Net Clinical Benefit of Oral Anticoagulation Among Frail Patients With Atrial Fibrillation: Nationwide Cohort Study.

BACKGROUND: Frail people with atrial fibrillation are often undertreated with oral anticoagulants (OACs), and evidence for the net clinical benefit (NCB) of OAC is sparse. We, therefore, examined the risk of thromboembolic events, major bleeding, and NCB of anticoagulation treatment. METHODS: This was a nationwide cohort study including frail patients aged with incident atrial fibrillation between 2013 and 2018. Patients were categorized according to OAC treatment exposure. One-year risks of thromboembolic events and major bleeding were ascertained where death was treated as a competing risk. The NCB of anticoagulation was assessed by a bivariate trade-off between thromboembolism and bleeding. RESULTS: We identified 36 223 frail patients with atrial fibrillation (median age, 79 years; 50.5% female), of whom 61.8% started OAC therapy, while 38.2% were untreated despite indication for stroke prevention. At 1 year, the risk of thromboembolic events was 2.1% (95% CI, 1.8%-2.3%) among patients not receiving OAC versus 1.5% (95% CI, 1.4%-1.7%) in patients with OAC. The bleeding risk was 3.2% (95% CI, 2.9%-3.5%) among patients without OAC versus 3.5% (95% CI, 3.2%-3.8%) among anticoagulated patients. The NCB was 0.70% (95% CI, 0.32%-1.08%), suggesting a benefit of OAC treatment; however, the NCB declined with age and increasing frailty and was lowest among patients >75 years of age or with high frailty level. CONCLUSIONS: Frail patients with atrial fibrillation are often untreated with OAC in routine clinical care despite an indication for stroke prevention. The NCB balancing thromboembolic events and major bleeding was in favor of anticoagulation but decreased with advancing age and increasing frailty.

Adherence and Persistence to Antiplatelet Therapy in Lower Extremity Peripheral Arterial Disease: A Danish Population Based Cohort Study.

OBJECTIVE: Adherence to antiplatelet therapy is recommended but unexplored in patients with symptomatic lower extremity peripheral arterial disease (PAD). Therefore, this study aimed to determine adherence and persistence to antiplatelet therapy in patients with PAD, defined as intermittent claudication and chronic limb threatening ischaemia. DESIGN: Population based nationwide cohort study. METHODS: This study included all Danish citizens aged ≥ 40 years with a first inpatient or outpatient diagnosis of symptomatic PAD between 2010 - 2017, and who had at least one prescription claim for aspirin and/or clopidogrel within 90 days after diagnosis. Adherence was determined by the proportion of days covered (PDC) during the first year after diagnosis. Persistence was defined as no treatment gap ≥ 30 days between prescription renewals over three year follow up. RESULTS: A total of 39 687 patients were eligible for inclusion, of whom 23 279 (58.7%) claimed a prescription for aspirin and/or clopidogrel within 90 days of diagnosis. Among these, 12 898 (55.4%) were prevalent users, while the remainder comprised new users who initiated the therapy after the index PAD diagnosis. The mean PDC was 74.5% (SD 35.0%) for prevalent users and 60.5% (SD 30.5%) for new users. Adherence increased with age and number of concomitant drugs. The overall one year cumulative incidence treatment discontinuation was 13.0% (95% CI 12.5 - 13.4%) overall, 17.2% (CI 16.6 - 17.9%) for prevalent users, and 7.9% (CI 7.4 - 8.4%) for new users. At three year follow up, the cumulative incidence of discontinuation was 31.5% (CI 30.9 - 32.2%) overall, 44.6% (CI 43.7 - 45.4%) for prevalent users, and 14.6% (CI 13.9 - 15.3) for new users. CONCLUSION: Less than 60% of patients with newly diagnosed symptomatic PAD claimed a prescription for antiplatelet therapy within 90 days of diagnosis, and both adherence and persistence were moderate during the first year after diagnosis. These findings underscore the importance of efforts to improve the initiation and continuation of antiplatelet therapy in patients with PAD.

