Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas.

OBJECTIVES: Growth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the more precise biomarker-based ABC (age, biomarkers, clinical history)-AF-bleeding and ABC-AF-death risk scores. Data from large trials indicate a geographic variability in regard to overall outcomes, including bleeding and mortality risk. Our aim was to assess the consistency of the association between GDF-15, ABC-AF-bleeding score and ABC-AF-death score, with major bleeding and death, across world geographic regions. METHODS: Data were available from 14 767 patients with AF from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and 8651 patients with AF from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial in this cohort study. GDF-15 was analysed from plasma samples obtained at randomisation. The geographical consistency of the associations between outcomes and GDF-15, ABC-AF-bleeding score and ABC-AF-death scores were assessed by Cox-regression models including interactions with predefined geographical region. RESULTS: GDF-15 and the ABC-AF-bleeding score were associated with major bleeding in both trials across regions (p<0.0001). Similarly, GDF-15 and the ABC-AF-death score were associated with all-cause mortality in both trials across regions (p<0.0001). Overall, the association between GDF-15, the ABC-AF-bleeding score and ABC-AF-death risk score with major bleeding and death was consistent across regions in both ARISTOTLE and the RE-LY trial cohorts. The ABC-AF-bleeding and ABC-AF-death risk scores were consistent regarding discriminative ability when comparing geographic regions in both trial cohorts. The C-indices ranged from 0.649 to 0.760 for the ABC-AF-bleeding and from 0.677 to 0.806 for the ABC-AF-death score by different geographic regions. CONCLUSIONS: In patients with AF on anticoagulation, GDF-15 and the biomarker-based ABC-AF-bleeding and ABC-AF-death risk scores are consistently associated with respectively increased risk of major bleeding and death and have similar prognostic value across world geographic regions. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry NCT00412984 and NCT00262600.

Inferring an animal's environment through biologging: quantifying the environmental influence on animal movement.

BACKGROUND: Animals respond to environmental variation by changing their movement in a multifaceted way. Recent advancements in biologging increasingly allow for detailed measurements of the multifaceted nature of movement, from descriptors of animal movement trajectories (e.g., using GPS) to descriptors of body part movements (e.g., using tri-axial accelerometers). Because this multivariate richness of movement data complicates inference on the environmental influence on animal movement, studies generally use simplified movement descriptors in statistical analyses. However, doing so limits the inference on the environmental influence on movement, as this requires that the multivariate richness of movement data can be fully considered in an analysis. METHODS: We propose a data-driven analytic framework, based on existing methods, to quantify the environmental influence on animal movement that can accommodate the multifaceted nature of animal movement. Instead of fitting a simplified movement descriptor to a suite of environmental variables, our proposed framework centres on predicting an environmental variable from the full set of multivariate movement data. The measure of fit of this prediction is taken to be the metric that quantifies how much of the environmental variation relates to the multivariate variation in animal movement. We demonstrate the usefulness of this framework through a case study about the influence of grass availability and time since milking on cow movements using machine learning algorithms. RESULTS: We show that on a one-hour timescale 37% of the variation in grass availability and 33% of time since milking influenced cow movements. Grass availability mostly influenced the cows' neck movement during grazing, while time since milking mostly influenced the movement through the landscape and the shared variation of accelerometer and GPS data (e.g., activity patterns). Furthermore, this framework proved to be insensitive to spurious correlations between environmental variables in quantifying the influence on animal movement. CONCLUSIONS: Not only is our proposed framework well-suited to study the environmental influence on animal movement; we argue that it can also be applied in any field that uses multivariate biologging data, e.g., animal physiology, to study the relationships between animals and their environment. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s40462-020-00228-4.

Emergency care of patients receiving non-vitamin K antagonist oral anticoagulants.

