Effect Of Oral Anticoagulant Therapy Research Articles

Screening for Atrial Fibrillation (AF) by handheld single-lead ECG and risk of all-cause mortality stratified by non-AF cardiovascular disease

Abstract Purpose Screening for Atrial fibrillation (AF) has been suggested as a strategy to increase early detection of silent AF. We aimed to evaluate all-cause mortality between patients with screen-detected and clinically-diagnosed AF, and the effect of oral anticoagulation therapy (OAC) on mortality. Methods We prospectively enrolled and performed AF screening using handheld single-lead ECG(AliveCor) on consecutive patients who attended medical outpatient clinics during December 2014 and December 2017. Repeat screening was performed among patients who had >1 clinic visits. All participants were divided into 5 cohorts: (i) previously known AF at baseline (kAF); (ii) initial screen-detected AF (S1-AF); (iii) subsequent screen-detected AF (FU-sAF); (iv) clinically-diagnosed AF during follow-up (FU-cAF); and (v) no AF. Risk of all-cause mortality was estimated by adjusted hazard ratio (HR) using COX proportional hazards regression, adjusting for age, gender, co-morbidities, concurrent chronic use of medications including OAC, with AF detection or clinical diagnosis and OAC therapy handled as time-varying variable. Subgroup analysis was conducted to identify heterogeneity of effect across with or without non-AF cardiovascular disease (CVD). Results Of 11,972 subjects (mean age 76.6±7.8, female 49.2%), 18.7% (n=2,236) had previously kAF, 1.9% (n=223) S1-AF, 0.6% (n=71) FU-sAF, 7.3% (n=867) FU-cAF, and 71.6% (n=8,559) no AF. During a median FU duration of 6.8(IQR: 5.2-8.1) years, patients with kAF (HR=1.8(1.6-2.0)), S1-AF (HR=1.6(1.3-1.9)) and FU-cAF (HR=1.6(1.4-1.8)) were at higher risk of all-cause mortality, compared to individuals without AF, whereas FU-sAF (HR=1.0(0.7-1.4)) had similar low risk of death as no AF. Heterogeneity of effect was detected in subgroup analysis. Among patients without non-AF CVD, FU-sAF (HR=6.0(1.8-19.8)) and FU-cAF (HR=4.7(3.3-6.7)) were at markedly higher risk of all-cause mortality. DOAC (HR=0.57(0.38-0.87)) but not VKA (HR=0.72(0.43-1.15) reduced mortality. However, in patients with CVD other than AF, risk of FU-sAF (HR=1.1(0.8-1.6)) decreased to as low as individuals without AF (P for interaction =0.0039).Both DOAC (HR=0.51(0.46-0.58)) and VKA (HR=0.87(0.78-0.98) were beneficial. Conclusion Likely delayed AF detection suggested by groups of FU-cAF and FU-sAF may be associated with significant rise in risk of mortality among patients without non-AF CVD. The effect diminished when non-AF CVD as potential competing risk existed. The role of VKA in reducing all-cause mortality warrants more studies.

Effect of oral anticoagulation therapy in atrial fibrillation patients with a history of intracranial hemorrhage: a systematic review and meta-analysis.

Use of oral anticoagulants (OACs) among atrial fibrillation (AF) patients surviving intracranial hemorrhage (ICH) represents a challenge due to the difficult balance between thrombosis and hemorrhage. We performed a systematic review and meta-analysis to evaluate the effectiveness and safety of OACs resumption in AF patients with a history of ICH during long-term follow-up. The outcome measures were ischemic stroke (IS), IS or systemic embolism (SE), all-cause death, recurrent ICH and major bleeding. Meta-analyses of pooled odds ratios (ORs) were conducted with random-effects models. A total of 2 randomized controlled trials (RCTs) and 9 observational studies were included, covering 18,115 patients with AF and a history of ICH. The risk of IS was not statistically different between the group of patients receiving OAC therapy and the no-OAC group (OR: 0.41, 95% CI: 0.16 to 1.0, P=0.05). The rate of IS or SE (OR: 0.42, 95% CI: 0.27 to 0.70, P=0.0008), all-cause death (OR: 0.54, 95% CI: 0.41 to 0.70, I2=42%, P<0.00001) were significantly decreased in patients receiving OAC therapy compared to those with no-OAC therapy. The pooled OR estimates for ICH recurrence (OR: 1.46, 95% CI: 0.94 to 2.26, P=0.09) and major bleeding (OR: 1.35, 95% CI: 0.86 to 2.11, P=0.19) were not significantly increased in the OAC therapy group. There was heterogeneity between the results of observational studies and RCTs in terms of all-cause death (I2=83.4%). Considering the heterogeneity in results between observational studies and RCTs, as well as the limited number and small size of RCTs, high grade evidences are needed. Pooled analysis is required when more RCTs are completed in the future to resolve this therapeutic dilemma.

