Antiplatelet Therapy in Patients With Abdominal Aortic Aneurysm Without Symptomatic Atherosclerotic Disease.

Importance: Patients with abdominal aortic aneurysm have a high risk of ischemic events associated with concomitant atherosclerotic cardiovascular disease, and current clinical practice guidelines recommend antiplatelet therapy to mitigate this risk. However, in patients with aneurysms without symptomatic atherosclerosis, the benefit of antiplatelet therapy has been sparsely investigated. Objective: To estimate the effect of antiplatelets on the risk of ischemic events and bleeding in individuals with abdominal aneurysms with no symptomatic atherosclerotic vascular disease. Design, Setting, and Participants: A comparative effectiveness research study using a target trial emulation framework was performed. Population-based, cross-linked observational data from Danish national health registries containing comprehensive, individual-level information on all Danish citizens were used to evaluate patients who were antiplatelet-naive and diagnosed with abdominal aortic aneurysms, with no record of symptomatic atherosclerotic vascular disease, from January 1, 2010, through August 21, 2021. Exposure: Prescription filled for aspirin or clopidogrel. Main Outcomes and Measures: Risk of ischemic events (myocardial infarction and/or ischemic stroke) and risk of major bleeding. For target trial emulation, trials were emulated as sequential, contingent on patient eligibility at the time of inclusion, and were evaluated by means of pooled logistic regression models to estimate the intention-to-treat and as-treated effects, expressed as hazard ratio (HR) and event-free survival. Results: A total of 6344 patients (65.2% men; age, 72 [IQR, 64-78] years) provided 131 047 trial cases; 3363 of these cases involved initiation of antiplatelet therapy and 127 684 did not. A total of 182 ischemic events occurred among initiators and 5602 ischemic events occurred among noninitiators, corresponding to an intention-to-treat HR of 0.91 (95% CI, 0.73-1.17) and an estimated absolute event-free survival difference of -0.6% (95% CI, -1.7% to 0.5%). After censoring nonadherent person-time, the treatment HR was 0.90 (95% CI, 0.68-1.20), with similar risk difference. For bleeding, the intention-to-treat HR was 1.26 (95% CI, 0.97-1.58) and the event-free survival difference was 1.0%. The treatment HR was 1.21 (95% CI, 0.82-1.72); the risk difference was similar. Conclusions and Relevance: In this study, no evidence of effectiveness of antiplatelet therapy to lower the risk of ischemic events and a trend toward higher bleeding risk was noted. The observed differences between the treatment groups were minimal, suggesting limited clinical relevance of antiplatelet treatment.

Incidence of venous thromboembolism following head and neck surgery.

PURPOSE: Venous thromboembolism (VTE) is associated with significant morbidity and mortality in patients undergoing surgery, but conflicting data exist on VTE risk in patients undergoing head and neck surgery for malignant and non-malignant conditions. Our aim was to examine the risk of VTE among patients with and without cancer undergoing head and neck surgery. METHODS: We conducted a nationwide cohort study to examine the risk of VTE among patients with an otolaryngological diagnosis using data from the Danish National Patient Register between 2010 and 2018. Analyses were stratified by cancer and anatomical areas of the surgical procedure. RESULTS: In total, 116,953 patients were included of whom 10% (n = 12,083) had active cancer. After 3 months, 1.2% of the patients with cancer and 0.3% of the patients without cancer experienced VTE, respectively. For patients undergoing mouth/throat surgery, 0.8% with cancer and 0.2% without cancer had VTE, respectively. After nose/sinuses surgery 0.7% and 0.2%, respectively. No patients experienced VTE after ear surgery; and after endoscopies the numbers were 1.3% and 0.6% respectively. CONCLUSIONS: While the minority of patients undergoing head and neck surgery develop VTE postoperatively, the risk increases among those with cancer. To support clinical decision making on anticoagulation, risk stratification tools could be further developed to recognize this hazard in patients with cancer undergoing head and neck surgery.

A global phylogeny of butterflies reveals their evolutionary history, ancestral hosts and biogeographic origins.