Epidemiological Trends and Projections of Incidence, Prevalence, and Disease Related Mortality Associated With Peripheral Arterial Disease: Observations Using Nationwide Danish Data.

OBJECTIVE: Peripheral arterial disease (PAD) trends remain unclear because contemporary data are sparse and conflicting. This nationwide cohort study quantified changes in PAD incidence, prevalence, and all cause mortality, and projected prevalence development through to 2040. METHODS: Population based registries covering the entire Danish population aged ≥ 40 years from 2000 to 2018 were linked to assess trends in PAD incidence, prevalence, and all cause mortality, overall and by sex and age groups. Based on observed trends in incidence and mortality, and estimated future annual age distribution and population mortality, the PAD prevalence through to 2040 was projected. RESULTS: The Danish population aged 40 - 99 years in 2000 - 2018 included 4 811 281 individuals, among whom 145 870 incident PAD diagnoses were identified. The age and sex standardised PAD incidence decreased from 2.26 per 1 000 person years in 2000 to 1.65 in 2018 (incidence RR 0.74, 95% CI 0.72 - 0.77). The incidence was approximately 20% higher in men than women but declined similarly over time. Concurrently, PAD prevalence in the Danish adult population increased from 1.3% to 1.6% (prevalence ratio 1.28, 95% CI 1.26 - 1.30). Among patients aged ≥ 80 years, the prevalence reached 5.7% in women and 7.9% in men. The age and sex standardised annual mortality among patients with PAD decreased from 9.8% in 2000 to 7.2% in 2018 (mortality ratio 0.75, 95% CI 0.72 - 0.78). Projections of PAD prevalence demonstrated that the rising PAD prevalence will continue until around 2030, followed by a decline towards 2040. Among individuals aged ≥ 80 years, the prevalence was projected to plateau at 8.9% for men and 6.2% for women before declining. CONCLUSION: Within an unselected nationwide population, the incidence and all cause mortality of PAD have declined over the last two decades. Concurrently, prevalence increased and is projected to increase further over the coming decade, emphasising the growing burden of this common atherosclerotic disease in ageing populations.

Temporal Changes in Secondary Prevention and Cardiovascular Outcomes After Revascularization for Peripheral Arterial Disease in Denmark: A Nationwide Cohort Study.

BACKGROUND: Patients with peripheral arterial disease (PAD) are at increased risk of cardiovascular morbidity and mortality. Medical prevention with antithrombotic and statin therapies is a mainstay of treatment to prevent adverse outcomes; nevertheless, patients with PAD are often undertreated. This study describes the temporal changes in medical prevention and adverse outcomes in a national cohort of patients with symptomatic PAD after revascularization. METHODS: We identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark, from 2000 to 2016. We examined temporal changes in the use of aspirin, clopidogrel, and statins and 1-year cause-specific hazard ratios for adverse clinical outcomes, after adjusting for procedure type, treatment indication, age, sex, and cardiovascular risk factors. The analyses were performed overall and within strata of index procedure (endovascular versus surgical), treatment indication, age, sex, and high-risk comorbidities. RESULTS: Between 2000 and 2016, we identified 32 911 patients who underwent revascularization for symptomatic PAD. The mean age was 69 years and increased over time, as did the burden of comorbidity. The cumulative incidence of medication use increased between 2000 to 2004 and 2013 to 2016, respectively, from 57.3% to 64.3% for aspirin, 3.6% to 24.8% for clopidogrel, and 36.2% to 77.1% for statins. Concurrently, the 1-year outcome rates declined. Compared with 2000 to 2004, the adjusted hazard ratios in 2013 to 2016 were 0.73 (95% CI, 0.62-0.84) for major adverse cardiovascular events, 0.92 (95% CI, 0.85-1.00) for major adverse limb events, 0.60 (95% CI, 0.48-0.74) for myocardial infarction, 0.94 (95% CI, 0.75-1.18) for ischemic stroke, 0.92 (95% CI, 0.75-1.12) for major bleeding, 0.54 (95% CI, 0.39-0.76) for cardiovascular death, and 0.80 (95% CI, 0.72-0.88) for all-cause death. These improvements in prognosis were most prominent from 2000 to 2004 to 2005 to 2008 and occurred in all strata of index procedure, treatment indication, sex, age, and comorbidity. In contrast, the adjusted hazard ratio for major amputations was 1.00 (95% CI, 0.90-1.11) when comparing 2013 to 2016 to 2000 to 2004. CONCLUSIONS: Medical prevention of adverse events has increased considerably over time in patients who underwent revascularization for symptomatic PAD. This increase was accompanied by reductions in all adverse outcomes, except major amputations.