Effects of oral anticoagulant therapy in patients with pulmonary diseases

BackgroundTo evaluate the effect of oral anticoagulants (OACs) therapy, including vitamin K antagonist (VKA) and direct oral anticoagulants (DOAC) in patients with pulmonary diseases.MethodsLiterature from PubMed, MEDLINE, and Cochrane Library were screened until June 2022. Studies assessing OACs for pulmonary hypertension (PH), pulmonary embolism (PE), pulmonary fibrosis (PF), or chronic obstructive pulmonary disease (COPD) were evaluated for inclusion.ResultsOur study indicated that in patients with PH, PE, and COPD, OACs could significantly reduce the mortality risk, and the effects of VKA and DOACs without statistical difference in reducing the risk of recurrent embolism events. In patients with sclerosis-associated pulmonary arterial hypertension (SSc-PAH) or idiopathic pulmonary fibrosis (IPF), vitamin K antagonist (warfarin) significantly increased the mortality risk, while DOACs were not. As for the safety outcome of OACs, existing studies indicate that compared with patients treated with warfarin, the users of DOAC have a lower risk of major bleeding, while there is no statistical significance between them in non-major bleeding events. In current guidelines, the anticoagulation regimen for patients with pulmonary disease has not been defined. The results of our study confirm that DOACs (apixaban, rivaroxaban, dabigatran, and edoxaban) are superior to VKAs in the efficacy and safety outcomes of patients with pulmonary disease.ConclusionsOral anticoagulant therapy brings benefits to patients with PH, PE, or COPD, while the anticoagulation regimen for patients with SSc-PAH or IPF requires serious consideration. Compared with VKA, DOAC is a non-inferior option for anticoagulation in pulmonary disease treatment. Further studies are still needed to provide more reliable evidence about the safety outcome of pulmonary disease anticoagulation.

What to do with device-detected atrial high-rate episodes: Summary of the evidences.

Cardiac implanted electronic devices (CIEDs), that perform atrial sensing via an atrial electrode, commonly detect self-terminating atrial arrhythmias. Nomenclature of these arrhythmias is defined as atrial high-rate episodes (AHREs) and subclinical atrial fibrillation (SCAF). We have provided a comprehensive summation of the trials regarding the incidence and adverse outcomes of AHREs. The reported incidence of AHRE varies considerably (approximately 10%-70%) between studies depending on the definition of AHRE, duration of follow-up and the clinical profile of the population. There is increasing evidence related with the association between AHREs' and stroke and/or systemic embolism. However, risk of stroke and/or systemic embolism seems to be less than the risk associated with clinical AF. There is still lack of sufficient evidence related with oral anticoagulation (OAC) in patients with AHRE to reduce thromboembolic risk. Although, the strongest association of OAC treatment with reduction in stroke has been reported to be observed among patients with device detected SCAF episodes of >24h; it is still questionable whether AHRE is a direct cause of thromboembolic event or just a marker of increased risk. Results of ongoing randomized clinical trials (NOAH-AFNET 6 and ARTESIA) will provide robust evidence on effect of OAC therapy on AHREs.

Antikoagulantna terapija u bolesnika s fibrilacijom atrija i kroničnom renalnom insuficijencijom

Atrial fibrillation is the most common cardiac arrhythmia and it is associated with a significantly increased risk of stroke and systemic embolism. To reduce this risk it is important to start these patients on life-term oral anticoagulation. Many patients with atrial fibrillation also have some degree of renal insufficiency, which further increases the risk of stroke and thromboembolism, as well as the risk of bleeding. Therefore it is crucial to carefully choose a type of anticoagulant medication that is effective and safe for patients suffering from atrial fibrillation and renal insufficiency. There are two types of oral anticoagulants, vitamin K antagonists and new oral anticoagulants (NOAC). Warfarin is the most commonly used vitamin K antagonist, while NOACs include dabigatran, rivaroxaban, apixaban and edoxaban. Considering NOACs are mostly renally excreted, only patients with mild to moderate renal insufficiency were included in the original clinical trials, but these trials showed that NOACs are as effective or superior to warfarin and are now the treatment of choice for patients with atrial fibrillation and mild or moderate renal insufficiency. Few NOAC pharmacokinetic studies were performed and found doses of these drugs that produce stable plasma levels in patients with severe renal insufficiency and could be effective in preventing thromboembolism. The results of studies that included warfarin treatment in these patients are heterogeneous, showing it could produce a satisfactory anticoagulant effect or it could even increase the stroke risk. Major bleeding also seems to be less frequent in patients with severe renal insufficiency treated with NOACs then in those treated with warfarin. Besides bleeding, an important factor of safety to keep in mind while treating patients with renal insufficiency is the progression of their kidney disease and the development of acute kidney injury. A specific type of kidney injury known as anticoagulant related nephropathy is a severe adverse effect of oral anticoagulant therapy, related mostly to warfarin use. It can occur even in patients with mild renal insufficiency or normal kidney function, often leading to life-long hemodialysis. Considering their superior safety profile as well as the possibility of achieving stable plasma levels even in severe kidney disease, NOACs seem to be a better option for anticoagulant treatment of patients with atrial fibrillation and renal insufficiency.