Butterflies are a diverse and charismatic insect group that are thought to have evolved with plants and dispersed throughout the world in response to key geological events. However, these hypotheses have not been extensively tested because a comprehensive phylogenetic framework and datasets for butterfly larval hosts and global distributions are lacking. We sequenced 391 genes from nearly 2,300 butterfly species, sampled from 90 countries and 28 specimen collections, to reconstruct a new phylogenomic tree of butterflies representing 92% of all genera. Our phylogeny has strong support for nearly all nodes and demonstrates that at least 36 butterfly tribes require reclassification. Divergence time analyses imply an origin ~100 million years ago for butterflies and indicate that all but one family were present before the K/Pg extinction event. We aggregated larval host datasets and global distribution records and found that butterflies are likely to have first fed on Fabaceae and originated in what is now the Americas. Soon after the Cretaceous Thermal Maximum, butterflies crossed Beringia and diversified in the Palaeotropics. Our results also reveal that most butterfly species are specialists that feed on only one larval host plant family. However, generalist butterflies that consume two or more plant families usually feed on closely related plants.

Small-Area Analysis of Treatment and Clinical Outcomes in Patients with Venous Thromboembolism in Denmark: A Nationwide Cohort Study.

OBJECTIVES: To investigate geographical variation in initiation and extended treatment with anticoagulants and clinical outcomes among patients hospitalized with first-time venous thromboembolism (VTE) in Denmark between 2007 and 2018. METHODS: Using nationwide health care registries, we identified all patients with a first-time VTE hospital diagnosis supported by imaging data from 2007 to 2018. Patients were grouped according to residential region (5) and municipality (98) at the time of VTE diagnosis. Cumulative incidence of initiation of and extended (beyond 365 days) anticoagulation treatment as well as clinical outcomes, including recurrent VTE, major bleeding, and all-cause death, were assessed. Sex- and age-adjusted relative risks (RRs) of the outcomes were computed when comparing across individual regions and municipalities. Overall geographic variation was quantified by computing the median RR. RESULTS: We identified 66,840 patients with a first-time VTE hospitalization. A difference in initiation of anticoagulation treatment of more than 20 percentage points between regions was observed (range: 51.9-72.4%, median RR: 1.09, 95% confidence interval [CI]: 1.04-1.13). Variation was also observed for extended treatment (range: 34.2-46.9%, median RR: 1.08, 95% CI: 1.02-1.14). The cumulative incidence of recurrent VTE ranged from 3.6 to 5.3% at 1 year (median RR: 1.08, 95% CI: 1.01-1.15). The difference remained after 5 years, and variation was also observed for major bleeding (median RR: 1.09, 95% CI: 1.03-1.15), whereas it appeared smaller for all-cause mortality (median RR: 1.03, 95% CI: 1.01-1.05). CONCLUSION: Substantial geographical variation in anticoagulation treatment and clinical outcomes occurs in Denmark. These findings indicate a need for initiatives to ensure uniform high-quality care for all VTE patients.

Stroke and Myocardial Infarction in Patients with Abdominal Aortic Aneurysm and New-Onset Atrial Fibrillation.

OBJECTIVE: We investigated the association between new-onset atrial fibrillation (AF) and risk of stroke and myocardial infarction (MI) in patients with abdominal aortic aneurysmal (AAA) disease. METHODS: Observational crossover study using Danish nationwide data, including patients with AAA and incident AF between 1997 and 2018. We estimated the 1-year risk of stroke and MI and the within-individual odds ratios (ORs) of ischemic events before and after an AF diagnosis, stratified by year of AF diagnosis (1997-2010 and 2011-2018), and supplemented with analyses on changes in use of antithrombotic therapy. RESULTS: A total of 3,035 AAA patients were included: 1,040 diagnosed during 1997 to 2010, and 1,995 during 2011 to 2018 (22.2% females, median age 78 years; median CHA2DS2-VASc score 4; interquartile range: 3-5). One-year risk of ischemic events after AF was 5.9% (confidence interval [CI] 95%: 4.6-7.5%) and 4.5% (CI 95%: 3.7-5.5%) for stroke and 5.4% (CI 95%: 4.2-6.9%) and 4.0% (CI 95%: 3.2-4.9%) for MI during 1997 to 2010 and 2011 to 2018, respectively. The OR of ischemic stroke before and after incident AF was 2.8 (CI 95%: 1.6-5.2) during 1997 to 2010; and 2.4 (CI 95%: 1.5 to 3.9) during 2011 to 2018, and 3.5 (CI 95%: 1.7-7.5) and 1.5 (CI 95%: 0.9-2.4) for MI. One-year proportion of prescription claims for oral anticoagulants after AF changed from 66.1% in 1997 to 2010 to 82.6% in 2011 to 2018, while antiplatelet prescription claims changed from 80.8 to 60.9%. CONCLUSION: Cardiovascular prognosis has improved in patients with prevalent AAA disease and new-onset AF in concordance with optimization of antithrombotic therapy over time. A diagnosis of AF conferred residual risk of stroke and MI.