Non-vitamin K antagonist oral anticoagulants (NOACs), which inhibit thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban, edoxaban) have been introduced in several clinical indications. Although NOACs have a favourable benefit-risk profile and can be used without routine laboratory monitoring, they are associated-as any anticoagulant-with a risk of bleeding. In addition, treatment may need to be interrupted in patients who need surgery or other procedures. The objective of this article, developed by a multidisciplinary panel of experts in thrombosis and haemostasis, is to provide an update on the management of NOAC-treated patients who experience a bleeding episode or require an urgent procedure. Recent advances in the development of targeted reversal agents are expected to help streamline the management of NOAC-treated patients in whom rapid reversal of anticoagulation is required.

Atherothrombosis and Thromboembolism: Position Paper from the Second Maastricht Consensus Conference on Thrombosis.

Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin-angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet-fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia-reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C-based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.

Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE-LY trial.

BACKGROUND: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF. OBJECTIVES: To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial. METHODS: HAS-BLED, ORBIT, ATRIA and HEMORR2 HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated. RESULTS: There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P < 0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all P < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P = 0.0019), ATRIA (P < 0.001) and HEMORR2 HAGES (P < 0.001) scores. HAS-BLED score showed a nonsignificant trend for interaction (P = 0.0607). CONCLUSIONS: Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

Comparison of the ecarin chromogenic assay and diluted thrombin time for quantification of dabigatran concentrations.

Essentials Routine monitoring is unnecessary but measuring dabigatran levels is helpful in certain situations. We compared ecarin chromogenic assay (STA-ECA-II) and dilute thrombin time (dTT) in patient samples. Both tests provided accurate measurements over a wide range of dabigatran concentrations. Adoption of STA-ECA-II and dTT into routine clinical practice will improve patient care. SUMMARY: Background Although routine coagulation monitoring is unnecessary, measuring plasma dabigatran concentrations can be useful for detecting drug accumulation in renal failure or overdose, assessing the contribution of dabigatran to serious bleeding, planning the timing of urgent surgery or intervention, or determining the suitability for thrombolytic therapy for acute ischemic stroke. Dabigatran concentrations can be quantified using chromogenic or clot-based tests, such as the ecarin chromogenic assay (ECA) and the diluted thrombin time (dTT), respectively. Objective The purpose of this study was to compare the results of these assays with dabigatran concentrations measured by the reference standard of mass spectrometry in samples from 50 dabigatran-treated patients collected at peak and trough after at least 4 months of drug intake. Methods Drug levels measured with either the STA Ecarin Chromogenic Assay-II (STA-ECA-II) or dTT were linearly correlated with those determined by mass spectrometry over a wide range of concentrations. Results and Conclusions For detection of levels below 50 ng mL-1 both tests have specificities of at least 96%, suggesting that they accurately detect even low levels of drug. Therefore, regardless of whether a chromogenic or clot-based platform is preferred, the STA-ECA-II and dTT are useful tests for measuring dabigatran concentrations. Unfortunately, neither test is licensed by the United States Food and Drug Administration. Although approved in other jurisdictions, the dTT and STA-ECA-II are not widely or rapidly available in most hospitals. Therefore, cooperation between regulators and hospitals is urgently needed to render these tests readily available to inform patient care.

Altered preoperative coagulation and fibrinolysis are associated with myocardial injury after non-cardiac surgery.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS), a complication with unclear pathogenesis, occurs within the first 30 days after surgery and worsens prognosis. Hypercoagulability induced by surgery might contribute to plaque rupture, with subsequent thrombosis and myocardial injury. This study assessed haemostatic markers before surgery and evaluated their association with MINS. METHODS: This is a substudy of VISION, a prospective cohort study of perioperative cardiovascular events. Of 475 consecutive vascular surgery patients, 47 (9.9%) developed MINS, defined as postoperative high-sensitivity troponin ≥50 ng litre -1 , with ≥20% elevation from the preoperative concentration. The control group consisted of 84 non-MINS patients matched for patient characteristics and co-morbidities. The following preoperative markers of hypercoagulability and fibrinolysis were measured: antithrombin, factor VIII activity, von Willebrand factor concentration and activity, fibrinogen, D-dimer, plasmin-antiplasmin complex, and tissue plasminogen activator. Moreover, C-reactive protein and CD40L concentrations were measured to assess inflammatory activity. RESULTS: Patients with MINS compared with the non-MINS group had a significantly higher concentration of factor VIII (186 vs 155%, P =0.006), von Willebrand factor activity (223 vs 160%, P <0.001), von Willebrand factor concentration (317 vs 237%, P =0.02), concentrations of fibrinogen (5.6 vs 4.2 g litre -1 , P =0.03), D-dimer (1680.0 vs 1090.0 ng ml -1 , P =0.04), plasmin-antiplasmin complex (747 vs 512 ng ml -1 , P =0.002) and C-reactive protein (10 vs 4.5 mg litre -1 , P =0.02) but not antithrombin (95 vs 94%, P =0.89), tissue plasminogen activator (11 vs 9.7 ng ml -1 , P =0.06) and CD40L (8790 vs 8580 pg ml -1 , P =0.73). CONCLUSIONS: Preoperative elevation of blood markers of hypercoagulability in patients undergoing vascular surgery is associated with a higher risk of MINS. CLINICAL TRIAL REGISTRATION: NCT00512109.