Effects of Oral Anticoagulant Therapy on Gene Expression in Crosstalk between Osteogenic Progenitor Cells and Endothelial Cells.

Direct oral anti-coagulants (DOACs) are employed in clinical practice for the prevention and treatment of recurrent venous thromboembolism and for the prevention of stroke in non-valvular atrial fibrillation. DOACs directly and reversibly inhibit activated factor X or thrombin and can interfere with other pathophysiological processes such as inflammation, lipid metabolism, and bone turnover. We aimed to evaluate the possible effects of DOACs on osteogenesis and angiogenesis. We treated 34 patients affected by cardiovascular disorders with DOACs; biochemical and molecular analyses were performed before and after three months of treatment. Circulating progenitors (CPs; CD34−, CD45−, CD14−, CD73+, CD105+), which share typical bone marrow stem cell (MSCs) features, were harvested from peripheral blood of the study subjects to monitor the expression of osteogenesis-related genes RUNX2 and SPARC. Human umbilical vein endothelial cells (HUVECs) were used to probe angiogenesis-related VEGF, CD31, and CD105 gene expression. We performed co-culture experiments using a commercial human mesenchymal stem cells line (hMSCs) obtained from bone marrow and HUVECs. Clinical parameters related to bone metabolism, coagulation, renal and liver function, and the lipid profile were evaluated. Values of the C-terminal telopeptide type I collagen (CTX) increased after the treatment. We found a significant increase in osteogenesis marker gene expression in CPs after three months of anticoagulant therapy. An increase in the RUNX2 expression determinant alone was detected instead in hMSCs co-cultured with HUVECs in the presence of treated patients’ sera. The VEGF, CD31, and CD105 marker genes appeared to be significantly upregulated in HUVECs co-cultured with hMSCs in the presence of treated patients’ sera. Under these conditions, new vessel formation increased as well. Our results highlight an unexpected influence of DOAC therapy on osteogenic commitment and vascular endothelial function promotion.

Risk factors for intracranial hemorrhage during vitamin K antagonist therapy in patients with nonvalvular atrial fibrillation: A case-control study.

Intracranial hemorrhage (ICH) is the most fearful side effect of oral anticoagulant therapy. It is still unclear which risk factor is involved in ICH during vitamin K antagonists (VKAs) treatment and if commonly used bleeding risk scores are able to predict ICH. Search for individual risk factors and bleeding risk scores (HAS-BLED, ATRIA and ORBIT) associated with ICHs in patients with atrial fibrillation treated with VKAs. This is a retrospective case-control study in a single Thrombosis Center. During a 7-year period, patients with nonvalvular atrial fibrillation (NVAF) who developed ICH during VKAs were identified as cases. Four control patients matched for gender, age and length of VKAs were assigned to each case. The association between considered risk factors and ICHs was evaluated using a linear logistic regression method and expressed as odds ratio. Receiver operator characteristic (ROC) curves to assess the predictive ability of bleeding risk scores HAS-BLED, ATRIA and ORBIT were also evaluated. Fifty-one cases of ICH, most of whom were 80years of age or older (72.5%), were retrieved from the Thrombosis Center's database. Compared to 204 controls, no individual risk factors were associated with ICH. Poor ability to predict ICH was also found using ROC curves (C-statistic for HAS-BLED, ATRIA, and ORBIT were 0.55, 0.53 and 0.54, respectively). ICHs during VKA therapy preferentially occur in very elderly patients. The risk of ICH is not predicted by the commonly used risk scores.

Effect of oral anticoagulant therapy on mortality in end-stage renal disease patients with atrial fibrillation: a prospective study.

