In a randomized trial, 1050 patients with cancer who had acute venous thromboembolism were assigned to receive either dalteparin or edoxaban for 6 to 12 months. Edoxaban was noninferior to dalteparin ...with respect to the outcome of recurrent venous thromboembolism or major bleeding.
Abstract
Background
The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure ...is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol.
Methods
PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group.
Conclusion
The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.
Activated coagulation Factor XII (FXIIa) infusion increases peripheral resistance (TPR) and mean arterial pressure (MAP) of Brown Norway but not plasma kininogen deficient Brown Norway Katholiek ...(BNK) rats. FXIIa concentrations are elevated in hypertensive end-stage renal disease patients receiving conventional haemodialysis (CHD). Conversion to nocturnal haemodialysis (NHD) lowers peripheral resistance and MAP.
To determine whether the plasma coagulation FXIIa-kallikrein-kinin axis contributes to the hypertension of chronic kidney disease (CKD).
Plasma FXIIa and haemodynamic data were acquired in 11 CHD patients before and after 2 months of NHD. Cardiac and systemic haemodynamics of Brown Norway and BNK rats rendered hypertensive and uremic by 5/6 nephrectomy (NX) were determined before and after acute FXIIa inhibition.
FXIIa was increased three-fold in CHD patients relative to control plasma (P < 0.05). After conversion to NHD, both ΔMAP and ΔTPR correlated with ΔFXIIa. In rats, plasma FXIIa was three-fold higher in both NX groups than respective SHAM controls (all P < 0.05), but MAP (147 ± 4 vs. 133 ± 2 mmHg; P < 0.05) and TPR (2.8 ± 0.2 vs. 2.3 ± 0.2 units; P < 0.05) were greater in Brown Norway NX (n = 16) than in BNK (n = 15) NX rats. FXIIa correlated with MAP only in Brown Norway NX, and plasma catecholamines were increased relative to SHAM only in Brown Norway NX (P < 0.05). In Brown Norway NX rats, FXIIa inhibitor infusion decreased MAP (-12 mmHg) and TPR (-0.5 Units) (both P < 0.05), and halved catecholamines (P < 0.05). No such changes occurred in BNK NX rats.
FXIIa-kininogen mediated vasoconstriction contributes significantly to CKD hypertension in Brown Norway rats; this novel mechanism may be active in humans with CKD.
Asymptomatic deep vein thrombosis (DVT) occurs in up to 11% of medical inpatients. The incidence of asymptomatic DVT among patients with inflammatory bowel disease (IBD) is unknown but may be even ...higher. D-dimer is effective for DVT screening, but its utility has not been studied in the IBD population.
Hospitalized and ambulatory patients with IBD during flares were recruited between 2009 and 2011. Those with clinical symptoms of venous thromboembolism or previous venous thromboembolism were excluded. We determined the prevalence of DVT among asymptomatic subjects using lower extremity Doppler ultrasound and assessed the performance characteristics of the D-dimer in this high-risk study population.
We enrolled 101 hospitalized and 49 ambulatory patients with IBD during active flares. There were no cases of proximal DVT detected by lower extremity Doppler ultrasound. The 95% confidence interval (CI) for the rate of proximal DVT was 0% to 2%. D-dimer was elevated in 60% of subjects without DVT, occurring more frequently among hospitalized than ambulatory subjects 89% versus 65%, P = 0.01; adjusted odds ratio (aOR), 4.16, 95% CI, 1.58-10.9. Other predictors of elevated D-dimer were incremental decade in age (aOR, 1.97; 95% CI, 1.24-3.14); ulcerative colitis versus Crohn's disease diagnosis (aOR, 3.38; 95% CI, 1.29-8.84); and every 10-unit increase in C-reactive protein (aOR, 1.33; 95% CI, 1.09-1.62).
From this pilot study, there appears to be low prevalence of asymptomatic DVTs among patients with IBD during flares. The high prevalence of elevated D-dimer in DVT-negative patients limits its utility in IBD.
... we believe that the clinical efficacy and cost-effectiveness of pharmacological prophylaxis in the population with inflammatory bowel disease should be proven before it is routinely recommended ...during acute flares.
By inducing BK (bradykinin)-stimulated adrenomedullary catecholamine release, bolus injection of the β-fragment of activated plasma coagulation Factor XII (β-FXIIa) transiently elevates BP (blood ...pressure) and HR (heart rate) of anaesthetized, vagotomized, ganglion-blocked, captopril-treated bioassay rats. We hypothesized that intravenous infusion of β-FXIIa into intact untreated rats would elicit a qualitatively similar vasoconstrictor response. BN (Brown Norway) rats received for 60 min either: (i) saline (control; n=10); (ii) β-FXIIa (85 ng/min per kg of body weight; n=9); or (iii) β-FXIIa after 2ADX (bilateral adrenalectomy; n=9). LV (left ventricular) volume and aortic BP were recorded before (30 min baseline), during (60 min) and after (30 min recovery) the infusion. TPR (total peripheral resistance) was derived from MAP (mean arterial pressure), SV (stroke volume) and HR. Saline had no haemodynamic effects. β-FXIIa infusion increased its plasma concentration 3-fold in both groups. In adrenally intact rats, β-FXIIa infusion increased MAP by 6% (5±2 mmHg) and TPR by 45% (0.50±0.12 mmHg/ml per min), despite falls in SV (-38±8 μl) and HR -18±5 b.p.m. (beats/min) (all P<0.05). In 2ADX rats, β-FXIIa had no HR effect, but decreased SV (-89±9 μl) and MAP (-4±1 mmHg), and increased TPR by 66% (0.59±0.15 mmHg/ml per min) (all P<0.05). After infusion, adrenally intact rats exhibited persistent vasoconstriction (MAP, 10±1 mmHg; TPR, 0.55±0.07 mmHg/ml per min; both P<0.05), whereas in 2ADX rats, MAP remained 5±1 mmHg below baseline (P<0.05) and TPR returned to baseline. End-study arterial adrenaline (epinephrine) concentrations in the three groups were 1.9±0.6, 9.8±4.1 and 0.6±0.2 nmol/l respectively. Thus, in neurally intact lightly anaesthetized untreated rats, β-FXIIa infusion induces both adrenal catecholamine-mediated and adrenally independent increases in peripheral resistance.