The impact of hunting on tropical mammal and bird populations.

Hunting is a major driver of biodiversity loss, but a systematic large-scale estimate of hunting-induced defaunation is lacking. We synthesized 176 studies to quantify hunting-induced declines of mammal and bird populations across the tropics. Bird and mammal abundances declined by 58% (25 to 76%) and by 83% (72 to 90%) in hunted compared with unhunted areas. Bird and mammal populations were depleted within 7 and 40 kilometers from hunters' access points (roads and settlements). Additionally, hunting pressure was higher in areas with better accessibility to major towns where wild meat could be traded. Mammal population densities were lower outside protected areas, particularly because of commercial hunting. Strategies to sustainably manage wild meat hunting in both protected and unprotected tropical ecosystems are urgently needed to avoid further defaunation.

Once versus twice daily aspirin after coronary bypass surgery: a randomized trial.

Essentials Coronary artery bypass graft (CABG) failure is associated with myocardial infarction and death. We tested whether more frequent dosing improves aspirin (ASA) response following CABG surgery. Twice-daily compared with once-daily dosing reduces ASA hyporesponsiveness after CABG surgery. The efficacy of twice-daily ASA needs to be tested in a trial powered for clinical outcomes. SUMMARY: Background Acetyl-salicylic acid (ASA) hyporesponsiveness occurs transiently after coronary artery bypass graft (CABG) surgery and may compromise the effectiveness of ASA in reducing thrombotic graft failure. A reduced response to ASA 81 mg once-daily after CABG surgery is overcome by four times daily ASA dosing. Objectives To determine whether ASA 325 mg once-daily or 162 mg twice-daily overcomes a reduced response to ASA 81 mg once-daily after CABG surgery. Methods Adults undergoing CABG surgery were randomized to ASA 81 mg once-daily, 325 mg once-daily or 162 mg twice-daily. The primary outcome was median serum thromboxane B2 (TXB2 ) level on postoperative day 4. We pooled the results with those of our earlier study to obtain better estimates of the effect of ASA 325 mg once-daily or in divided doses over 24 h. Results We randomized 68 patients undergoing CABG surgery. On postoperative day 4, patients randomized to receive ASA 81 mg once-daily had a median day 4 TXB2 level of 4.2 ng mL-1 (Q1, Q3: 1.5, 7.5 ng mL-1 ), which was higher than in those randomized to ASA 162 mg twice-daily (1.1 ng mL-1 ; Q1, Q3: 0.7, 2.7 ng mL-1 ) and similar to those randomized to ASA 325 mg once-daily (1.9 ng mL-1 ; Q1, Q3: 0.9, 4.7 ng mL-1 ). Pooled data showed that the median TXB2 level on day 4 in groups receiving ASA 162 mg twice-daily or 81 mg four times daily was 1.1 ng mL-1 compared with 2.2 ng mL-1 in those receiving ASA 325 mg once-daily. Conclusions Multiple daily dosing of ASA is more effective than ASA 81 mg once-daily or 325 mg once-daily at suppressing serum TXB2 formation after CABG surgery. A twice-daily treatment regimen needs to be tested in a clinical outcome study.