The aim of this study was to evaluate, in a cohort of haemodialysis patients with atrial fibrillation (AF), the relationship between oral anticoagulant therapy (OAT) and mortality, thromboembolic events and haemorrhage. Two hundred and ninety patients with AF were prospectively followed for 4years. Warfarin and antiplatelet intake, age, dialytic age, comorbidities, CHA2DS2-VASc and HAS-BLED scores were considered as predictors of risk of death, thromboembolism and bleeding events. In patients taking OAT, the international normalized ratio (INR) was assessed and the percentage time in the target therapeutic range (TTR) was calculated. At recruitment, 134/290 patients were taking warfarin. During follow-up there were 170 deaths, 28 thromboembolic events and 95 bleedings. After balancing for treatment propensity, intention-to-treat analysis on OAT intake at recruitment did not show differences in total mortality, thromboembolic events and bleedings, while the as-treated analysis, accounting for treatment switch, showed that patients taking OAT at recruitment had a significantly lower mortality than those not taking it [hazard ratio, HR 0.53 (95% confidence interval 0.28-0.90), p = 0.04], with a decrease of thromboembolic events [HR 0.36 (0.13-1.05), p = 0.06], and an increase of bleedings [HR 1.79 (0.72-4.39), p = 0.20], both non-significant. Among patients taking OAT at recruitment, those continuing to take warfarin had a significant reduction in the risk of total [HR 0.28 (0.14-0.53), p < 0.001] and cardiovascular [HR 0.21 (0.11-0.40), p < 0.001] mortality compared to patients stopping OAT. In haemodialysis patients with AF, continuously taking warfarin is associated with a reduction of the risk of total and cardiovascular mortality.

Antiplatelet versus anticoagulation treatment for patients with heart failure in sinus rhythm.

Morbidity in patients with chronic heart failure is high, and this predisposes them to thrombotic complications, including stroke and thromboembolism, which in turn contribute to high mortality. Oral anticoagulants (e.g. warfarin) and antiplatelet agents (e.g. aspirin) are the principle oral antithrombotic agents. Many heart failure patients with sinus rhythm take aspirin because coronary artery disease is the leading cause of heart failure. Oral anticoagulants have become a standard in the management of heart failure with atrial fibrillation. However, a question remains regarding the appropriateness of oral anticoagulants in heart failure with sinus rhythm. This update of a review previously published in 2012 aims to address this question. To assess the effects of oral anticoagulant therapy versus antiplatelet agents for all-cause mortality, non-fatal cardiovascular events and risk of major bleeding in adults with heart failure (either with reduced or preserved ejection fraction) who are in sinus rhythm. We updated the searches in September 2015 on CENTRAL (The Cochrane Library), MEDLINE and Embase. We searched reference lists of papers and abstracts from cardiology meetings and contacted study authors for further information. We did not apply any language restrictions. Additionally, we searched two clinical trials registers: ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal apps.who.int/trialsearch/) (searched in July 2016). We included randomised controlled trials comparing antiplatelet therapy versus oral anticoagulation in adults with chronic heart failure in sinus rhythm. Treatment had to last at least one month. We compared orally administered antiplatelet agents (aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor, dipyridamole) versus anticoagulant agents (coumarins, warfarin, non-vitamin K oral anticoagulants). Two review authors independently assessed trials for inclusion and assessed the risks and benefits of antithrombotic versus antiplatelet therapy using relative measures of effects, such as risk ratios (RR), accompanied with 95% confidence intervals (CI). The data extracted included data relating to the study design, patient characteristics, study eligibility, quality, and outcomes. We used GRADE criteria to assess the quality of the evidence. This update identified one additional study for inclusion, adding data for 2305 participants. This addition more than doubled the overall number of patients eligible for the review. In total, we included four randomised controlled trials (RCTs) with a total of 4187 eligible participants. All studies compared warfarin with aspirin. One RCT additionally compared warfarin with clopidogrel. All included RCTs studied patients with heart failure with reduced ejection fraction.Analysis of all outcomes for warfarin versus aspirin was based on 3663 patients from four RCTs. All-cause mortality was similar for warfarin and aspirin (RR 1.00, 95% CI 0.89 to 1.13; 4 studies; 3663 participants; moderate quality evidence). Oral anticoagulation was associated with a reduction in non-fatal cardiovascular events, which included non-fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism (RR 0.79, 95% CI 0.63 to 1.00; 4 studies; 3663 participants; moderate quality evidence). The rate of major bleeding events was twice as high in the warfarin groups (RR 2.00, 95% CI 1.44 to 2.78; 4 studies; 3663 participants; moderate quality evidence). We generally considered the risk of bias of the included studies to be low.Analysis of warfarin versus clopidogrel was based on a single RCT (N = 1064). All-cause mortality was similar for warfarin and clopidogrel (RR 0.93, 95% CI 0.72 to 1.21; 1 study; 1064 participants; low quality evidence). There were similar rates of non-fatal cardiovascular events (RR 0.85, 95% CI 0.50 to 1.45; 1 study; 1064 participants; low quality evidence). The rate of major bleeding events was 2.5 times higher in the warfarin group (RR 2.47, 95% CI 1.24 to 4.91; 1 study; 1064 participants; low quality evidence). Risk of bias for this study can be summarised as low. There is evidence from RCTs to suggest that neither oral anticoagulation with warfarin or platelet inhibition with aspirin is better for mortality in systolic heart failure with sinus rhythm (high quality of the evidence for all-cause mortality and moderate quality of the evidence for non-fatal cardiovascular events and major bleeding events). Treatment with warfarin was associated with a 20% reduction in non-fatal cardiovascular events but a twofold higher risk of major bleeding complications (high quality of the evidence). We saw a similar pattern of results for the warfarin versus clopidogrel comparison (low quality of the evidence). At present, there are no data on the role of oral anticoagulation versus antiplatelet agents in heart failure with preserved ejection fraction with sinus rhythm. Also, there were no data from RCTs on the utility of non-vitamin K antagonist oral anticoagulants compared to antiplatelet agents in heart failure with sinus rhythm.

Anticoagulation therapy in atrial fibrillation after intracranial hemorrhage

The effect of oral anticoagulation therapy (OAT) in patients with atrial fibrillation (AF) with a history of intracranial hemorrhage (ICH) is poorly defined. The purpose of this study was to evaluate the efficacy and safety of OAT in patients with AF with an ICH history. We retrospectively compared the composite end point, including thromboembolic and major bleeding events, between patients with AF with a history of ICH who were (OAT group, n = 254) and those who were not (no-OAT group, n = 174) taking OAT. During a mean follow-up of 39.5 ± 31.9 months, 5.5 and 3.1 major bleeding events/100 patient-years were observed in the OAT and no-OAT groups, respectively (P = .024). Recurrent ICH was observed only in patient with OAT. Thromboembolic events occurred in 2.4 and 8.3 events/100 patient-years in OAT and no-OAT groups, respectively (P < .001). There was no significant differences in composite end points between OAT and no-OAT groups (11.5 events/100 patient-years vs 7.9 events/100 patient-years; P = .154). Patients with OAT who achieved a time-in-therapeutic range of ≥60% of the international normalized ratio of 2.0-3.0 demonstrated a better cumulative survival free of the composite end point (P < .001) than did patients without OAT. Early (<2 weeks) OAT after an index ICH did not improve composite end points because of the increased incidence of major bleeding events. However, OAT at 2 weeks after an index ICH was associated with decreased clinical events including thromboembolic events and composite end point. In patients with AF who require anticoagulation and have a history of ICH, maintaining optimal OAT with time-in-therapeutic range ≥ 60% and the initiation of OAT at least 2 weeks after an index ICH were associated with improved clinical outcomes.

Effects of oral anticoagulant therapy in older medical in-patients with atrial fibrillation: a prospective cohort observational study.

Uncertainties about efficacy and safety of oral anticoagulant therapy (OAT) among older and frail medical patients with atrial fibrillation (AF) largely contribute to under-prescription of these drugs. In this prospective observational cohort study, we investigated mortality, and ischemic and hemorrhagic events, in hospital-discharged older patients with AF. Stroke and bleeding risk were evaluated using CHA2DS2-VASC and HAS-BLED scores. Comorbidity, frailty, cognitive and nutritional status and functional autonomy were evaluated using standardized scales. Independent associations between clinical variables, including OAT use, and all-cause mortality, fatal and non-fatal ischemic and hemorrhagic events, were evaluated. Further clinical outcomes comparison between patients treated with OAT and those untreated was performed after adjustment for significant differences in patient baseline characteristics with propensity score matching. Of 452 patients included (mean age 81.6years, 54.9% women, roughly 30% cognitively impaired and/or functionally dependent, mean CHA2DS2-VASC and HAS-BLED scores 4.6 and 2.8, respectively), 151 (33.4%) died during a mean follow-up period of 300.5days; ischemic and hemorrhagic stroke occurred in 4.0 and 0.4% of patients, respectively, and major bleedings in 6.2%. After multivariate analysis, OAT at discharge was associated with lower overall mortality and reduced occurrence of ischemic stroke, the first finding being confirmed in propensity score matched analysis. Among older vulnerable AF patients with high post discharge death rate, OAT was associated, among other multiple factors, with reduced mortality and lower occurrence of ischemic stroke.

自宅退院が可能であった心原性脳塞栓症患者における経口抗凝固薬が在院日数および医療費に与える影響

【目的】経口抗凝固薬が在院日数および医療費に与える影響について後方視的に検討した．【方法】心原性脳塞栓症患者（CE）で，経口抗凝固薬を処方され自宅退院した159 例を対象に非ビタミンK 拮抗経口抗凝固薬群（NOACs: NG）とワルファリン群（WG）に分け，在院日数と医療費（DPC による総報酬点数）を検討した．【結果】NG が68 例（43％），WG が91 例（57％）であった．在院日数（中央値）は，NG で有意に短く（NG 13 日vs. WG 18 日，P<0.001），総報酬点数（中央値）もNG で有意に低かった（NG 72,954 点 vs. 95,628 点，P<0.001）．ロジステック回帰分析ではNOACs は在院日数短縮に関与した（OR 0.168; 95％ CI 0.074–0.382; P<0.001）．【結論】急性期病院におけるCE のNOACs による治療は在院日数短縮と医療費削減に関連した．

