External Validation of the OAC3-PAD Bleeding Score in a Nationwide Population of Patients Undergoing Invasive Treatment for Peripheral Arterial Disease.

OBJECTIVE: The OAC3-PAD score was developed to predict bleeding risk in patients with lower extremity peripheral arterial disease (PAD), but its performance in concomitant international cohorts is largely unknown. This study aimed to validate the OAC3-PAD score in an unselected nationwide population of patients undergoing invasive treatment for symptomatic PAD. METHODS: This was a nationwide cohort study including all patients who underwent a first revascularisation procedure or major amputation for symptomatic PAD in Denmark from 2000 - 2021. The study population was stratified based on OAC3-PAD score, and the one year risk of major bleeding was assessed, accounting for the competing risk of death. The score performance was evaluated using calibration plots, C statistic, Brier score, and the index of prediction accuracy (IPA). RESULTS: A total of 52 016 patients were included (mean age 71 years, 43.8% female). The one year risk of major bleeding increased with higher OAC3-PAD score, ranging from 1.6% (95% confidence interval [CI] 1.4 - 1.8%) to 2.3% (95% CI 2.0 - 2.5%), 3.5% (95% CI 3.2 - 3.8%), and 5.2% (95% CI 4.8 - 5.6%) for patients with low, low moderate, moderate high, and high score, respectively. Using patients with low risk as reference, the OAC3-PAD score effectively categorised patients, demonstrating statistically significant differences in bleeding risk across strata. However, the score showed modest discriminative performance, with a C statistic of 65% (95% CI 63 - 66%) and a Brier score of 2.6% (95% CI 2.5 - 2.7%). Nevertheless, it performed significantly better than the null model, as indicated by an IPA of 3.1%. CONCLUSION: Among patients who underwent invasive treatment for symptomatic PAD in routine care, the OAC3-PAD score was associated with greater risk of major bleeding with increasing score level. However, its discriminatory ability was modest, and the clinical utility remains to be determined.

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.

Similarities and differences in systemic risk factors for retinal artery occlusion and retinal vein occlusion: A nationwide case-control study.

BACKGROUND: To investigate the relationship between risk factors for retinal artery occlusion (RAO) and retinal vein occlusion (RVO) and thereby identify similarities and differences between the two types of retinal vascular occlusions. METHODS: In this case-control study, 5708 patients with RAO were included and matched with three patients with RVO each. The patients with RVO were matched on sex and age at index date. All patients, personal information, diagnoses, and prescriptions were obtained from the Danish nationwide registries. Adjusted conditional logistic regression was used to investigate the association of RAO and RVO with the included risk factors. RESULTS: RAO was stronger associated with arterial hypertension, heart failure, ischemic heart disease, peripheral artery disease, and stroke than RVO, with effect measures ranging from 1.10 to 2.21. RVO was associated with cataract and glaucoma with effect measures of 0.80 (95% CI 0.73-0.87) and 0.65 (95% CI 0.56-0.76), respectively. CONCLUSION: Differences in the level of associations with the included risk factors suggests differences in the pathophysiologies of the two diseases. The main pathophysiology associated with RAO was atherosclerosis, whereas the main pathophysiology associated with RVO was changes in the pressure gradients of the eyes.

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.

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.

Revascularisation for Symptomatic Peripheral Artery Disease: External Applicability of the VOYAGER PAD Trial.

