Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study.

BACKGROUND: Comparative data of non-vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF). OBJECTIVE: We compared effectiveness and safety of standard and reduced dose NOAC in AF patients. METHODS: Using Danish nationwide registries, we included all oral anticoagulant-naïve AF patients who initiated NOAC treatment (2012-2016). Outcome-specific and mortality-specific multiple Cox regressions were combined to compute average treatment effects as 1-year standardized differences in stroke and bleeding risks (g-formula). RESULTS: Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran-reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1-year standardized absolute risks of stroke/thromboembolism were 1.73-1.98% and 2.51-2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1-year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42-3.17%); corresponding absolute risk differences (95% CI) were for dabigatran -0.93% (-1.45% to -0.38%) and apixaban, -0.54% (-0.99% to -0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1-year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22-0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06-0.41%) and apixaban, 0.18% (0.01-0.34%). CONCLUSIONS: Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban.

Initiation of anticoagulation in atrial fibrillation: which factors are associated with choice of anticoagulant?

BACKGROUND: The use of non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prophylaxis in atrial fibrillation (AF) is increasing rapidly. We compared characteristics of AF patients initiated on NOACs versus vitamin K antagonists (VKAs). METHODS: Using Danish nationwide registry data, we identified AF patients initiating either a VKA or a NOAC from 22 August 2011 until 30 September 2016. We compared patient characteristics including age, gender, comorbidities, concomitant pharmacotherapy and CHA2 DS2 -VASc and HAS-BLED scores in patients initiated on a VKA, dabigatran, rivaroxaban or apixaban. Differences were examined using multivariable logistic regression models. RESULTS: The study population comprised 51 981 AF patients of whom 19 989 (38.5%) were initiated on a VKA, 13 242 (25.5%) on dabigatran, 8475 (16.3%) on rivaroxaban and 10 275 (19.8%) on apixaban. Those patients initiated on apixaban had higher mean ± SD CHA2 DS2 -VASc scores than those initiated on a VKA (3.1 ± 1.6 vs. 2.9 ± 1.6). Those initiated on dabigatran had lower mean CHA2 DS2 -VASc scores (2.7 ± 1.6) than all other groups. Patients with a history of a prior stroke were significantly more likely to be initiated on a NOAC compared with a VKA [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.28-1.43]. By contrast, patients with a history of myocardial infarction were less likely to be initiated on a NOAC compared with a VKA (OR 0.72, 95% CI 0.67-0.77). CONCLUSIONS: Atrial fibrillation patients who were initiated on apixaban had higher stroke risk scores than patients initiated on VKAs. Interestingly, opposite results were found for dabigatran.

Antipsychotics and associated risk of out-of-hospital cardiac arrest.

Antipsychotic drugs have been associated with sudden cardiac death, but differences in the risk of out-of-hospital cardiac arrest (OHCA) associated with different antipsychotic drug classes are not clear. We identified all OHCAs in Denmark (2001-2010). The risk of OHCA associated with antipsychotic drug use was evaluated by conditional logistic regression analysis in case-time-control models. In total, 2,205 (7.6%) of 28,947 OHCA patients received treatment with an antipsychotic drug at the time of the event. Overall, treatment with any antipsychotic drug was associated with OHCA (odds ratio (OR) = 1.53, 95% confidence interval (CI): 1.23-1.89), as was use with typical antipsychotics (OR = 1.66, CI: 1.27-2.17). By contrast, overall, atypical antipsychotic drug use was not (OR = 1.29, CI: 0.90-1.85). Two individual typical antipsychotic drugs, haloperidol (OR = 2.43, CI: 1.20-4.93) and levomepromazine (OR = 2.05, CI: 1.18-3.56), were associated with OHCA, as was one atypical antipsychotic drug, quetiapine (OR = 3.64, CI: 1.59-8.30).

Retinal vein and artery occlusions: a risk factor for stroke in atrial fibrillation.