Mortality outcomes in patients transfused with fresher versus older red blood cells: a meta-analysis.

BACKGROUND: Among transfused patients, the effect of the duration of red blood cell storage on mortality remains unclear. This study aims to compare the mortality of patients who were transfused with fresher versus older red blood cells. METHODS: We performed an updated systematic search in the CENTRAL, MEDLINE, EMBASE and CINAHL databases, from January 2015 to October 2016. RCTs of hospitalized patients of any age comparing transfusion of fresher versus older red blood cells were eligible. We used a random-effects model to calculate pooled risk ratios (RRs) with corresponding 95% confidence interval (CI). RESULTS: We identified 14 randomized trials that enrolled 26 374 participants. All-cause mortality occurred in 1219 of 9531 (12·8%) patients who received a transfusion of fresher red blood cells and 1810 of 16 843 (10·7%) in those who received older red blood cells (RR: 1·04, 95% CI: 0·98-1·12, P = 0·90, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). In six studies, in-hospital death occurred in 691 of 7479 (9·2%) patients receiving fresher red cells and 1291 of 14 757 (8·8%) receiving older red cells (RR: 1·06, 95% CI: 0·97-1·15, P = 0·81, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). CONCLUSION: Transfusion of fresher red blood cells does not reduce overall or in-hospital mortality when compared with older red blood cells. Our results support the practice of transfusing patients with the oldest red blood cells available in the blood bank.

Effect of standardized perioperative dabigatran interruption on the residual anticoagulation effect at the time of surgery or procedure.

UNLABELLED: ESSENTIALS: Anticoagulants need to be stopped preprocedure so there is little or no remaining anticoagulant effect. We assessed the residual anticoagulant effect with standardized interruption for patients on dabigatran. With this protocol, 80-86% of patients had no residual anticoagulant effect at the time of a procedure. A standardized perioperative dabigatran protocol appears to be safe, but requires further study. BACKGROUND: In patients taking dabigatran who require treatment interruption for a surgery/procedure, a sufficient interruption interval is needed so that there is little or no residual anticoagulant effect at the time of the surgery/procedure. METHODS: A prospective cohort study of patients receiving dabigatran (110 mg or 150 mg twice daily) who required an elective surgery/procedure and received a standardized dabigatran interruption protocol based on surgery/procedure bleeding risk and renal function was performed. Before the surgery/procedure, a blood sample was taken for measurement of the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and dilute thrombin time (dTT). We determined the proportion of all patients and those having a high bleeding risk surgery/procedure with normal coagulation test results at the time of the surgery/procedure. The APTT and dTT were considered to be most likely to reflect a dabigatran anticoagulant effect. Patients were followed up for 30 days postprocedure to assess for bleeding and thromboembolism. RESULTS: One hundred and eighty-one patients were studied: 118 with low bleeding risk, and 63 with high bleeding risk. For all patients, the proportions with normal PT, APTT, TT dTT levels were 92.8%, 79.6%, 33.1%, and 80.7%, respectively. In patients with high bleeding risk, the proportions with normal PT, APTT, TT dTT levels were 93.7%, 85.7%, 57.1%, and 87.3%, respectively. During follow-up, there was one (0.6%) major bleed, there were nine (5.0%) minor bleeds, and there was one (0.6%) transient ischemic attack. CONCLUSIONS: In patients receiving dabigatran who require an elective surgery/procedure, a standardized interruption protocol yielded 80-86% of patients with no residual anticoagulant effect at the time of surgery/procedure, and with a low incidence of bleeding.

Management of bleeding with oral anticoagulants in patients with atrial fibrillation.