OBJECTIVE: In the VOYAGER PAD trial, rivaroxaban 2.5 mg plus aspirin significantly reduced the primary composite efficacy outcome of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death compared with aspirin alone. However, patients enrolled in the trial may not reflect patients encountered in daily clinical practice. This study described the proportion of patients eligible for VOYAGER PAD within the nationwide Danish Vascular Registry (DVR), reasons for ineligibility, and outcomes according to eligibility. METHODS: In total, 32 911 patients who underwent lower extremity revascularisation for symptomatic peripheral arterial disease (PAD) in the DVR (2000-2016) were identified. Trial inclusion and exclusion criteria were applied, and the three year cumulative incidence of primary and secondary trial outcomes was estimated. RESULTS: Altogether, 27.1% of patients with PAD in the DVR were "VOYAGER eligible". Of those not included, 30.7% had at least one exclusion criterion ("VOYAGER excluded"), and an additional 42.3% did not fulfil the inclusion criteria ("VOYAGER not included"). The main reasons for exclusion were atrial fibrillation (32.3%), poorly regulated hypertension (20.6%), requirement for long term dual antiplatelet therapy (10.9%), cytochrome P450 inhibitors or inducers (9.7%), and renal failure (9.3%). The three year rate of the primary efficacy outcome was 10.08 per 100 person years among the "VOYAGER eligible", 16.32 among "VOYAGER excluded", and 6.98 among the "VOYAGER not included". For the primary safety outcome of thrombolysis in myocardial infarction (TIMI) major bleeding, rates were 2.24, 3.76, and 1.17, respectively. Rates of secondary endpoints were also consistently lower for patients who did not meet the inclusion criteria (predominantly due to central aorto-iliac procedures) and highest for "VOYAGER excluded" patients. "VOYAGER eligible" patients experienced a higher cumulative incidence of most endpoints than patients enrolled in the control arm of the VOYAGER PAD trial. CONCLUSION: Among patients in routine clinical practice, 27.1% were eligible for the VOYAGER PAD trial. These patients were older, had more severe vascular symptoms, higher bleeding risk, and worse prognosis than trial participants.

Similarities and Differences in Systemic Risk Factors for Retinal Artery Occlusion and Stroke: A Nationwide Case-Control Study.

BACKGROUND: Retinal artery occlusion (RAO) has been considered a stroke equivalent. This study compares risk factor profiles for thromboembolism among patients with RAO and stroke, respectively. METHODS: This case-control study is based on 5683 RAO patients entered in the Danish National Patient Register between 1st of January 2000 and 31st of December 2018. Cases were matched on sex, year of birth, and age at event with 28,415 stroke patients. The Danish nationwide registries were used to collect information about age, sex, previous diagnoses, and drug prescriptions. Adjusted conditional logistic regression models were used to investigate the association between hypothesised risk factors and the patient outcome. RESULTS: For atrial fibrillation, a substantially stronger association to stroke was found, with an odds ratio (OR) of 0.52 (95% CI: 0.47-0.58) when comparing RAO patients with stroke patients. RAO was stronger associated with arterial hypertension, peripheral artery disease, retinal vein occlusion, cataract, and glaucoma with OR's ranging from 1.21-11.70. The identified effect measures reached equivalence or was close to equivalence for diabetes, heart failure, ischemic heart disease, and renal disease. CONCLUSION: The differences in risk factor profiles between RAO and stroke suggests differences in the pathophysiology of the two diseases. These variations in pathophysiologies between the two diseases may indicate that different interventions are needed to ensure the optimal long-term prognosis for the patients.

Clinical risk factors for retinal artery occlusions: a nationwide case-control study.

PURPOSE: This study seeks to examine potential risk factors for the development of retinal artery occlusions (RAO). METHODS: We used data obtained from Danish nationwide registries to evaluate potential risk factors for RAO present up to 5 years prior to the RAO diagnosis. The study included 5312 patients diagnosed with RAO registered in the Danish National Patient Register and 26,560 controls assessed from the general population matched on sex and age at index date. Adjusted conditional logistic regression was used to estimate the odds ratio of included risk factors for RAO diagnosis. We conducted supplementary analyses stratified on sex and age, and on RAO subtype. In addition, interaction analyses were performed between strata in the stratified analyses. RESULTS: Risk factors associated with the development of RAO included diabetes, arterial hypertension, ischemic heart disease, peripheral artery disease, stroke, renal disease, cataract, and glaucoma, with ORs ranging from 1.33 to 4.94. Atrial fibrillation and sleep apnea yielded effect measures close to equivalence. The presence of a risk factor was generally associated with higher odds of RAO among the population ≤ 55 of age. Arterial hypertension was stronger associated with RAO in male patients than in female patients. The association with arterial hypertension was stronger for CRAO than for BRAO subtype. CONCLUSION: The investigated risk factors suggest that atherosclerosis and conditions changing the intraocular pressure are involved in the pathophysiology of RAO.

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.

Disease progression after ablation for atrial flutter compared with atrial fibrillation: A nationwide cohort study.