The Khorana score and venous and arterial thrombosis in patients with cancer treated with immune checkpoint inhibitors: A Danish cohort study.

BACKGROUND: Thrombosis is common among patients with cancer. Primary thromboprophylaxis guided by the Khorana score is endorsed by guidelines but recommendations rely mainly on data from patients treated with chemotherapy. OBJECTIVES: To explore if the Khorana score could risk stratify patients with cancer treated with immune checkpoint inhibitors according to risk of venous and arterial thrombosis. PATIENTS/METHODS: The study population and Khorana score were defined using administrative Danish health registries. The primary outcome was 6-month risk of venous thromboembolism after initiation of checkpoint inhibitor treatment. Secondary outcomes were arterial thrombosis and any thromboembolic event. Death was considered a competing risk event. RESULTS: Among 3946 patients with cancer initiating checkpoint inhibitor treatment without other indications for anticoagulation, the overall 6-month incidence of venous thromboembolism was 2.6% (95% confidence interval [CI]: 2.1-3.1). Risks were 2.1% (95% CI: 1.5-3.0), 2.6% (95% CI: 2.0-3.4), and 3.7% (95% CI: 2.1-5.9) in low (score 0), intermediate (score 1-2), and high risk (score ≥3) Khorana categories, respectively. Among patients eligible for primary thromboprophylaxis according to guidelines (Khorana score ≥2), risk of venous thromboembolism was 4.1% (95% CI: 3.1-5.4). Higher Khorana risk category was also associated with higher 6-month risk of both arterial thrombosis and any thromboembolic events. CONCLUSIONS: The Khorana score was able to risk stratify patients with cancer treated with immune checkpoint inhibitors according to 6-month risk of thromboembolic events. Risks of venous thromboembolism were lower than in randomized thromboprophylaxis trials, thus questioning the absolute benefit of routine primary thromboprophylaxis in an unselected population of patients treated with immune checkpoint inhibitors.

Temporal trends in abdominal aortic aneurysmal disease: a nationwide cohort study on cardiovascular morbidity and medical cardioprotective therapy.

AIMS: Abdominal aortic aneurysmal disease is associated with increased risk of cardiovascular morbidity and death, which potentially can be reduced with cardioprotective medical therapy. The aim of this study was to observe temporal trends in prevalence and incidence of cardiovascular comorbidity as well as use of medical cardioprotective treatment in patients diagnosed with abdominal aortic aneurysmal disease. METHODS AND RESULTS: This was a population-based cohort study based on data from national health registries, including all patients diagnosed with abdominal aortic aneurysms between 1998 and 2018. Data were stratified into four time periods (1999-2003, 2004-2008, 2009-2013, and 2014-2018) to illustrate trends over time. Outcome measures were (i) cardiovascular comorbidity and medical cardioprotective therapy at time of diagnosis, (ii) new admissions for atherosclerotic cardiovascular disease, and (iii) all-cause mortality after 2-year follow-up. The study cohort included 33 296 individuals. Mean age was 74 years. Prevalence of atherosclerotic cardiovascular comorbidity at diagnosis decreased from 41.5 to 32.6%. Use of statins increased from 17.9 to 66.9%, antiplatelets from 45.6 to 63.3%, and combined therapy with both antiplatelets and statins from 11.3 to 44.8%, and from 12.1 to 50.7% when anticoagulant therapy was included. Developments in medication use plateaued after 2013. Prevalence and incidence of atherosclerotic cardiovascular disease decreased through all four time periods. The same applied to all-cause mortality, which decreased from 24.3 to 12.4 deaths (per 100 person-years). CONCLUSION: In patients diagnosed with abdominal aortic aneurysm, cardiovascular comorbidity at diagnosis, risk of future cardiovascular events, and all-cause mortality is decreasing. Nevertheless, cardiovascular burden and mortality rates remain substantial, and medical cardioprotective therapy can be further improved.

Thromboembolic Risk in Patients With Pneumonia and New-Onset Atrial Fibrillation Not Receiving Anticoagulation Therapy.