Risk of Cerebrovascular Events in Intracerebral Hemorrhage Survivors With Atrial Fibrillation: A Nationwide Cohort Study.

BACKGROUND: In patients with intracerebral hemorrhage (ICH) and prevalent atrial fibrillation (AF), the optimal stroke prevention strategy is unclear. We sought to estimate the risk of cerebrovascular events among ICH survivors with AF. METHODS: We used the Danish Stroke Registry to identify patients with incident ICH and prevalent AF between 2003 and 2018. Key inclusion/exclusion criteria of the PRESTIGE-AF (Prevention of Stroke in Intracerebral hemorrhage Survivors With Atrial Fibrillation) trial were applied. Cumulative incidence of recurrent ICH, cerebrovascular ischemic event, and all-cause death were investigated after one year. RESULTS: A total of 1885 patients (median age 80.0 years; 47.6% females) were included in the study. We observed 191 cerebrovascular events and 650 all-cause deaths, and more cerebrovascular ischemic events (N=63) than recurrent ICH events (N=40). Risks of recurrent ICH, cerebrovascular ischemic event, and all-cause death were 1.5%, 3.2%, and 30.3%, respectively, among patients not exposed to OAC during follow-up. The cumulative incidences were 2.8% for recurrent ICH, 3.2% for cerebrovascular ischemic events, and 22.0% for all-cause death among patients initiating/resuming OAC during follow-up. CONCLUSIONS: We observed a high risk of cerebrovascular ischemic events and a very high risk of all-cause death at one year after the incident ICH. The results of ongoing clinical trials are warranted to determine optimal stroke prevention treatment among ICH survivors with concomitant AF.

Oral anti-coagulant treatment patterns in atrial fibrillation patients diagnosed with cancer: A Danish nationwide cohort study.

Data on the use of oral anti-coagulants (OAC) for stroke prevention in cancer patients with atrial fibrillation (AF) are sparse. Nationwide cohort study of patients with AF (2012-2018) and an indication for OAC who were diagnosed with cancer at least one year later (N = 12 756). We identified treatment with OAC at cancer diagnosis and the following year and described the incidence of discontinuing or switching between warfarin and direct oral anti-coagulants (DOACs). We also described baseline characteristics associated with OAC non-persistence. One third of the cancer patients received no OAC therapy, whereas 42% received warfarin and 24% received DOAC treatment. Switching incidence between OACs was higher for those receiving warfarin treatment (8.6%) than DOAC treatment (1.7%) within one year. Treatment discontinuation was 61% for warfarin and 26% for DOAC. Females were less likely to discontinue DOAC than males (ratio 0.77, 95% confidence interval: 0.66, 0.90). Increasing cancer stage was associated with discontinuation of DOAC, but not warfarin. OAC for stroke prevention in AF was used by two thirds of patients with newly diagnosed cancer. Switching between OACs and discontinuation was more common for warfarin than DOAC, and females had higher persistence with DOACs.

Disparities in oral anticoagulation initiation in patients with schizophrenia and atrial fibrillation: A nationwide cohort study.