AIMS: The aim of this study was to study the risk of death and development of arrhythmia and/or subsequently heart failure after an atrial flutter ablation procedure compared with an atrial fibrillation (AF) ablation procedure. METHODS: This observational study is based on data from Danish nationwide health databases. Patients with a first-time ablation procedure for either atrial flutter or AF in the period 2000-2016 were included. Rates of renewed arrhythmia, heart failure or death were compared and reported as adjusted hazard ratios (HR). RESULTS: The study population consisted of 2,004 and 3,803 patients with an incident atrial flutter or AF ablation procedure, respectively. All-cause mortality among atrial flutter patients was significantly higher compared with the AF group (HR 1.80, 95% confidence interval [CI] 1.39-2.35). The incidence of renewed arrhythmia without heart failure was lower in atrial flutter (HR 0.76, 95% CI 0.69-0.84). Renewed atrial flutter ablation and pacemaker implantations were significantly more frequent (HR 2.42, 95% CI 2.02-2.91 and HR 1.42, 95% CI 1.13-1.79, respectively) in atrial flutter compared with AF. The risk of heart failure was higher for atrial flutter, both after the initial ablation (HR 1.48, 95% CI 1.08-2.03), and after a further arrhythmia management event (HR 1.98, 95% CI 1.33-2.94). CONCLUSION: There was a higher mortality risk after atrial flutter ablation procedures compared with patients undergoing AF ablation. Rates of heart failure and further renewed (non-AF) arrhythmia management were higher in atrial flutter.

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.

Effect of Anticoagulation on Hospitalization Costs After Intracranial Hemorrhage in Atrial Fibrillation: A Registry Study.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is the most feared adverse event with oral anticoagulant therapy in patients with atrial fibrillation. The health economic aspects of resuming oral anticoagulant therapy after ICH are unknown. The aim was to estimate hospitalization costs of thromboembolism and hemorrhage subsequent to ICH in 2 patient groups with atrial fibrillation surviving the first 90 days post ICH: (1) patients resuming warfarin therapy within 90 days post ICH and (2) patients discontinuing therapy. METHODS: Retrospective data from Danish national registries were linked to identify patients with atrial fibrillation who suffered an ICH between January 1, 1997, and April 1, 2011. Study start was 90 days after incident ICH. Mortality was evaluated using the Kaplan-Meier estimate. Occurrence of hospitalization-requiring thromboembolism and hemorrhage was used to estimate hospitalization costs by linkage of International Classification of Diseases, Tenth Revision, codes to Danish Diagnosis-Related Group tariffs. The effect of resuming warfarin therapy on average 3-year hospitalization costs was estimated by regression analysis adjusted for between-group differences in baseline characteristics. RESULTS: In the inclusion period, 2162 patients had an ICH; 1098 survived the first 90 days and were included for analysis, and of those, 267 resumed warfarin therapy. Therapy resumption reduced the mean 3-year hospitalization cost of hospitalized patients significantly by US$ 1588 (95% confidence interval, -2925 to -251) and was significantly correlated with fewer hospitalization days per hospitalized patient (-4.6 [95% confidence interval, -7.6 to -1.6]). The marginal effect of therapy resumption on hospitalization costs per patient was US$ -407 (95% confidence interval, -815 to 2). CONCLUSIONS: Resuming warfarin therapy within 90 days after ICH in patients with atrial fibrillation is associated with a decrease in average hospitalization costs.

Multiple Silent Lacunes Are Associated with Recurrent Ischemic Stroke.

BACKGROUND: Silent lacunes are a common finding on brain imaging in ischemic stroke patients, but the prognostic significance of these lesions is uncertain. We aimed at investigating the association of silent lacunes and the risk of ischemic stroke recurrence, death, and cardiovascular events in a cohort of patients with incident ischemic stroke and no atrial fibrillation (AF). METHODS: We included 786 patients (mean age 59.5 (SD 14.0); 42.9% females) in a registry-based, observational cohort study on patients with first-ever ischemic stroke. On brain MRI we assessed the number of silent lacunes as none, single, or multiple and we calculated stratified incidence rates of the outcomes. Cox proportional hazard ratios (HRs) adjusted for age, gender, congestive heart failure, hypertension, diabetes, and vascular disease were calculated with no silent lacunes as reference. In additional analyses, we further adjusted for white matter hyperintensities. Patients were followed up until death or recurrence of ischemic stroke. RESULTS: In 81 (10.3%) patients, a single silent lacune was present, and in 87 (11.1%) patients, multiple silent lacunes were present. Patients with at least one silent lacune were older (mean age 66.1 vs. 57.7, p < 0.001) and were more often hypertensive (60.1 vs. 43.4%, p < 0.001) compared to patients with no silent lacunes. During a median follow-up time of 2.9 (interquartile range 3.1) years, we observed 53 recurrent ischemic strokes, 76 deaths, and 96 cardiovascular events. Incidence rates per 100 person-years of ischemic stroke recurrence were 1.6, 2.5, and 5.0 for none, single, and multiple silent lacunes respectively. Corresponding incidence rates were 2.6, 2.4, and 4.4 for death, and 3.4, 4.0, and 6.6 for cardiovascular events respectively. Adjusted HRs of ischemic stroke recurrence were 1.53 (0.67-3.49) and 2.52 (1.25-5.09) for a single and multiple silent lacunes, respectively. Further adjustment for white matter hyperintensities maintained positive association although not significant. Corresponding adjusted HRs were 0.56 (0.25-1.25) and 0.65 (0.33-1.25) for death and 1.16 (0.61-2.22) and 1.51 (0.86-2.66) for cardiovascular events. CONCLUSIONS: In this large cohort of patients with incident ischemic stroke and no AF, an increasing number of silent lacunes was associated with increasing incidence rates of ischemic stroke recurrence. In the adjusted Cox proportional hazard analyses, the presence of multiple silent lacunes was significantly associated with an increased risk of ischemic stroke recurrence. The risk of death or cardiovascular events was not significantly influenced by the presence of silent lacunes.