BACKGROUND: Retinal vascular occlusions may constitute an independent risk factor for stroke in patients with atrial fibrillation. METHODS: We performed a retrospective study on a nationwide cohort with atrial fibrillation from 1997 to 2008. The rate of stroke/systemic thromboembolism (TE)/transitory ischemic attack (TIA) was determined for atrial fibrillation patients with and without a history of retinal vascular occlusion. A Cox regression analysis, adjusted for risk factors and medications, was performed to determine the independent predictive value of retinal arterial or venous occlusion for the risk of ischemic stroke, TE or TIA in atrial fibrillation patients. RESULTS: We included 87 202 patients with non-valvular atrial fibrillation. At baseline, a history of retinal arterial occlusion was diagnosed in 224 patients (0.26%) and a history of retinal venous occlusion in 361 (0.41%). Patients without retinal occlusion had a rate of stroke/TE/TIA of 4.52 (95% confidence interval [CI] 4.44-4.60). For patients with retinal arterial occlusion, the rate of stroke/TE/TIA was 8.16 (95% CI 6.35-10.49) per 100 person-years, and for patients with retinal venous occlusion it was 7.28 (95% CI 5.93-8.94) per 100 person-years. In multivariate analysis, both retinal arterial occlusions (hazard ratio [HR] 1.39, 95% CI 1.08-1.79) and retinal venous occlusions (HR 1.26, 95% CI 1.02-1.54) were associated with an increased risk of future stroke/TE/TIA. CONCLUSIONS: A history of retinal arterial or retinal venous occlusion is associated with an increased risk of stroke/TE/TIA in patients with atrial fibrillation. Thus, prior retinal vascular occlusion may be considered as a previous thromboembolic event when evaluating stroke risk in patients with atrial fibrillation.

Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study.

BACKGROUND: Female sex has been suggested as a risk factor for stroke/thromboembolism in patients with non-valvular atrial fibrillation (AF) and has therefore been included within risk scores, e.g., the CHA2 DS2 -VASc score, and guidelines. OBJECTIVES: To investigate the risk of stroke/thromboembolism associated with female sex in non-valvular AF patients. PATIENTS/METHODS: Using the national Danish registers, we identified non-anticoagulated patients discharged with non-valvular AF (1997-2008), and subdivided the population into three age intervals: < 65, 65-74 and ≥ 75 years. We calculated stroke rates according to sex, and assessed the stroke risk associated with female sex by using Cox regression analysis. RESULTS: We included 87,202 AF patients, and 44,744 (51.3%) were female. The rate of stroke/thromboembolism for females aged < 65 and 65-74 years was not increased as compared with men, whereas the rate for females aged ≥ 75 years was increased. At both 1-year and 12-year follow-up, female sex did not increase the risk of stroke for patients aged < 75 years. At 1-year follow-up, the hazard ratios associated with female sex were 0.89 (95% confidence interval [CI] 0.70-1.13) and 0.91 (95 CI 0.79-1.05) for patients aged < 65 and 65-74 years, respectively, and being female and aged ≥ 75 years was associated with an increased risk of stroke of 1.20 (95 CI 1.12-1.28). CONCLUSION: Female sex was only associated with an increased risk of stroke for AF patients aged ≥ 75 years. Our study suggests that female sex should not be automatically included as an independent stroke/thromboembolic risk factor in guidelines or in the CHA2 DS2 -VASc score, without careful prior consideration of the 'age < 65 and lone AF' criterion.

Antidepressant use and risk of out-of-hospital cardiac arrest: a nationwide case-time-control study.