Importance: New-onset atrial fibrillation (AF) is commonly reported in patients with severe infections. However, the absolute risk of thromboembolic events without anticoagulation remains unknown. Objective: To investigate the thromboembolic risks associated with AF in patients with pneumonia, assess the risk of recurrent AF, and examine the association of initiation of anticoagulation therapy with new-onset AF. Design, Setting, and Participants: This population-based cohort study used linked Danish nationwide registries. Participants included patients hospitalized with incident community-acquired pneumonia in Denmark from 1998 to 2018. Statistical analysis was performed from August 15, 2021, to March 12, 2022. Exposures: New-onset AF. Main Outcomes and Measures: Thromboembolic events, recurrent AF, and all-cause death. Estimated risks were calculated for thromboembolism without anticoagulation therapy, new hospital or outpatient clinic contact with AF, initiation of anticoagulation therapy, and all-cause death at 1 and 3 years of follow-up. Death was treated as a competing risk, and inverse probability of censoring weights was used to account for patient censoring if they initiated anticoagulation therapy conditioned on AF. Results: Among 274 196 patients hospitalized for community-acquired pneumonia, 6553 patients (mean age [SD], 79.1 [11.0] years; 3405 women [52.0%]) developed new-onset AF. The 1-year risk of thromboembolism was 0.8% (95% CI, 0.8%-0.8%) in patients without AF vs 2.1% (95% CI, 1.8%-2.5%) in patients with new-onset AF without anticoagulation; this risk was 1.4% (95% CI, 1.0%-2.0%) among patients with AF with intermediate stroke risk and 2.8% (95% CI, 2.3%-3.4%) in patients with AF with high stroke risk. Three-year risks were 3.5% (95% CI, 2.8%-4.3%) among patients with intermediate stroke risk and 5.3% (95% CI, 4.4%-6.5%) among patients with high stroke risk. Among patients with new-onset AF, 32.9% (95% CI, 31.8%-34.1%) had a new hospital contact with AF, and 14.0% (95% CI, 13.2%-14.9%) initiated anticoagulation therapy during the 3 years after incident AF diagnosis. At 3 years, the all-cause mortality rate was 25.7% (95% CI, 25.6%-25.9%) in patients with pneumonia without AF vs 49.8% (95% CI, 48.6%-51.1%) in patients with new-onset AF. Conclusions and Relevance: This cohort study found that new-onset AF after community-acquired pneumonia was associated with an increased risk of thromboembolism, which may warrant anticoagulation therapy. Approximately one-third of patients had a new hospital or outpatient clinic contact for AF during the 3-year follow-up, suggesting that AF triggered by acute infections is not a transient, self-terminating condition that reverses with resolution of the infection.

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.

Comparative effectiveness and safety of direct acting oral anticoagulants in nonvalvular atrial fibrillation for stroke prevention: a systematic review and meta-analysis.

PURPOSE: To systematically review available evidence of indirect comparisons from RCTs and direct comparisons from observational studies regarding the comparative effectiveness and safety of DOACs in patients with AF. METHODS: Electronic databases including EMBASE, MEDLINE, and PUBMED were searched up to June 5th, 2020. Primary endpoints included effectiveness (stroke or systemic embolism [SE]) and safety (major bleeding) outcomes. Bucher methods and random-effects models were conducted for indirect and direct comparisons among DOACs, respectively. Ranking probability analyses and the number needed to treat for net effect (NNTnet) were applied. RESULTS: A total of 36 studies, involving 7 RCTs (n = 60,292 patients) and 29 observational studies (n = 1,164,821 patients), were included for analyses. Regarding the risk of stroke/SE, no significant differences were found from indirect comparisons of RCTs among the DOACs. For major bleeding, apixaban tended to be safer than rivaroxaban and dabigatran based on both direct and indirect comparisons (all p < 0.05; evidence quality: very low to moderate). Ranking probability analysis showed that apixaban had a high probability of being the best treatment in decreased risk of stroke/SE and major bleeding (80.30% and 91.30%, respectively). Likewise, apixaban was found to have the highest net clinical benefit (0.02, 95% CI: 0.014-0.029) and smallest NNTnet (48, 95% CI: 35-74). CONCLUSIONS: Apixaban appeared to have a favorable effectiveness-safety profile compared with the other DOACs in AF for stroke prevention, based on evidence from both direct and indirect comparisons. However, additional high-quality evidence is needed to support firm recommendations on clinical decision-making.

Thromboembolic and bleeding outcomes in patients with atrial fibrillation and valvular heart disease: A descriptive nationwide cohort study.