AIMS: Schizophrenia is associated with poor anticoagulation control and clinical prognosis in patients with atrial fibrillation (AF). Little is known about initiation of oral anticoagulation therapy (OAC) in this patient population. METHODS: In the nationwide Danish health registries, we identified all patients with incident AF and schizophrenia with indication for OAC treatment. Patients with schizophrenia (n = 673) were matched 1:5 on sex, age, stroke risk score, and calendar-period to incident AF patients without schizophrenia. We calculated absolute risk and risk difference (RD) of OAC initiation, adjusting for stroke and bleeding risk factors. Analyses were stratified by calendar period (2000-2011 and 2012-2018) to account for changes after the introduction of non-vitamin K OACs (NOAC). RESULTS: Among patients with schizophrenia (mean age 69.5 years, 50.3% females), 33.7% initiated OAC within the first year after AF diagnosis, compared with 54.4% of patients without schizophrenia, corresponding to an adjusted RD of -20.7 (95% confidence interval [CI]: -24.7 to -16.7). OAC initiation increased over time regardless of schizophrenia status. During 2000-2011, 18.3% of patients with schizophrenia and 42.9% without schizophrenia initiated OAC (adjusted RD -23.6%, 95% CI -28.8 to -18.6). During 2012-2018, this was 48.5% and 65.7%, respectively (adjusted RD -14.4%, 95% CI -20.4 to -8.4). CONCLUSION: Initiation of OAC was substantially lower among patients with AF and schizophrenia compared with matched AF peers. These findings accentuate the importance of close attention to disparities in initiation of OAC treatment, and potential missed opportunities for prevention of disabling strokes in AF patients with schizophrenia.

'Real-world' observational studies in arrhythmia research: data sources, methodology, and interpretation. A position document from European Heart Rhythm Association (EHRA), endorsed by Heart Rhythm Society (HRS), Asia-Pacific HRS (APHRS), and Latin America HRS (LAHRS).

The field of observational studies or "real world studies" is in rapid development with many new techniques introduced and increased understanding of traditional methods. For this reason the current paper provides an overview of current methods with focus on new techniques. Some highlights can be emphasized: We provide an overview of sources of data for observational studies. There is an overview of sources of bias and confounding. Next There is an overview of causal inference techniques that are increasingly used. The most commonly used techniques for statistical modelling are reviewed with focus on the important distinction of risk versus prediction. The final section provides examples of common problems with reporting observational data.

Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation: Should We Use a CHA2DS2-VA Score Rather Than CHA2DS2-VASc?

BACKGROUND: Stroke risk in atrial fibrillation is assessed by using the CHA2DS2-VASc score. Sex category (Sc, ie, female sex) confers 1 point on CHA2DS2-VASc. We hypothesized that female sex is a stroke risk modifier, rather than an overall risk factor, when added to a CHA2DS2-VA (sex-independent thromboembolism risk) score scale. METHODS: Using 3 nationwide registries, we identified patients with incident nonvalvular atrial fibrillation from January 1, 1997, through December 31, 2015. Patients receiving oral anticoagulant treatment at baseline were excluded, and person-time was censored at the time of treatment initiation (if any). CHA2DS2-VA scores were calculated for men and women, and were followed for up to 1 year in the Danish National Patient Registry. The primary outcome was a primary hospital code for ischemic stroke or systemic embolism (thromboembolism). We calculated crude event rates for risk strata as events per 100 person-years. For quantifying absolute risk of stroke, we calculated risks based on the pseudovalue method. Female sex as a prognostic factor was investigated by inclusion as an interaction term on the CHA2DS2-VA score to calculate the thromboembolic risk ratio for different score points. RESULTS: A total of 239 671 patients with atrial fibrillation (48.7% women) contributed to the analyses. The mean ages for women and men were 76.6 years and 70.3 years, respectively; the mean CHA2DS2-VA scores were 2.7 for women and 2.3 for men. The overall 1-year thromboembolic rate per 100 person-years for women was 7.3 and 5.7 for men. The 1-year absolute risk of thromboembolism was 0.5% among men and women with a CHA2DS2-VA score of 0 and increased up to >7% among very comorbid patients (score >5). The risk ratio (male as reference) across points >1 indicated that women exhibit a higher stroke risk. The interaction was statistically significant (P<0.001). CONCLUSIONS: Female sex is a risk modifier for stroke in patients with atrial fibrillation. Initial decisions on oral anticoagulant treatment could be guided by a CHA2DS2-VA score (ie, excluding the sex category criterion), but the Sc risk component modifies and accentuates stroke risk in women who would have been eligible for oral anticoagulant treatment on the basis of ≥2 additional stroke risk factors.

Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Atrial Fibrillation Patients With Intracerebral Hemorrhage.

Background and Purpose- Recurrent bleeding associated with oral anticoagulants (OACs) causes a dilemma in patients with atrial fibrillation (AF) sustaining an intracerebral hemorrhage. Treatment recommendations guiding clinical practice on optimal OAC agent selection in this population are lacking. This study aimed to investigate the comparative effectiveness and safety of non-vitamin K antagonist OAC (NOAC) versus warfarin in patients with AF sustaining an intracerebral hemorrhage. Methods- We conducted a nationwide observational cohort study including patients with AF sustaining an intracerebral hemorrhage and who subsequently claimed an OAC prescription. Contrasts of 1-year risks for ischemic stroke and intracerebral hemorrhage risks were obtained and evaluated by inverse probability treatment weighted absolute risk reduction and risk ratios. Results- Among 622 AF patients with intracerebral hemorrhage, 274 claimed a warfarin prescription and 348 a NOAC prescription. Mean age was 76 years (39% females); 72% had an index nonsevere event and 28% moderate to severe index event according to the Scandinavian Stroke Severity scale. The 1-year ischemic stroke risk was 7.85% for warfarin and 4.01% for NOACs, with a weighted absolute risk reduction of 3.78% (95% CI, -0.15% to 7.71%); the weighted risk ratio was 0.52 (0.27-1.00). For recurrent intracerebral hemorrhage, the risk was 7.00% for warfarin and 5.07% for NOACs. The absolute risk reduction was 1.93% (-2.02% to 5.87%), with an a weighted risk ratio of 0.72 (0.38-1.38). Conclusions- NOACs were associated with a nonsignificant lower risk of ischemic stroke and recurrent intracerebral hemorrhage compared with warfarin. The results add to current recommendations of selecting a NOAC agent for stroke prophylaxis treatment in patients with AF, including those with sustaining an intracerebral hemorrhage.

Risk Stratification for Ischemic Cerebrovascular Events and Mortality among Intracerebral Hemorrhage Patients with and without Atrial Fibrillation: A Nationwide Cohort Study.

BACKGROUND: Intracerebral hemorrhage is a devastating clinical event, and secondary prevention is pivotal to avoid further cerebral complications, but no clear guidance exist for selecting high-risk patients. The CHA2DS2-VASc score is a widespread tool to assess the risk of stroke among patients with atrial fibrillation (AF). OBJECTIVES: We investigated the ability of the CHA2DS2-VASc score for estimating cerebrovascular ischemic events in patients with recent intracerebral hemorrhage with or without comorbid AF. METHODS: Patients with a diagnosis of intracerebral hemorrhage between 2003 and 2018 were considered for inclusion. Four registries were linked to obtain individual-level information, and included patients were followed for the occurrence of cerebrovascular ischemic events and all-cause mortality. We report absolute risks at 5 years stratified by baseline CHA2DS2-VASc score and AF prevalence. RESULTS: The study included 12,245 patients (46.4% females) of whom 19% had prevalent AF. Patients without AF were younger (mean age: 70 vs. 78 years) and had a lower CHA2DS2-VASc score (2.5 vs. 3.6). The overall 5-year risk of cerebrovascular ischemic events was 5.2% (95% CI 4.7-5.6) for patients without AF and 7.3% (95% CI 6.0-8.5) for AF patients; all-cause mortality was higher than 30 and 50% in patients without or with AF, respectively. The predictive performance of the CHA2DS2-VASc score was poor with c-statistics around 0.56 regardless of AF status. Among patients without AF, a score ≥6 was associated with a 7.0% risk of cerebrovascular ischemic events. In patients with AF, the associated risk was lowest for patients with a CHA2DS2-VASc score of 1 (4.1%) and highest among those with a score of 5 (11.9%). CONCLUSION: In this nationwide cohort of intracerebral hemorrhage patients with or without AF, the risk of cerebrovascular ischemic events and mortality was substantial. The CHA2DS2-VASc score may be used for the estimation of stroke risk in patients sustaining an intracerebral hemorrhage, although its discriminative performance was poor.