Treatment with some types of antidepressants has been associated with sudden cardiac death. It is unknown whether the increased risk is due to a class effect or related to specific antidepressants within drug classes. All patients in Denmark with an out-of-hospital cardiac arrest (OHCA) were identified (2001-2007). Association between treatment with specific antidepressants and OHCA was examined by conditional logistic regression in case-time-control models. We identified 19,110 patients with an OHCA; 2,913 (15.2%) were receiving antidepressant treatment at the time of OHCA, with citalopram being the most frequently used type of antidepressant (50.8%). Tricyclic antidepressants (TCAs; odds ratio (OR) = 1.69, confidence interval (CI): 1.14-2.50) and selective serotonin reuptake inhibitors (SSRIs; OR = 1.21, CI: 1.00-1.47) were both associated with comparable increases in risk of OHCA, whereas no association was found for serotonin-norepinephrine reuptake inhibitors/noradrenergic and specific serotonergic antidepressants (SNRIs/NaSSAs; OR = 1.06, CI: 0.81-1.39). The increased risks were primarily driven by: citalopram (OR = 1.29, CI: 1.02-1.63) and nortriptyline (OR = 5.14, CI: 2.17-12.2). An association between cardiac arrest and antidepressant use could be documented in both the SSRI and TCA classes of drugs.

Bleeding risk in 'real world' patients with atrial fibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort.

BACKGROUND: Oral anticoagulation (OAC) in patients with atrial fibrillation (AF) is a double-edged sword, because it decreases the risk of stroke at the cost of an increased risk of bleeding. We compared the performance of a new bleeding prediction scheme, HAS-BLED, with an older bleeding prediction scheme, HEMORR(2)HAGES, in a cohort of 'real-world' AF patients. METHODS: By individual-level-linkage of nationwide registers, we identified all patients (n = 118,584) discharged with non-valvular AF in Denmark during the period 1997-2006, with and without OAC. Major bleeding rates during 1 year of follow-up were determined, and the predictive capabilities of the two schemes were compared by c-statistics. The risk of bleeding associated with individual risk factors composing HAS-BLED was estimated using Cox proportional-hazard analyses. RESULTS: Of AF patients receiving OAC (n = 44,771), 34.8% and 47.3% were categorized as 'low bleeding risk' by HAS-BLED and HEMORR(2)HAGES, respectively, and the bleeding rates per 100 person-years were 2.66 (95% confidence interval [CI], 2.40-2.94) and 3.06 (2.83-3.32), respectively. C-statistics for the two schemes were 0.795 (0.759-0.829) and 0.771 (0.733-0.806), respectively. The risk factors composing HAS-BLED were associated with varying risks, with a history of bleeding (hazard ratio [HR] 2.98; 95% CI 2.68-3.31) and being elderly (HR 1.93; 95% CI 1.71-2.18) being associated with the highest risks. Comparable results were found in AF patients not receiving OAC (n = 77,813). CONCLUSIONS: In an unselected nationwide cohort of hospitalized patients with atrial fibrillation, the HAS-BLED score performs similarly to HEMORR(2)HAGES in predicting bleeding risk but HAS-BLED is much simpler and easier to use in everyday clinical practise.

Prognosis following first-time myocardial infarction in patients with psoriasis: a Danish nationwide cohort study.

OBJECTIVES: The magnitude of cardiovascular risk associated with psoriasis has been debated and the prognostic impact of psoriasis following myocardial infarction (MI) is unknown. Therefore, we investigated the risk of mortality and adverse cardiovascular events in patients with psoriasis following first-time MI. DESIGN, SETTING AND PARTICIPANTS: Cohort study of the entire Danish population including all individuals who experienced first-time MI during the period 2002-2006. Multivariable Cox regression models were used to assess the post-MI prognostic impact of psoriasis. Main outcome measures. All-cause mortality and a composite cardiovascular end-point of recurrent MI, stroke and cardiovascular death. RESULTS: A total of 462 patients with psoriasis and 48 935 controls (mean age 69.5 and 70.6 years, respectively) were identified with first-time MI during the study period. The mean follow-up was 19.5 months [standard deviation (SD) 16.5] for patients with psoriasis and 22 .0 months (SD 18.7) for those without psoriasis. Incidence rates (IRs) per 1000 patient-years for all-cause mortality were 119.4 [95% confidence interval (CI) 117.2-138.3] and 138.3 (95% CI 114.1-167.7) for patients without and with psoriasis, respectively, and the adjusted hazard ratio (HR) associated with psoriasis was 1.18 (95% CI 0.97-1.43). For the composite end-point, the IRs were 149.7 (95% CI 147.1-152.4) and 185.6 (95% CI 155.8-221.0) for patients without and with psoriasis, respectively, with an HR of 1.26 (95% CI 1.04-1.54) for patients with psoriasis. CONCLUSION: This first study of the impact of psoriasis on prognosis after first-time MI indicated a significantly impaired prognosis in patients with psoriasis. Further studies of this novel association are warranted.

Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study.

OBJECTIVE: The magnitude of the cardiovascular risk from psoriasis and psoriatic arthritis is debated. We therefore investigated the psoriasis-related risk of adverse cardiovascular events and mortality. DESIGN, SETTING AND SUBJECTS: We conducted a cohort study of the entire Danish population aged ≥18 years followed from 1997 to 2006 by individual-level linkage of nationwide registers. Psoriasis was defined by prescription claims and classified as severe if patients received hospital-based treatment. Time-dependent Poisson regression models were applied to assess cardiovascular risk in patients with psoriasis and psoriatic arthritis. MAIN OUTCOME MEASURES: All-cause mortality, cardiovascular mortality and hospitalizations for myocardial infarction (MI), stroke and coronary revascularization were recorded. RESULTS: A total of 34 371 patients with mild psoriasis and 2621 with severe psoriasis, including 607 with psoriatic arthritis, were identified and compared with 4 003 265 controls. The event rates and rate ratios (RRs) of all-cause mortality, cardiovascular death, MI, coronary revascularization, stroke and a composite of MI, stroke and cardiovascular death were increased in patients with psoriasis. The rate ratio increased with disease severity and decreased with age of onset. The overall RRs for the composite endpoint were 1.20 (95% confidence interval [CI] 1.14-1.25) and 1.58 (95% CI 1.36-1.82) for mild and severe psoriasis, respectively. The corresponding RRs for cardiovascular death were 1.14 (95% CI 1.06-1.22) and 1.57 (95% CI1.27-1.94). The risk was similar in patients with severe skin affection alone and those with psoriatic arthritis. CONCLUSIONS: Psoriasis is associated with increased risk of adverse cardiovascular events and all-cause mortality. Young age, severe skin affection and/or psoriatic arthritis carry the most risk. Patients with psoriasis may be candidates for early cardiovascular risk factor modification.

Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study.

AIMS/HYPOTHESIS: The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern. We investigated the risk of all-cause mortality associated with individual glucose-lowering treatment regimens used in current clinical practice in Denmark. METHODS: All patients aged ≥ 30 years hospitalised for the first time for heart failure in 1997-2006 were identified and followed until the end of 2006. Patients who received treatment with metformin, a sulfonylurea and/or insulin were included and assigned to mono-, bi- or triple therapy groups. Multivariable Cox proportional hazard regression models were used to assess the risk of all-cause mortality. RESULTS: A total of 10,920 patients were included. The median observational time was 844 days (interquartile range 365-1,395 days). In total, 6,187 (57%) patients died. With sulfonylurea monotherapy used as the reference, adjusted hazard ratios for all-cause mortality associated with the different treatment groups were as follows: metformin 0.85 (95% CI 0.75-0.98, p = 0.02), metformin + sulfonylurea 0.89 (95% CI 0.82-0.96, p = 0.003), metformin + insulin 0.96 (95% CI 0.82-1.13, p = 0.6), metformin + insulin + sulfonylurea 0.94 (95% CI 0.77-1.15, p = 0.5), sulfonylurea + insulin 0.97 (95% CI 0.86-1.08, p = 0.5) and insulin 1.14 (95% CI 1.06-1.20, p = 0.0001). CONCLUSIONS/INTERPRETATION: Treatment with metformin is associated with a low risk of mortality in diabetic patients with heart failure compared with treatment with a sulfonylurea or insulin.

A role for calcium/calmodulin kinase in insulin stimulated glucose transport.