Fear of bleeding is a common barrier to the use of anticoagulants. Warfarin has been the only oral anticoagulant for more than 60 years and warfarin-related bleeding is reported to be the most common drug-related cause of emergency hospitalization in elderly Americans. Non-vitamin K oral antagonists were introduced five years ago and compared with warfarin are associated with lower risk of intracranial bleeding, and similar or lower case fatality after major bleeding. Despite their superior safety profile, serious bleeding can occur. Most bleeding can be managed with holding the drug, local measures to control the bleeding and transfusion support as required because the NOACs have a relatively short half life and their anticoagulant effect rapidly dissipates. In patients with ongoing bleeding despite supportive measures and in those with life-threatening bleeding, consideration may be given to the use of general hemostatic agents. Experimental and animal evidence suggests that 3 and 4 factor prothrombin complex concentrates can improve hemostasis in the presence of a NOAC and this is reinforced by anecdotal evidence in humans. Specific antidotes are currently in phase 3 trials and could become available in the near future.

Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial.

BACKGROUND: Anemia may predispose to thromboembolic events or bleeding in anticoagulated patients with atrial fibrillation (AF). OBJECTIVES: To investigate whether anemia is associated with thromboembolic events and bleeding in patients with AF. PATIENTS AND METHODS: We retrospectively analyzed the RE-LY trial database, which randomized 18 113 patients with AF and a risk of stroke to receive dabigatran or warfarin for a median follow-up of 2 years. Cox regression analysis was used to determine whether anemia predicted cardiovascular events and bleeding complications in these patients. RESULTS: Anemia was present in 12% of the population at baseline, and the presence of anemia was associated with a higher risk of thromboembolic cardiovascular events, including the composite endpoint of all-cause mortality or myocardial infarction (adjusted hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.32-1.71) and the primary RE-LY outcome of stroke or systemic embolism (adjusted HR 1.41, 95% CI 1.12-1.78). Anemia was also associated with a higher risk of major bleeding complications (adjusted HR 2.14, 95% CI 1.87-2.46) and discontinuation of anticoagulants (adjusted HR 1.40, 95% CI 1.28-1.79). The association between anemia and outcome was similar irrespective of cardiovascular comorbidities, randomized treatment allocation, or prior use of warfarin. The incidence of events was lower in patients with transient anemia than in patients in whom anemia was sustained (adjusted HR 0.66, 95% CI 0.49-0.91). CONCLUSIONS: Anemia is associated with an increased risk of thromboembolic events, bleeding complications and mortality in anticoagulated patients with AF. These findings suggest that patients with anemia should be monitored closely during all types of anticoagulant treatment.

Active metabolite concentration of clopidogrel in patients taking different doses of aspirin: results of the interaction trial.

BACKGROUND: The CURRENT-OASIS-7 and PLATO trials suggest that the benefit of clopidogrel is influenced by the dose of aspirin. OBJECTIVE: To explore a potential pharmacokinetic interaction between aspirin and clopidogrel, and determinants of clopidogrel active metabolite (AM) levels. METHODS: In part 1, using a 2 × 2 factorial design, we randomized patients to clopidogrel 600 mg loading dose (LD) followed by 150 mg day(-1) for 6 days and 75 mg day(-1) thereafter, or clopidogrel 300 mg LD followed by 75 mg day(-1) thereafter, and compared aspirin at 325 mg or 81 mg day(-1) . In part 2, patients were given a 600-mg clopidogrel LD, and were randomly allocated to aspirin 325 mg or 81 mg day(-1) . We combine the data from the two parts. Blood samples were collected 1 h after administration of the study drug. RESULTS: We randomized 302 patients (mean age 60.4 ± 9.9 years). Clopidogrel AM levels were similar in patients randomized to aspirin 325 or 81 mg (geometric mean, 12.70 ng mL(-1) ; 95% CI, 10.96-14.72 ng mL(-1) ; and geometric mean, 12.55 ng mL(-1) ; 95% CI, 10.80-14.58 ng mL(-1) ; P = 0.91). Blood levels of clopidogrel were lower in CYP2C19*2 loss-of-function (LOF) carriers compared with non-carriers (10.72 ng mL(-1) ; 95% CI, 8.83-13.01 ng mL(-1) ; and 15.21 ng mL(-1) ; 95% CI, 13.30-17.40 ng mL(-1) , respectively; P = 0.003) whereas levels in gain of function carriers and non-carriers were similar (13.31 ng mL(-1) ; 95% CI, 11.53-15.35 ng mL(-1) ; and 14.07 ng mL(-1) ; 95% CI, 11.74-16.87 ng mL(-1) , respectively; P = 0.4). Independent baseline predictors of clopidogrel AM levels were LOF genotype, body mass index, diabetes, proton pump inhibitor use and creatinine clearance, but accounted for only 20% of the variability in levels. CONCLUSION: Aspirin dose does not predict clopidogrel AM levels 1 h post-LD. Most of the variability in clopidogrel AM levels is not explained by patient characteristics or CYP2C19 metabolizer status.