Effects of Oral Anticoagulant Therapy in Medical Inpatients ≥65 Years With Atrial Fibrillation

In this retrospective cohort observational study, we investigated mortality, ischemic, and hemorrhagic events in patients ≥65 years with atrial fibrillation consecutively discharged from an Acute Geriatric Ward in the period 2010 to 2013. Stroke and bleeding risk were evaluated using CHA2DS2-VASC (congestive heart failure/left ventricular dysfunction, hypertension, aged ≥75 years, diabetes mellitus, stroke/transient ischemic attack/systemic embolism, vascular disease, aged 65 to 74 years, gender category) and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) scores. Co-morbidity, cognitive status, and functional autonomy were evaluated using standardized scales. Independent associations among clinical variables, including use of vitamin K antagonist-based oral anticoagulant therapy (OAT), all-cause mortality, and fatal and nonfatal ischemic and hemorrhagic events, were evaluated. Further clinical outcomes comparison between patients treated with OAT and those untreated was performed after adjustment for significant differences in patient baseline characteristics with propensity score matching. Of 980 patients discharged (mean age 83 years, 60% women, roughly 30% cognitively impaired or functionally dependent, mean CHA2DS2-VASC and HAS-BLED scores 4.8 and 2.1, respectively), 505 (51.5%) died during a mean follow-up period of 571 days; ischemic and hemorrhagic stroke occurred in 82 (12.3%) and 13 patients (1.3%), respectively, and major bleedings in 43 patients (4.4%). Vitamin K antagonists' use was independently associated with reduced mortality (odds ratio 0.524) and with a nonsignificant reduction in incidence of ischemic stroke, without excess in bleeding risk. Similar findings were observed in the 2 propensity score-matched cohorts of patients. In conclusion, among vulnerable patients with atrial fibrillation ≥65 years with high post-discharge death rate, OAT was associated, among other multiple factors, with reduced mortality.

Warfarin use, mortality, bleeding and stroke in haemodialysis patients with atrial fibrillation.

Oral anticoagulation therapy (OAT) is the choice treatment for thromboembolism prevention in atrial fibrillation (AF), although data about OAT use in haemodialysis (HD) patients with AF are contradictory. The effect of OAT on the risk of mortality, stroke and bleeding was prospectively evaluated in a population of HD patients with AF. All the patients of 10 HD Italian centres alive on 31 October 2010 with documented AF episode(s) were recruited and followed-up for 2 years. OAT and antiplatelet intake, age, dialytic age, comorbidities and percentage time in the target international normalized ratio (INR) range (target therapeutic range; TTR) were considered as predictors of hazard of death, thromboembolic and bleeding events. At recruitment, 134 patients out of 290 were taking OAT. During the follow-up, 115 patients died (4 strokes, 3 haemorrhagic and 1 thromboembolic). Antiplatelet therapy, but not OAT, was associated with increased mortality (HR 1.71, CI 1.10-2.64, P = 0.02). The estimated survival of patients always taking OAT tended to be higher than that of patients who stopped taking (68.6 versus 49.6%, P = 0.07). OAT was not correlated to a significant decreased risk of thromboembolic events (HR 0.12, CI 0.00-3.59, P = 0.20), while it was associated with an increased risk of bleeding (HR 3.96, CI 1.15-13.68, P = 0.03). Higher TTR was associated with a reduced bleeding risk (HR 0.09, CI 0.01-0.76, P = 0.03), while previous haemorrhagic events were associated with higher haemorrhagic risk (HR 2.17, CI 1.09-4.35, P = 0.03). In our population of HD patients with AF, the mortality is very high. OAT is not associated with increased mortality, while antiplatelet drugs are. OAT seems, on the contrary, associated with a better survival; however, it does not decrease the incidence of ischaemic stroke, whereas it increases the incidence of bleeding. Bleeding risk is lower in subjects in whom the INR is kept within the therapeutic range.

Use of oral anticoagulants and risk of prostate cancer: a population-based case-control study in Montreal, Canada.

A few recent epidemiological observations suggest that anticoagulant medications may protect against prostate cancer development. Most studies have been small or subjected to methodological issues, including potential confounding. We provide here new evidence on this association in the context of a population-based case-control study of prostate cancer conducted in Montreal, Canada. Cases were 1,588 men with incident prostate cancer, aged ≤75years, diagnosed across French hospitals in the Montreal area between 2005 and 2009. Concurrently, 1,618 population controls from the same residential area and age distribution (±5years) were randomly selected from the electoral list of French-speaking men. In-person interviews elicited information on socio-demographic, lifestyle and environmental factors, along with a detailed medical history. Unconditional logistic regression was used to assess the association between lifetime use of anticoagulants and prostate cancer risk. 102 subjects (2.6% of cases and 3.7% of controls) reported a history of oral anticoagulant therapy. After controlling for age, ancestry, education, family history of prostate cancer, prostate cancer screening frequency, diabetes, body mass index and statin use, ever use of oral anticoagulants showed a weak inverse, non-statistically significant association with prostate cancer (odds ratio 0.76, 95% confidence interval 0.50-1.16). Similar results were observed in analyses considering duration of use or indication for use, restricted to subjects recently screened or stratified by cancer aggressiveness. Our findings provide weak support for a protective effect of oral anticoagulant therapy against prostate cancer. Further confirmation is required, especially in light of potential bleeding complications associated with anticoagulants.