Previous research has shown that the CAMK (calcium/calmodulin dependent protein kinase) inhibitor, KN62, can lead to reductions in insulin stimulated glucose transport. Although controversial, an L-type calcium channel mechanism has also been hypothesized to be involved in insulin stimulated glucose transport. The purpose of this report was to determine if 1) L-type calcium channels and CAMK are involved in a similar signaling pathway in the control of insulin stimulated glucose transport and 2) determine if insulin induces an increase in CAMKII phosphorylation through an L-type calcium channel dependent mechanism. Insulin stimulated glucose transport was significantly (p<0.05) inhibited to a similar extent ( approximately 30%) by both KN62 and nifedipine in rat soleus and epitrochelaris muscles. The new finding of these experiments was that the combined inhibitory effect of these two compounds was not greater than the effect of either inhibitor alone. To more accurately determine the interaction between CAMK and L-type calcium channels, we measured insulin induced changes in CAMKII phosphorylation using Western blot analysis. The novel finding of this set of experiments was that insulin induced an increase in phosphorylated CAMKII ( approximately 40%) in rat soleus muscle that was reversed in the presence of KN62 but not nifedipine. Taken together these results suggest that a CAMK signaling mechanism may be involved in insulin stimulated glucose transport in skeletal muscle through an L-type calcium channel independent mechanism.

Evidence for the involvement of a phospholipase C--protein kinase C signaling pathway in insulin stimulated glucose transport in skeletal muscle.

The primary purpose of this investigation was to determine the relationship between phospholipase C (PLC) and diacylglycerol (DAG) sensitive protein kinase C isoforms in insulin signaling in skeletal muscle. Using an in vitro preparation of rat soleus muscle we found that insulin (0.6 nM) stimulated glucose transport was inhibited approximately 20 and 25% by the PKC inhibitor GF109203X and the phospholipase C inhibitor U73122 respectively (p<0.05). The combined effects of these inhibitors were no greater than the inhibitory effects of either compound alone. Western blot analysis revealed that insulin induced a redistribution of PKC beta II from the cytosol to the membrane that was reversed in the presence of GF109203X (1 microM) and U73122 (20 microM). Similarly, U73122 and GF109203X reversed the insulin induced increase in membrane associated phosphorylated (ser 660) PKC beta II. The novel finding of this investigation is that insulin induces an increase in PKC beta II translocation and phosphorylation through a U73122 sensitive pathway in quantatively the most important insulin responsive tissue, skeletal muscle. Furthermore, these results imply that PKC beta II may be one of the DAG sensitive isoforms involved in glucose transport.

Distribution of Ehrlichia chaffeensis (Rickettsiales: Rickettsiaeceae) in Amblyomma americanum in southern Indiana and prevalence of E. chaffeensis--reactive antibodies in white-tailed deer in Indiana and Ohio in 1998.

To continue monitoring the prevalence and distribution of Ehrlichia chaffeensis (Rickettsiales: Rickettsiaeceae) in southern Indiana, a total of 498 Amblyomma americanum (L.) ticks (262 adults and 292 nymphs) was collected from five southern Indiana counties during May and June 1998. Ticks were pooled and examined for the presence of E. chaffeensis using nested polymerase chain reaction and primers specific for the 16S rRNA gene of E. chaffeensis. The average minimum infection rate for adult ticks collected in 1998 was 3.8% (ranging from 0 to 7.7% in various counties) as compared with previous average minimum infection rates of 1.6% in 1995 and 4.9% in 1997. None of the pools of A. americanum nymphs tested positive. In addition, blood samples were collected from 325 white-tailed deer taken in Indiana and 327 taken in Ohio in November 1998. Serum samples were tested for the presence of E. chaffeensis-like organisms reactive to antibodies using an indirect immunofluorescence assay (IFA). Antibodies were found in deer from six Indiana counties where infection rates ranged from 42.6 to 66.7% and in four Ohio countries where infection rates ranged from 4.4 to 25%. The results of this study reconfirm that E. chaffeensis is well established in southern Indiana and also provide the first evidence of E. chaffeensis-like organisms infecting white-tailed deer in Ohio, suggesting the need to survey Ohio ticks for the presence of Ehrlichia.