Multiple daily doses of acetyl-salicylic acid (ASA) overcome reduced platelet response to once-daily ASA after coronary artery bypass graft surgery: a pilot randomized controlled trial.

BACKGROUND: The efficacy of ASA for prevention of graft failure following CABG surgery may be limited by incomplete platelet inhibition due to increased post-operative platelet turnover. OBJECTIVES: To determine whether acetyl-salicylic acid (ASA) 325 mg once-daily or 81 mg four-times daily overcomes the impaired response to ASA 81 mg once-daily in post-operative coronary artery bypass graft (CABG) patients. METHODS: We randomized 110 patients undergoing CABG surgery to either ASA 81 mg once-daily, 81 mg four times daily or 325 mg once-daily and compared their effects on serum thromboxane B2 (TXB2 ) suppression and arachidonate-induced platelet aggregation. RESULTS: One hundred patients were included in the final analysis. Platelet counts fell after surgery, reached a nadir on day 2, and then gradually increased. Although there was near complete suppression of TXB2 on the second or third post-operative day, TXB2 levels increased in parallel with the rise in platelet count on subsequent days. This increase was most marked in patients receiving ASA 81 mg once-daily and less evident in those receiving ASA four times daily. On post-operative day 4, (i) median TXB2 levels were lower with four times daily ASA than with either ASA 81 mg once-daily (1.1 ng/mL; Quartile(Q) Q1,Q3: 0.5, 2.4 and 13.3 ng/mL; Q1,Q3: 7.8, 30.8 ng/mL, respectively; P < 0.0001) or ASA 325 mg once-daily (3.4 ng/mL; Q1,Q3: 2.0, 8.2 ng/mL; P = 0.002), and (ii) ASA given four times daily was more effective than ASA 81 mg once-daily and 325 mg once-daily at suppressing platelet aggregation. CONCLUSIONS: Four times daily ASA is more effective than ASA 81 and 325 mg once-daily at suppressing serum TXB2 formation and platelet aggregation immediately following CABG surgery.

Real-world variability in dabigatran levels in patients with atrial fibrillation.

BACKGROUND: In clinical practice, physicians are given the choice of selecting one of two dabigatran doses based on patient characteristics, with the lower dose typically used in patients at a higher risk of bleeding. OBJECTIVES: The objectives of the study were to (i) estimate the inter- and intra-patient variability in dabigatran levels with 110 mg (DE110) and 150 mg (DE150) doses, (ii) examine the effect of physicians' dose selection on levels in DE110 and DE150 subgroups, and (iii) explore whether a single trough measurement identifies patients with extreme levels on subsequent visits. METHODS: In this prospective observational study of 100 patients with atrial fibrillation (AF), peak and trough levels of dabigatran were measured with the Hemoclot(®) assay at baseline and every 2 months thereafter (maximum four visits). RESULTS: Inter-patient variability in dabigatran levels (geometric coefficient of variation [gCV], 51-64%) was greater than intra-patient variability (gCV, 32-40%). Similar medians and distributions of levels were observed in DE110 and DE150 subgroups. Patients receiving DE110 were older, had lower renal function and weighed less than those receiving DE150. Up to 40% of patients whose trough levels were in the upper extremes, and up to 80% of patients whose trough levels were in the lower extremes at baseline, showed subsequent levels that fell in the middle quartiles. CONCLUSIONS: Our data support the practice of selecting the dabigatran dose based upon clinical characteristics because it results in similar levels of drug exposure in patients given DE110 or DE150. They do not support the concept that a single Hemoclot(®) measurement reliably identifies patients with consistently high or low values.