Effect of Oral Anticoagulant Therapy on Coagulation Activity and Inflammatory Markers in Patients with Atrial Fibrillation Undergoing Ablation: A Randomized Comparison between Dabigatran and Warfarin.

Atrial fibrillation (AF) is associated with inflammatory and hypercoagulability state. Previous studies evaluated the safety and efficacy of dabigatran and warfarin in prevention of thrombothic complications. This study was intended to assess the influence of these drugs on hemostatic and inflammatory markers among patient underwent pulmonary vein ablation. A total of 100 patients with AF who underwent catheter ablation were randomized to treatment with dabigatran (D) 110 mg twice daily or warfarin (W) adjusted to an international normalized ratio (INR) of 2.0 to 3.0 for 3 months after ablation procedure. C - reactive protein (CRP), D-dimer, prothrombin fragment F1 + 2 (F1 + 2), were measured at baseline before ablation procedures, after 30 days and after 90 days of treatment. After 3 months, the D-dimer was 164.9 ± 48.9 in Dabigatran and 197.2 ± 58.6 in warfarin group, F1 + 2 was 0.4 ± 0.2 in dabigatran and 0.8 ± 0.2 in warfarin group and CRP level was 1.8 ± 1.6 in Dabigatran and 5.1 ± 5 in warfarin group. (All p-values < 0.05) The results showed that treatment with dabigatran made greater changes in the serum level of CRP, D-dimer, F1 + 2. The pattern of changes in serum CRP levels D-dimer, F1 + 2 is much faster and with a greater slope in the dabigatran group.

Combination therapy with warfarin plus clopidogrel improves outcomes in femoropopliteal bypass surgery patients

Patients having undergone femoropopliteal bypass surgery remain at significant risk of graft failure. Although antithrombotic therapy is of paramount importance in these patients, the effect of oral anticoagulation therapy (OAT) on outcomes remains unresolved. We performed a randomized, prospective study to assess the impact of OAT plus clopidogrel vs dual antiplatelet therapy on peripheral vascular and systemic cardiovascular outcomes in patients who had undergone femoropopliteal bypass surgery. Three hundred forty-one patients who had undergone femoropopliteal surgery were enrolled and randomized: 173 patients received clopidogrel 75 mg/d plus OAT with warfarin (C + OAT), and 168 patients received dual antiplatelet therapy with clopidogrel 75 mg/d plus aspirin 100 mg/d (C + acetylsalicylic acid [ASA]). Study end points were graft patency and the occurrence of severe peripheral arterial ischemia, and the incidence of bleeding episodes. Follow-up ranged from 4 to 9 years. The graft patency rate and the freedom from severe peripheral arterial ischemia was significantly higher in C + OAT group than in C + ASA group (P = .026 and .044, respectively, Cox-Mantel test). The linearized incidence of minor bleeding complications was significantly higher in C + OAT group than in C + ASA group (2.85% patient-years vs 1.37% patient-years; P = .03). The incidence of major adverse cardiovascular events, including mortality, was found to be similar (P = .34) for both study groups. In patients who have undergone femoropopliteal vascular surgery, combination therapy with clopidogrel plus warfarin is more effective than dual antiplatelet therapy in increasing graft patency and in reducing severe peripheral ischemia. These improvements are obtained at the expenses of an increase in the rate of minor anticoagulation-related complications.

Effects of oral anticoagulant therapy and haplotype 1 of the endothelial protein C receptor gene on activated protein C levels