Stroke and bleeding risk scores in patients with atrial fibrillation and valvular heart disease: evaluating 'valvular heart disease' in a nationwide cohort study.

AIMS: Substantial interest has been directed towards stroke risk stratification in patients with atrial fibrillation (AF) but prior studies have focused on AF without significant valvular heart disease (VHD), so-called 'non-valvular AF'. A formal validation exercise addressing stroke risks in relation to the CHA2DS2-VASc risk factor(s) in AF patients with VHD is lacking. Also, the use of the HAS-BLED score in anticoagulated patients with VHD has not been previously studied. The aim of this study was to investigate stroke and bleeding rates in AF patients with VHD in relation to the CHA2DS2-VASc and HAS-BLED scores. METHODS AND RESULTS: We conducted a nationwide cohort study. VHD were categorized based on the 2017 joint European consensus document definition, i.e. Evaluated Heartvalves, Rheumatic or Artificial (EHRA) categorization, as follows: (i) EHRA Type 1 VHD, which refers to AF patients with 'VHD needing therapy with a Vitamin K antagonist (VKA)', thus including severe native mitral stenosis and prosthetic mechanical heart valves and (ii) EHRA Type 2 VHD, which refers to AF patients with 'VHD needing therapy with a VKA or a non-VKA oral anticoagulant (NOAC)', thus including all other forms of VHD. We identified 25 818 AF patients with VHD with EHRA Type 2 in 90% (n = 23 253). Thromboembolism and bleeding events increased with increasing CHA2DS2-VASc and HAS-BLED scores, whether with 1 or 2.5 years follow-up. EHRA Type 1 outcomes: The predictive value of CHA2DS2-VASc score for thromboembolism was modest, c-indexes 0.62 (0.55-0.70) at 1 year. The predictive value of the HAS-BLED score for bleeding was also modest being 0.59 (0.53-0.65) at 1 year. EHRA Type 2 outcomes: The predictive value of CHA2DS2-VASc score for thromboembolism was modest, c-indexes 0.63 (0.60-0.65) at 1 year. The predictive value of the HAS-BLED score for bleeding was also modest being 0.59 (0.53-0.65) at 1 year. CONCLUSION: This is the first validation of CHA2DS2-VASc and HAS-BLED scores in AF patients with VHD (so-called 'valvular AF') using the new EHRA classification. Both scores are modestly predictive of thromboembolism and bleeding events in VHD, respectively. Event rates increased with increasing risk factors as evident by increasing CHA2DS2-VASc and HAS-BLED score points, consistent with performance of these clinical scores in 'non-valvular AF' patients.

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.

Effectiveness and safety of direct oral anticoagulation vs. warfarin in frail patients with atrial fibrillation.