AIMS: The risks of thromboembolism and bleeding in patients with atrial fibrillation (AF) and valvular heart disease (VHD) are sparsely described. We described the risk of events in non-anticoagulated and anticoagulated patients with AF and VHD according to the evaluated heart valves, rheumatic or artificial valve classification (EHRA classification), EHRA Type 1 and Type 2 VHD, and within subgroups of EHRA Type 1 and Type 2 VHD. METHODS AND RESULTS: Cohort study of AF patients with coexisting VHD, identified in nationwide Danish registries from 2000 to 2018. Risk of thromboembolism and bleeding after 1 year of follow-up were calculated in each group. We identified 28 770 incident AF patients with VHD. Not surprisingly, we observed the highest risks of thromboembolism in the non-anticoagulated AF patients with EHRA Type 1 and Type 2 VHD (4.9% vs 2.6% and 3.2% vs 1.9%) and the highest risks of bleeding in the anticoagulated AF patients with EHRA Type 1 and Type 2 VHD (6.6% vs 4.3% and 6.1% vs 4.9%). However, within the subgroups of AF patients with EHRA Type 1 and Type 2 VHD, we observed a large proportion of non-anticoagulated patients (32.9%-49.2%), despite a CHA2 DS2 -VASc score of 2≤ in the majority of these patients (81.9%-95.6%). CONCLUSIONS: When using data reflecting contemporary clinical practice, we observed markedly different risks of thromboembolism and bleeding in EHRA Type 1 and Type 2 VHD. Additionally, we observed a potential underuse of oral anticoagulation within the subgroups of AF patients with EHRA Type 1 and Type 2 VHD, underlining need for further attention on this patient group.

Effect of a Physiotherapist-Guided Home-Based Exercise Intervention on Physical Capacity and Patient-Reported Outcomes Among Patients With Acute Pulmonary Embolism: A Randomized Clinical Trial.

Importance: Survivors of acute pulmonary embolism (PE) experience long-term negative physical and mental consequences, but the effects of rehabilitation on outcomes among these patients have not been investigated. Objective: To investigate the effect of a rehabilitation intervention, comprising an 8-week home-based exercise program and nurse consultations, on physical capacity and patient-reported outcomes among patients with acute PE. Design, Setting, and Participants: This multicenter randomized clinical superiority trial was conducted at 4 regional hospitals and 1 university hospital in Denmark. The 140 consecutively included participants had been diagnosed with an acute PE between April 2016 and February 2018 and had 6 months of follow-up. An intention-to-treat analysis was conducted. Intervention: Patients in the control group received a brief nurse consultation, while patients in the exercise group participated in an 8-week home-based exercise program in addition to receiving nurse consultations. Main Outcomes and Measures: The primary outcome was the Incremental Shuttle Walk Test, and secondary outcomes were the Pulmonary Embolism Quality of Life and the EuroQol-5 Dimensions-3 Levels questionnaires, self-reported number of sick-leave days, and self-reported use of psychotropic drugs. Results: A total of 140 patients (90 [64.3%] men) were included, with a mean (SD) age of 61 (11) years. Of 70 participants (50.0%) randomized to each group, 69 participants (49.3%) received the intervention and 68 (48.6%) received the control intervention. Both groups achieved improvements in all outcomes (eg, mean [SD] improvement on Incremental Shuttle Walk Test: control group, 78 (127) m; intervention group, 104 [106] m; median [interquartile range] improvement on Pulmonary Embolism Quality of Life: control group, -17 [-22 to -11] points; intervention group, -20 [-24 to -15] points). Between-group differences were nonsignificant. The mean differences between the intervention group and the control group were 25 m (95% CI, -20 to 70 m; P = .27) on the Incremental Shuttle Walk Test, 3.0 points (95% CI, -3.7 to 9.9 points; P = .39) on the Pulmonary Embolism Quality of Life questionnaire, and 0.017 point (95% CI, -0.032 to 0.065 point; P = .50) on the EuroQol-5 Dimensions-3 Levels questionnaire. Of the 27 patients in the intervention group on sick leave at baseline, 24 (88.9%) reported fit-for-duty at the 6-month follow-up, and of 18 patients in the control group on sick leave, 17 (94.4%) reported fit-for-duty at the 6-month follow up. The between-group risk difference was not significant (5.5 points; P = .49). Conclusions and Relevance: An 8-week rehabilitation intervention with exercise added to nurse consultations did not show significantly better outcomes than nurse consultations alone. However, because of a ceiling effect on the primary outcome of physical capacity and an inclusion of patients with a low comorbidity burden and low PE disease severity, definitive conclusions could not be drawn. Initiating an exercise intervention shortly after pulmonary embolism was safe and without adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT02684721.