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.

Age dependence of risk factors for stroke and death in young patients with atrial fibrillation: a nationwide study.

BACKGROUND AND PURPOSE: The risk of stroke and death in patients with atrial fibrillation is strongly associated with age and concomitant comorbidities. The aim of this study was to examine the age dependence of risk factors for stroke and mortality in young patients with atrial fibrillation. METHODS: This study is a population-based cohort study of 30- to 65-year-old patients with atrial fibrillation and diagnosed during 2000 to 2011, identified by record linkage between nationwide Danish registries. Cox regression models were used to estimate the risk of stroke and mortality according to risk factors within age groups: 30 to 50, 50 to 65, and 65 to 75 years. RESULTS: We identified 73,799 nonvalvular atrial fibrillation patients, of which 37,782 (51.2%) were <65 years old (mean age 62.8). A higher modified cardiac failure or dysfunction, hypertension, age 75 (doubled), diabetes, stroke (doubled), vascular disease, age 65-74 and sex category (female) score (CHA2DS2-VASc score) was associated with decreased survival probability in all age groups. The overall incidence of stroke per year for 1 year (5 years) follow-up was 1.2% (0.6%), 3.5% (1.6%), and 5.6% (2.8%), respectively, for the age groups of 30 to 50, 50 to 65, and 65 to 75. Overall, risk factors such as previous stroke, heart failure, vascular disease, diabetes mellitus, and hypertension remained independent predictors of stroke and death in patients<65 years old with nonvalvular atrial fibrillation. CONCLUSIONS: The CHA2DS2-VASc score is an applicable tool for all age groups and in nonvalvular atrial fibrillation patients<65 years old, the same risk factors apply.

Does atrial pacing lead to atrial fibrillation in patients with sick sinus syndrome? Insights from the DANPACE trial.

AIMS: Paroxysmal atrial fibrillation (AF) is common in patients with sick-sinus syndrome (SSS) and pacemakers leading to morbidity and an increased risk of stroke or death. Previous studies indicate that atrial pacing may precipitate AF. We investigated the relation between atrial pacing and the occurrence of AF during long-term follow-up among patients with SSS, no prior AF, and dual-chamber pacemakers (DDDRs). METHODS AND RESULTS: We analysed data from 396 patients who received DDDR pacemakers in the DANPACE trial. The percentage of atrial pacing (%AP) was compared with the number of mode-switch (MS) episodes collected by the pacemaker at each follow-up as an indicator of AF. Mean follow-up was 4.2 ± 2.4 years. The mean proportion of atrial and ventricular pacing was 59 ± 31 and 65 ± 33%, respectively. Approximately 72% developed AF as indicated by MS episodes at some point during follow-up. Unadjusted regression analysis indicated a relation between %AP and AF (P = 0.04), but after adjustment for possible confounders (sex, age, hypertension, diabetes, myocardial infarction, PQ interval, and left atrial diameter) there was no significant relationship (P = 0.37). CONCLUSION: Atrial fibrillation is very common among patients with SSS. No association between %AP and development of AF was found in patients with SSS. Future trials may randomize patients to different levels of AP exposure.

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.