Cardiovascular Risk in Young Patients Diagnosed With Obstructive Sleep Apnea.

BACKGROUND: In older adults, obstructive sleep apnea (OSA) has been associated with several cardiovascular complications. Whether young patients diagnosed with OSA also are at higher risk of developing subsequent cardiovascular disease is uncertain. We aimed to estimate the risk of developing an incident cardiovascular event among young patients diagnosed with OSA. METHODS AND RESULTS: We linked nationwide Danish health registries to identify a cohort of patients aged ≤50 years with OSA using data from 2010 through 2018. Cases without OSA from the general population were matched as controls (1:5). The main outcome was any cardiovascular event (including hypertension, diabetes, atrial fibrillation, ischemic heart disease, ischemic stroke, heart failure, and venous thromboembolism). All-cause mortality was a secondary outcome. The study included 20 240 patients aged ≤50 years with OSA (19.6% female; mean±SD age 39.9±7.7 years) and 80 314 controls. After 5-year follow-up, 31.8% of the patients with OSA developed any cardiovascular event compared with 16.5% of the controls, with a corresponding relative risk (RR) of 1.96 (95% CI, 1.90-2.02). At 5-year follow-up, 27.3% of patients with OSA developed incident hypertension compared with 15.0% of the controls (RR, 1.84 [95% CI, 1.78-1.90]). Incident diabetes occurred in 6.8% of the patients with OSA and 1.4% of controls (RR, 5.05 [95% CI, 4.60-5.54]). CONCLUSIONS: Similar to older adults, young adults with OSA demonstrate increased risk of developing cardiovascular events. To prevent cardiovascular disease progression, accumulation of cardiovascular risk factors, and mortality, risk stratification and prevention strategies should be considered for these patients.

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.

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.

Comparative effectiveness and safety of edoxaban versus warfarin in patients with atrial fibrillation: A nationwide cohort study.

BACKGROUND AND PURPOSE: The effectiveness and safety of edoxaban 60 mg and 30 mg for stroke prevention compared with warfarin in patients with atrial fibrillation have not been well-described in a nationwide cohort of Caucasian patients treated in standard clinical practice. METHODS: We used Danish nationwide registries to identify patients with atrial fibrillation during June 2016 and November 2018 who were treated with edoxaban or warfarin and computed rates per 100 person-years of thromboembolic, all-cause mortality, and bleeding events using an inverse probability of treatment weighting approach to account for baseline confounding. We used weighted pooled logistic regression to compute hazard ratios with 95% confidence intervals comparing events between edoxaban 60 mg and warfarin users; edoxaban 30 mg was not included in formal comparisons. RESULTS: We identified 6451 atrial fibrillation patients, mean age was 72 years and 40% were females. A total of 1772 patients were treated with edoxaban 60 mg, 537 with edoxaban 30 mg, and 4142 with warfarin. The median CHA2DS2-VASc score was similar between warfarin and edoxaban 60 mg with a score of 3 (interquartile range (IQR) 2-4). In the inverse probability of treatment-weighted pseudo-population, the thromboembolic event rate for edoxaban 60 mg was 0.95 and 1.0 for warfarin, corresponding weighted hazard ratio of 1.00 (95% confidence intervals (CI) 0.59, 1.71). Edoxaban 60 mg users were associated with lower rates of all-cause mortality (3.93) compared to warfarin (6.04), with a hazard ratio of 0.64 (95% CI 0.47 to 0.88). The event rates for bleeding were 3.36 and 3.14, respectively; hazard ratio 1.09 (95% CI 0.77, 1.57). CONCLUSION: Edoxaban 60 mg is a safe and effective treatment compared with warfarin for stroke prevention in routine clinical care for Danish (mainly Caucasian) patients with AF, with non-significantly different risks for stroke and clinically relevant bleeding, but lower all-cause mortality.

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.

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.

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.

Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation.

OBJECTIVE: To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up. METHODS: A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for ≥3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method. RESULTS: Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27-0.74, p = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29-0.77, p = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79-2.30, p = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45-1.90, p = 0.84). CONCLUSIONS: In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF.

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.

Non-valvular atrial fibrillation patients with none or one additional risk factor of the CHA2DS2-VASc score. A comprehensive net clinical benefit analysis for warfarin, aspirin, or no therapy.

Oral anticoagulation (OAC) to prevent stroke has to be balanced against the potential harm of serious bleeding, especially intracranial haemorrhage (ICH). We determined the net clinical benefit (NCB) balancing effectiveness and safety of no antithrombotic therapy, aspirin and warfarin in AF patients with none or one stroke risk factor. Using Danish registries, we determined NCB using various definitions intrinsic to our cohort (Danish weights at 1 and 5 year follow-up), with risk weights which were derived from the hazard ratio (HR) of death following an event, relative to HR of death after ischaemic stroke. When aspirin was compared to no treatment, NCB was neutral or negative for both risk strata. For warfarin vs no treatment, NCB using Danish weights was neutral where no risk factors were present and using five years follow-up. For one stroke risk factor, NCB was positive for warfarin vs no treatment, for one year and five year follow-up. For warfarin vs aspirin use in patients with no risk factors, NCB was positive with one year follow-up, but neutral with five year follow-up. With one risk factor, NCB was generally positive for warfarin vs aspirin. In conclusion, we show a positive overall advantage (i.e. positive NCB) of effective stroke prevention with OAC, compared to no therapy or aspirin with one additional stroke risk factor, using Danish weights. 'Low risk' AF patients with no additional stroke risk factors (i.e.CHA2DS2-VASc 0 in males, 1 in females) do not derive any advantage (neutral or negative NCB) with aspirin, nor with warfarin therapy in the long run.

Sample-to-SNP kit: a reliable, easy and fast tool for the detection of HFE p.H63D and p.C282Y variations associated to hereditary hemochromatosis.

Classical hereditary hemochromatosis involves the HFE-gene and diagnostic analysis of the DNA variants HFE p.C282Y (c.845G>A; rs1800562) and HFE p.H63D (c.187C>G; rs1799945). The affected protein alters the iron homeostasis resulting in iron overload in various tissues. The aim of this study was to validate the TaqMan-based Sample-to-SNP protocol for the analysis of the HFE-p.C282Y and p.H63D variants with regard to accuracy, usefulness and reproducibility compared to an existing SNP protocol. The Sample-to-SNP protocol uses an approach where the DNA template is made accessible from a cell lysate followed by TaqMan analysis. Besides the HFE-SNPs other eight SNPs were used as well. These SNPs were: Coagulation factor II-gene F2 c.20210G>A, Coagulation factor V-gene F5 p.R506Q (c.1517G>A; rs121917732), Mitochondria SNP: mt7028 G>A, Mitochondria SNP: mt12308 A>G, Proprotein convertase subtilisin/kexin type 9-gene PCSK9 p.R46L (c.137G>T), Plutathione S-transferase pi 1-gene GSTP1 p.I105V (c313A>G; rs1695), LXR g.-171 A>G, ZNF202 g.-118 G>T. In conclusion the Sample-to-SNP kit proved to be an accurate, reliable, robust, easy to use and rapid TaqMan-based SNP detection protocol, which could be quickly implemented in a routine diagnostic or research facility.

A common Greenlandic Inuit BRCA1 RING domain founder mutation.

Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit, representing almost ~2% of the total Greenlandic Inuit population, showed that the frequency of the mutation was 1.0%. We conclude that the BRCA1 nucleotide 234 T > G is a common Greenlandic Inuit founder mutation. The relative high frequency in the general population, together with the ease of screening and possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented.