to identify and offer protection to individuals at risk. Our aim was to determine the nationwide prevalence of AF among patients with ischemic stroke, as well as their use of oral anticoagulation. Methods— Cross-sectional study of unselected patients in cross-linked nationwide Swedish health registers. All 94 083 patients with a diagnosis of ischemic stroke in the nationwide stroke register Riks-Stroke between 2005 and 2010 were studied. Information about previously diagnosed AF, and comorbidity, was obtained from the nationwide Patient Register and cross-referenced with the national Drug Register containing data on all dispensed pharmacological prescriptions in Sweden. Results— Combination of data from Riks-Stroke and from the Patient Register showed that 31 428 (33.4%) patients with ischemic stroke had previously known, or newly diagnosed, AF. Of those, only 16.2% had received warfarin in a pharmacy within 6 months before stroke onset. After hospital discharge, only 35.0% of the survivors received warfarin within the first 3 months after discharge. The likelihood for underlying AF was strongly correlated to the CHA2DS2-VASC score, which is a point based scheme for assessment of stroke risk in AF but which also predicts likelihood of AF. In this scheme points are given for age, previous stroke or transient ischemic attack, hypertension, heart failure, diabetes, vascular disease and female sex. Conclusions— Access to nationwide register data shows that AF is more common among patients with ischemic stroke than those previously reported. Few patients with stroke and AF had anticoagulant treatment before the event, and few got it after the event. CHA2DS2-VASc could be a useful monitoring tool to intensify efforts to diagnose AF among patients with cryptogenic stroke.

Balancing stroke and bleeding risks in patients with atrial fibrillation and renal failure: the Swedish Atrial Fibrillation Cohort study

BACKGROUND Patients who have both atrial fibrillation (AF) and renal failure have an increased risk of thrombo-embolism. Renal failure is also a risk factor for bleeding, which makes decisions regarding thromboprophylaxis complicated. Our aim was to determine risks for ischaemic stroke and bleeding in patients with AF and renal failure in relation to anticoagulant strategies. METHODS AND RESULTS This is retrospective non-randomized study of Swedish health registers comprising 307 351 patients with AF, of whom 13 435 had a previous diagnosis of renal failure. Ischaemic stroke occurred more often in AF patients with renal failure (annual rate, 3.9% vs. no renal failure, 2.9%), but this was related to concomitant comorbidities [adjusted hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.95-1.10]. Adding renal failure to the established stroke risk stratification schemes (CHADS2 and CHA2DS2-VASc) did not improve their predictive value. Renal failure was an independent risk factor for intracranial bleeding [adjusted HR: 1.27 (1.09-1.49)]. Most patients with renal failure benefited from warfarin treatment, despite their high bleeding risk. The incidence of the combined endpoint ischaemic or haemorrhagic stroke or death was lower among those who used warfarin than among those who did not use warfarin (adjusted HR: 0.76, CI 0.72-0.80). CONCLUSIONS Patients with both AF and renal failure will probably benefit most from having the same treatment as is recommended for other patients with AF, without setting a higher or lower threshold for treatment. Adding additional points for renal failure to the CHADS2 and CHA2DS2-VASc scores did not improve their predictive value.

Safety and efficacy of well managed warfarin: A report from the Swedish quality register Auricula

The safety and efficacy of warfarin in a large, unselected cohort of warfarin-treated patients with high quality of care is comparable to that reported for non-vitamin K antagonists. Warfarin is commonly used for stroke prevention in atrial fibrillation, as well as for treatment and prevention of venous thromboembolism. While reducing risk of thrombotic/embolic incidents, warfarin increases the risk of bleeding. The aim of this study was to elucidate risks of bleeding and thromboembolism for patients on warfarin treatment in a large, unselected cohort with rigorously controlled treatment. This was a retrospective, registry-based study, covering all patients treated with warfarin in the Swedish national anticoagulation register Auricula, which records both primary and specialised care. The study included 77,423 unselected patients with 100,952 treatment periods of warfarin, constituting 217,804 treatment years. Study period was January 1, 2006 to December 31, 2011. Atrial fibrillation was the most common indication (68 %). The mean time in therapeutic range of the international normalised ratio (INR) 2.0-3.0 was 76.5 %. The annual incidence of severe bleeding was 2.24 % and of thromboembolism 2.65 %. The incidence of intracranial bleeding was 0.37 % per treatment year in the whole population, and 0.38 % among patients with atrial fibrillation. In conclusion, warfarin treatment where patients spend a high proportion of time in the therapeutic range is safe and effective, and will continue to be a valid treatment option in the era of newer oral anticoagulants.