Direct comparative effectiveness and safety between non-vitamin K antagonist oral anticoagulants for stroke prevention in nonvalvular atrial fibrillation: a systematic review and meta-analysis of observational studies.

The non-vitamin K antagonist oral anticoagulants (NOACs) have been increasingly prescribed in clinical practice for stroke prevention in patients with nonvalvular atrial fibrillation (AF). Direct comparisons between NOACs in trials are lacking, leaving an important clinical decision-making gap. We aimed to perform a systematic review and meta-analysis to summarize the evidence of observational studies for direct comparative effectiveness and safety amongst NOACs in patients with AF. Conference proceedings and electronic databases including MEDLINE, CINAHL, EMBASE and PUBMED were systematically searched. We included observational studies directly comparing individual NOACs in patients with nonvalvular AF who were aged ≥ 18 years for stroke prevention. Primary outcome included effectiveness outcome (stroke or systemic embolism) and safety outcome (major bleeding). Data were extracted in duplicated by two reviewers independently. A random-effects meta-analysis was conducted to synthesize the data from included observational studies. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to rate the overall quality of evidence for each outcome. Fifteen studies were included for qualitative synthesis, twelve studies for meta-analyses. It was found that rivaroxaban and dabigatran were similar with regard to risk of stroke or systemic embolism (Hazard ratio [HR] = 1.00, 95% CI 0.91-1.10; evidence quality: low), but rivaroxaban was associated with higher risk of major bleeding (HR = 1.39, 95% CI 1.28-1.50; evidence quality: moderate). Compared with apixaban, a significantly higher risk of major bleeding was observed with rivaroxaban (HR = 1.71, 95% CI 1.51-1.94; evidence quality: low). Apixaban was associated with lower risk of major bleeding, in comparison with dabigatran (HR = 0.80, 95% CI 0.68-0.95; evidence quality: low). No differences in risk of stroke or systemic embolism was observed between rivaroxaban versus apixaban, and apixaban versus dabigatran. In this study, apixaban was found to have the most favorable safety profile amongst the three NOACs. No significant difference was observed in risk of stroke or systemic embolism between the NOACs. Such findings may provide some decision-making support for physicians regarding their choices amongst NOACs in patients with AF.Registration PROSPERO (identifier: CRD42016052908).

Type 1 versus type 2 diabetes and thromboembolic risk in patients with atrial fibrillation: A Danish nationwide cohort study.

BACKGROUND: Atrial fibrillation is a common cause of stroke, and diabetes increases stroke risk. Stroke risk may vary depending on the type of diabetes. We investigated whether type 1 and type 2 diabetes are associated with different risks of thromboembolism among patients with atrial fibrillation. METHODS: We used data from Danish nationwide registries to identify patients with a prior diagnosis of diabetes and an incident nonvalvular atrial fibrillation diagnosis in the period of January 1, 2005 to December 31, 2015. Cox regression analysis was used to estimate hazard ratios (HR) for the outcome thromboembolism. RESULTS: The study population included 10,058 patients with a prior diagnosis of diabetes and an incident diagnosis of atrial fibrillation. At three-year follow-up, type 2 diabetes was not associated with a higher risk of thromboembolism compared to type 1 diabetes, with an adjusted HR of 1.15 (95% CI: 0.91-1.44). In an age-stratified analysis, patients aged below 65 years of age had an adjusted HR of 1.97 (95% CI: 1.07-3.61), whereas patients aged 65-74 years or ≥75 years had adjusted HRs of 0.99 (95% CI: 0.67-1.46) and 1.10 (95% CI: 0.80-1.51), respectively. CONCLUSION: We found no overall credible association between the type of diabetes and risk of thromboembolism in this cohort of non-anticoagulated patients with incident atrial fibrillation. Nonetheless, the subset of patients aged below 65 years of age displayed a higher risk of thromboembolism among patients with type 2 diabetes as compared to patients with type 1 diabetes.