Summary
Background
Preliminary evidence suggests that use of antipsychotic drugs is associated with an increased risk of venous thromboembolism.
Objective
To evaluate the relationship between ...antipsychotic or antidepressant drug use and venous thromboembolism among adults aged 65 years and older.
Design
Retrospective cohort study using linked health care administrative databases over a nine year period.
Setting
The entire province of Ontario, Canada.
Participants
Individuals aged 65 years and over exclusively prescribed either antipsychotic drugs (n = 22514), antidepressant drugs (n = 75649) or thyroid replacement hormones (33033), the referent control group. We excluded those with an antecedent history of cardiovascular disease, venous thromboembolism or cancer, as well as those dispensed warfarin before study entry.
Measurements
Diagnosis of deep vein thrombosis or pulmonary embolism.
Results
Relative to those prescribed thyroid hormones, neither anti-depressant (adjusted hazard ratio 1.02, 95% CI 0.91-1.14) nor anti-psychotic (adjusted hazard ratio 1.13, 95% CI 0.96-1.32) drug use was associated with an increased risk for deep vein thrombosis. Similar risk estimates were found for deep vein thrombosis or pulmonary embolism. In a sub-group analysis, only butyrophenone use was found to be associated with a slightly increased risk of deep vein thrombosis (adjusted HR 1.51, 95% CI 1.23-1.86) as well as deep vein thrombosis or pulmonary embolism (adjusted HR 1.43, 95% CI 1.18-1.74).
Conclusions
In a large cohort of adults aged 65 years and older, neither antipsychotic or antidepressant drug use was associated with an increased risk of venous thromboembolism, with the exception of a slightly increased risk among those prescribed butyrophenones. Further data are required before use of these psychoactive drugs can be considered a risk factor for venous thromboembolism.
We describe the first sandwich enzyme-linked immunosorbent assay (ELISA) capable of recognizing both rat and human activated coagulation Factor XII (FXIIa). Increased plasma concentrations of FXIIa ...have been associated with adverse outcomes in several cardiovascular disease states. In humans, the FXIIa antigen in plasma is quantified by a direct sandwich ELISA employing an antibody (mAb 2/215) raised against its β-fragment (β-FXIIa), but this assay is unable to detect rat β-FXIIa antigen. Thus, experimental models are at present limited in their capacity to reveal mechanisms by which FXIIa might contribute to cardiovascular pathology. Consistent with overlap between human and rat FXIIa protein epitope sequences, Western blot analysis and ELISA demonstrate that another previously developed antibody against human FXIIa (mAb 201/9) detects β-FXIIa in both human and rat plasma, with no evidence for cross-reactivity with the FXII zymogen or FXIIa complexed with its endogenous inhibitor. The mAb 201/9 based ELISA identified similar elevations in FXIIa in plasma from rats and humans with chronic renal failure. The capacity of this ELISA to identify rat plasma FXIIa has potential application to a wide range of experimental models of human cardiovascular disease.
To study patients with coronary artery disease (CAD) scheduled for coronary angioplasty and to examine platelet activation in response to mental stress as a potential mechanism involved in the ...association between psychosocial factors and cardiac outcomes. Psychosocial factors have been identified as risk factors for CAD and adverse cardiac outcomes, although the underlying mechanisms are poorly understood.
Markers of platelet activation and platelet reactivity in response to experimentally induced mental stress (mental arithmetic and anger recall) were examined, using flow cytometry analysis and beta-thromboglobulin (BTG) assays among 249 CAD patients (age = 60.3 +/- 9.0 years, 15% women) who were scheduled to undergo elective percutaneous coronary intervention.
Mental stress-induced increases in platelet activation (CD41 (GP IIb/IIIa), p = .002; percent of mononuclear cells positive for CD41, p = .01; CD62P (P-selectin) expression, p = .005; and percent platelets positive for CD62P, p < .001). The degree of platelet reactivity was not related to demographic, clinical, or psychological variables, or cardiovascular hemodynamic changes.
Experimentally induced mental stress induced platelet activation in patients with CAD. This mechanism may partially explain the link between psychosocial variables and the development of adverse cardiac outcomes in patients with CAD.
IMPORTANCE: Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative ...management is uncertain. OBJECTIVE: To investigate the safety of a standardized perioperative DOAC management strategy. DESIGN, SETTING, AND PARTICIPANTS: The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. INTERVENTIONS: A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low–bleeding-risk procedure and 2 days before a high–bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low–bleeding-risk procedure and 2 to 3 days after a high–bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. MAIN OUTCOMES AND MEASURES: Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (<50 ng/mL) at the time of the procedure. RESULTS: The 3007 patients with AF (mean SD age of 72.5 9.39 years; 1988 men 66.1%) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high–bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high–bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort. CONCLUSIONS AND RELEVANCE: In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism.
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