Oral anticoagulants (OACs) reduce activated protein C (APC) plasma levels less than those of protein C (PC) in lupus erythematosus and cardiac patients. Carriers of the H1 haplotype of the endothelial PC receptor gene (PROCR) have higher APC levels than non-carriers. We aimed to confirm these results in a large group of patients treated with OACs because of venous thromboembolism (VTE) and to assess whether the effect is influenced by the PROCR H1 haplotype. We evaluated APC, PC, and factor (F)II levels in 502 VTE patients (158 with and 344 without OACs) and in 322 healthy individuals. Mean APC, PC and FII levels were significantly lower in OAC patients than in patients not taking OACs. During anticoagulant therapy, the FII/PC ratios were independent of the PC values, whereas APC/FII and APC/PC ratios significantly increased when FII and PC levels decreased. Of the 22 OAC patients carrying the H1H1genotype, 11 (50%) showed APC/PCag ≥2.0 and 10 (45%) APC/FIIag ratios ≥2.0, whereas for the 49 OAC patients non-carrying the H1 haplotype these figures were 6 (12%) and 4 (8%), respectively (p<0.001). Barium citrate adsorption of plasma from OAC patients showed that most of the circulating free and complexed APC, but only part of PCag, is fully carboxylated. In conclusion, during anticoagulant therapy VT patients have APC levels disproportionately higher than the corresponding PC levels, mainly due to the presence of the PROCR H1 haplotype. Furthermore, a sufficiently carboxylated PC Gla-domain seems to be essential for PC activation in vivo.

Warfarin-related intraventricular hemorrhage

Oral anticoagulation therapy (OAT) with warfarin increases mortality and disability after intracerebral hemorrhage (ICH), the result of increased ICH volume and risk of hematoma expansion. We investigated whether OAT also influences risk of development of intraventricular hemorrhage (IVH), the volume of IVH and IVH expansion, and whether IVH is a substantive mediator of the overall effect of OAT on ICH outcome. We performed a retrospective analysis of a prospectively collected single-center cohort of 1,879 consecutive ICH cases (796 lobar, 865 deep, 153 cerebellar, 15 multiple location, 50 primary IVH) from 1999 to 2009. ICH and IVH volumes at presentation, as well as hematoma expansion (>33% or >6 mL increase) and IVH expansion (>2 mL increase), were determined using established semiautomated methods. Outcome was assessed at 90 days using either the modified Rankin Scale or Glasgow Outcome Scale. Warfarin use was associated with IVH risk, IVH volume at presentation, and IVH expansion in both lobar and deep ICH (all p < 0.05) in a dose-response relationship with international normalized ratio. Warfarin was associated with poor outcome in both lobar and deep ICH (p < 0.01), and >95% of this effect was accounted for by baseline ICH and IVH volumes, as well as ICH and IVH expansion. Warfarin increases IVH volume and risk of IVH expansion in lobar and deep ICH. These findings (along with effects on ICH volume and expansion) likely represent the mechanisms by which anticoagulation worsens ICH functional outcome.

The Efficacy and Safety of Prothrombin Complex Concentrate In Patients Requiring Urgent Reversal of Warfarin, A Retrospective Canadian Experience

AbstractAbstract 3344 Background:Major bleeding remains the most frequent adverse effect of oral anticoagulant therapy. A rapid method of reversal is required for patients on warfarin who suffer acute bleeding or require emergency surgery. Octaplex is a prothrombin complex concentrate recently recommended for use by the National Advisory Committee for Blood and Blood Products of Canada (Canadian Blood Services) at a dose of 1000 IU of factor IX activity. It ensures rapid INR correction by providing vitamin K-dependent factors without a large volume load. The main goal of this study was to investigate both the efficacy and safety of Octaplex use in a tertiary care center in Quebec, Canada. Materials and Methods:A retrospective review was conducted on the charts of patients who received Octaplex for urgent warfarin reversal between 1 January 2009 and 31 October 2009. Data collected included INRs pre and post Octaplex administration, and documentation of any adverse events. Results:We identified 146 occasions when Octaplex was administered for urgent INR reversal. A total of 118 patients were included in the study with a median age of 77. The three most frequent indications for Octaplex were: 1) gastrointestinal bleeding, 2) intracranial hemorrhage, and 3) pre-procedural INR reversal. The majority of patients (90.7%) were treated with Octaplex at a dose of 1000 IU of factor IX activity, with a range of 500 IU to 5000 IU. The average mean pre-and post INRs were 4.00 and 1.65, respectively. Overall, 89.8% (130/146) of patients corrected to an INR < 2.0, of which 51.5% (67/130) corrected to an INR < 1.5. Although 8.2% (12/146) of patients were considered to have a poor response (post INR > 2.1), these patients tended to have a higher mean pre-INR value (5.28 vs. 2.69) and still achieved important absolute drops in INR (range 1.1–9.3, mean 2.91). Only 4 patients (2.7%) did not experience a reversal of their INR. Seventeen patients received second doses of Octaplex, 70.6% (12/17) of whom achieved a post INR < 1.5 and 94.1% (16/17) achieved a post INR < 2.0. There were 8 reported thrombotic events amongst 118 patients: 3 myocardial infarctions, 3 DVTs, 1 ischemic limb and 1 intracardiac clot. All patients with these adverse events had other co-morbities that could have also contributed to these toxicities. Conclusion:Octaplex is efficient and appears to be safe in the urgent reversal of INR in patients taking vitamin K antagonists. Disclosures:No relevant conflicts of interest to declare.