Antithrombotic Therapy in Atrial Fibrillation Associated with Valvular Heart Disease: Executive Summary of a Joint Consensus Document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, Endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

Management strategies for patients with atrial fibrillation (AF) in association with valvular heart disease (VHD) have been less informed by randomized trials, which have largely focused on 'non-valvular AF' patients. Thromboembolic risk also varies according to valve lesion and may also be associated with CHA2DS2-VASc score risk factor components, rather than only the valve disease being causal. Given the need to provide expert recommendations for professionals participating in the care of patients presenting with AF and associated VHD, a task force was convened by the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group (WG) on Thrombosis, with representation from the ESC WG on Valvular Heart Disease, Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE) with the remit to comprehensively review the published evidence, and to produce a consensus document on the management of patients with AF and associated VHD, with up-to-date consensus statements for clinical practice for different forms of VHD, based on the principles of evidence-based medicine. This is an executive summary of a consensus document which proposes that the term 'valvular AF' is outdated and given that any definition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional EHRA (Evaluated Heartvalves, Rheumatic or Artificial) categorization in relation to the type of OAC use in patients with AF, as follows: (1) EHRA (Evaluated Heartvalves, Rheumatic or Artificial) type 1 VHD, which refers to AF patients with 'VHD needing therapy with a vitamin K antagonist (VKA)' and (2) EHRA (Evaluated Heartvalves, Rheumatic or Artificial) type 2 VHD, which refers to AF patients with 'VHD needing therapy with a VKA or a non-VKA oral anticoagulant also taking into consideration CHA2DS2-VASc score risk factor components.

Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

Atrial fibrillation (AF) is a major worldwide public health problem, and AF in association with valvular heart disease (VHD) is also common. However, management strategies for this group of patients have been less informed by randomized trials, which have largely focused on 'non-valvular AF' patients. Thrombo-embolic risk also varies according to valve lesion and may also be associated with CHA2DS2VASc score risk factor components, rather than only the valve disease being causal. Given marked heterogeneity in the definition of valvular and non-valvular AF and variable management strategies, including non-vitamin K antagonist oral anticoagulants (NOACs) in patients with VHD other than prosthetic heart valves or haemodynamically significant mitral valve disease, there is a need to provide expert recommendations for professionals participating in the care of patients presenting with AF and associated VHD. To address this topic, a Task Force was convened by the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Thrombosis, with representation from the ESC Working Group on Valvular Heart Disease, Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE) with the remit to comprehensively review the published evidence, and to publish a joint consensus document on the management of patients with AF and associated VHD, with up-to-date consensus recommendations for clinical practice for different forms of VHD. This consensus document proposes that the term 'valvular AF' is outdated and given that any definition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional Evaluated Heartvalves, Rheumatic or Artificial (EHRA) categorization in relation to the type of OAC use in patients with AF, as follows: (i) EHRA Type 1 VHD, which refers to AF patients with 'VHD needing therapy with a Vitamin K antagonist (VKA); 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)', also taking into consideration CHA2DS2VASc score risk factor components. This consensus document also summarizes current developments in the field, and provides general recommendations for the management of these patients based on the principles of evidence-based medicine.

Effectiveness and safety of rivaroxaban and warfarin in patients with unprovoked venous thromboembolism: a propensity-matched nationwide cohort study.

BACKGROUND: Deep vein thrombosis (DVT) and pulmonary embolism are collectively known as venous thromboembolism (VTE), which is a common vascular disease and a major cause of morbidity and mortality worldwide. We compare effectiveness and safety of rivaroxaban versus warfarin in a prospective cohort of routine care patients with incident unprovoked VTE. METHODS: In this propensity-matched cohort study, we linked nationwide Danish health registries to identify all patients with a first hospital diagnosis of unprovoked VTE who were new users of rivaroxaban or warfarin. Excluded patients included those who had not been residents in Denmark for at least 1 year before VTE diagnosis, patients with outpatient VTE diagnosis only, patients with other indications for oral anticoagulation treatment, patients with previous experience of oral anticoagulation, patients who did not have a prescription for rivaroxaban or warfarin within 7 days of VTE, and patients who redeemed prescriptions for both rivaroxaban and warfarin, or other oral anticoagulants. Primary effectiveness outcome was recurrent VTE and primary safety outcome was major bleeding. We used propensity matching and Cox regression to compare rates of the outcomes with rivaroxaban versus standard treatment. RESULTS: From Dec 9, 2011, to Feb 28, 2016, we identified 29 963 patients with incident VTE. After exclusion, we identified 1734 propensity-matched patients given rivaroxaban (1751 before propensity matching) and 2945 propensity-matched patients given warfarin. The rate of recurrent VTE at 6 months' follow-up was 9·9 incidents per 100 person-years with rivaroxaban versus 13·1 incidents per 100 person-years with warfarin, yielding a hazard ratio (HR) of 0·74 (95% CI 0·56-0·96). The rate of major bleeding was 2·4 per 100 person-years at 6 months in rivaroxaban users versus 2·0 in warfarin users (HR 1·19, 95% CI 0·66-2·13). INTERPRETATION: In this clinical practice setting, rivaroxaban in patients with unprovoked VTE was associated with reduced risk of recurrent VTE compared with standard treatment, without compromising safety. FUNDING: Obel Family Foundation.