AIMS: Although frail patients with atrial fibrillation (AF) carry a high risk of stroke and treatment-related bleeding complications, evidence for the safety and effectiveness of anticoagulation remains sparse. This study investigated the effectiveness and safety of direct oral anticoagulant (DOAC) vs. warfarin in frail AF patients. METHODS AND RESULTS: Nationwide registry-based cohort study including 32 048 anticoagulation naïve frail patients (median age 80 years, 53% female) with incident AF during 2012-20. Frailty was assessed using the hospital frailty risk score. To address baseline confounding, we applied inverse probability of treatment weighting (IPTW) and marginal structural models with weighted pooled regression to compute weighted hazard ratios (wHRs) and risk differences for thromboembolism and major bleeding comparing specific DOAC doses with warfarin. After AF diagnosis, 6747 (21.1%) initiated warfarin, 17 076 (50.3%) initiated standard-dose DOAC, and 9179 (28.6%) initiated reduced-dose DOAC. Comparative effectiveness analyses in the IPTW pseudo-populations revealed similar thromboembolism risk between standard-dose DOAC and warfarin [wHR 0.95, 95% confidence interval (CI) 0.80-1.13] and between reduced-dose DOAC and warfarin (wHR 0.97, 95% CI 0.77-1.23). The 1-year thromboembolic event-free survival difference was -0.2% for DOAC, regardless of dosing, vs. warfarin. Major bleeding risk was significantly lower with standard-dose DOAC (wHR 0.69, 95% CI 0.59-0.87) and reduced-dose DOAC (wHR 0.67, 95% CI 0.55-0.81) vs. warfarin. The 1-year bleeding risk difference with DOAC ranged from -1.3% to -3.0%. CONCLUSION: Our findings indicate comparable thromboembolism risk and significantly lower bleeding risk with both standard and reduced DOAC regimens compared with warfarin in frail AF patients in routine care.

Risk of stroke in male and female patients with atrial fibrillation in a nationwide cohort.

Female sex has been suggested as a risk modifier for stroke in patients with atrial fibrillation (AF) with comorbid prevalent stroke risk factors. Management has evolved over time towards a holistic approach that may have diminished any sex difference in AF-related stroke. In a nationwide cohort of AF patients free from oral anticoagulant treatment, we examine the time trends in stroke risk overall and in relation to risk differences between male and female patients. Here we show that among 158,982 patients with AF (median age 78 years (IQR: 71 to 85); 52% female) the 1-year thromboembolic risk was highest between 1997-2000 with a risk of 5.6% and lowest between 2013-2016 with a risk of 3.8%, declining over the last two decades. The excess stroke risk for female vs male patients has also been declining, with risk-score adjusted relative risk estimates suggesting limited sex-difference in recent years.

Positive predictive value and sensitivity of cancer-associated venous thromboembolism diagnoses in the Danish National Patient Register.

INTRODUCTION: Hospital discharge diagnoses from administrative registries are frequently used in studies of cancer-associated venous thromboembolism, but the validity of International Classification of Diseases (ICD) codes for identifying such events is unknown. MATERIALS AND METHODS: Using patient samples from the Danish National Patient Register, we calculated positive predictive values (PPV), i.e., the proportion of registered ICD codes, which could be confirmed after manual search of the electronic health record. Sensitivity was estimated in a sample of patients with imaging-verified venous thromboembolism but without prior knowledge about their ICD coding status. Sensitivity was calculated as the proportion of these patients, who were discharged with an ICD code for venous thromboembolism. RESULTS: The overall PPV of an ICD-10 diagnosis of cancer-associated venous thromboembolism was 75.9 % (95 % confidence interval 71.3-80.0). In subgroups, the PPV was particularly low for recurrent venous thromboembolism (44.2 %), diagnoses in a secondary position (55.7 %), outpatient diagnoses (65.3 %), and diagnoses given at surgical (66.7 %), emergency wards (48.4 %), or via hospices/palliative teams (0 %). The overall sensitivity was 68 %, meaning 32 % of patients with cancer diagnosed in hospital with venous thromboembolism were discharged without any registered ICD code for venous thromboembolism. CONCLUSIONS: The positive predictive value of an ICD diagnosis of cancer-associated venous thromboembolism in the Danish Patient Register was overall adequate for research purposes, but with notable variation across subgroups. Sensitivity was limited, as 1/3 of patients with venous thromboembolism were discharged without any relevant ICD code. Cautious interpretation of incidence of cancer-associated venous thromboembolism based on administrative register-based data is warranted.