Temporal Trends in Incidence, Prevalence, and Mortality of Atrial Fibrillation in Primary Care.

BACKGROUND: Incidence and prevalence of atrial fibrillation (AF) are expected to increase dramatically; however, we currently lack comprehensive data on temporal trends in unselected clinical populations. METHODS AND RESULTS: Analysis of the UK Clinical Practice Research Datalink (CPRD) from 1998 to 2010 of patients with incident AF, excluding major valvular disease, linked to hospital admission data and national statistics. Fifty-seven thousand eight hundred eighteen adults were identified with mean age 74.2 (SD, 11.7) years and 48.3% women. Overall age-adjusted incidence of AF per 1000 person years was 1.11 (95% CI, 1.09-1.13) in 1998-2001, 1.33 (1.31-1.34) in 2002-2006, and 1.33 (1.31-1.35) in 2007-2010. Ongoing increases in incidence were noted for patients aged ≥75 years, with similar temporal patterns in women and men. Associated comorbidities varied over time, with a constant prevalence of previous stroke, increases in hypertension and diabetes mellitus, and decreases in ischemic heart disease. Among patients aged 55 to 74 years, there was a significant reduction in mortality over time (P<0.001), but mortality rates in patients aged ≥75 years remained static at 14% to 15% per year (P=0.84). Projections of AF prevalence demonstrated a constant yearly rise, increasing from 700 000 patients in 2010 to between 1.3 and 1.8 million patients with AF in the United Kingdom by 2060. CONCLUSIONS: In a large general practice population, incident AF increased and then plateaued overall, with a continued increase in patients aged ≥75 years. The large projected increase in AF prevalence associated with temporal changes in AF-related comorbidities suggests the need for comprehensive implementation of AF prevention and management strategies.

Butterflies of Guinea-Bissau: VIII. New data, new reports, corrections and biodiversity (Lepidoptera: Papilionoidea).

New records are added to the Papilionoidea of Guinea-Bissau, many of which were obtained within the country's Protected Areas. Examination of the collected material yielded 9 new genera and 47 new species for the country, significantly increasing the knowledge of local butterfly diversity. 99 genera and 244 species are now known to occur in Guinea-Bissau, representing an increase of almost 20 % in the number of species and 7 % in the genera in relation to previous data. For each species, the studied material, probable abundance and proposed conservation status in the country are reported; some corrections relative to a few previous misidentifications are added. A gazetteer of the prospected localities is included, as well as species' occurrences within the Protected Areas and previous bibliographic references in Guinea-Bissau. The known geographical range, primary habitat and host-plants of each species/subspecies are also provided.

Stroke prevention strategies in patients with atrial fibrillation and heart valve abnormalities: perceptions of 'valvular' atrial fibrillation: results of the European Heart Rhythm Association Survey.

The purpose of this European Heart Rhythm Association (EHRA) Survey was to assess the perceptions of 'valvular' atrial fibrillation (AF) and management of AF patients with various heart valve abnormalities in daily clinical practice in European electrophysiology (EP) centres. Questionnaire survey was sent via the Internet to the EHRA-EP Research Network Centres. Of the 52 responding centres, 42 (80.8%) were university hospitals. Choosing the most comprehensive definition of valvular AF, a total of 49 centres (94.2%) encountered a mechanical prosthetic heart valve and significant rheumatic mitral stenosis, 35 centres (67.3%) also considered bioprosthetic valves, and 25 centres (48.1%) included any significant valvular heart disease, requiring surgical repair in the definition of valvular AF. Only three centres (5.8%) would define valvular AF as the presence of any (even mild) valvular abnormality. None of the centres would use non-vitamin K antagonist oral anticoagulants (NOACs) in AF patients with mechanical prosthetic valves, only 5 centres (9.8%) would use NOACs in patients with significant mitral stenosis, 17 centres (32.7%) would consider the use of NOACs in patients with bioprosthetic valves, and 21 centres (41.2%) would use NOACs in patients with a non-recent transcatheter valve replacement/implantation, while 13 centres (25.5%) would never consider the use of NOACs in AF patients with even mild native heart valve abnormality. Our survey showed marked heterogeneity in the definition of valvular AF and thromboprophylactic treatments, with the use of variable NOACs in patients with valvular heart disease other than prosthetic heart valves or significant mitral stenosis, indicating that this term may be misleading and should not be used.