Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation

2012 ◽  
Vol 107 (05) ◽  
pp. 925-934 ◽  
Author(s):  
Jeanne Mendell ◽  
Helen Kastrissios ◽  
Michelle Green ◽  
Timothy J. Carrothers ◽  
SaeHeum Song ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Renal Impairment ◽  
Factor Xa ◽  
Phase Iii ◽  
Response Analysis ◽  
Response Model ◽  
Bleeding Events ◽  
Extrinsic Factors ◽  
Minimum Concentration ◽  
Exposure Response

SummaryEdoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.The results of this study were previously presented at the 2009 International Society on Thrombosis and Haemostasis, July 2009, Boston, Massachusetts, USA.

scholarly journals Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation

2011 ◽  
Vol 105 (03) ◽  
pp. 535-545 ◽  
Author(s):  
Hui-Kyung Jeon ◽  
Li-Ming Lien ◽  
Wen-Ter Lai ◽  
Hung-Fat Tse ◽  
Wook-Sung Chung ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Factor Xa ◽  
Phase Iii ◽  
Factor Xa Inhibitor ◽  
Thromboembolic Events ◽  
Bleeding Events ◽  
Asian Patients

SummaryEdoxaban is an oral, reversible, direct factor Xa inhibitor in phase III clinical development for the prevention of stroke in atrial fibrillation (AF). A phase II study was undertaken to evaluate the safety and efficacy of edoxaban in Asian patients with non-valvular AF with CHADS2 score ≥1. In a multicentre, active-controlled, double-blind edoxaban and open-label warfarin, parallel-group study, a total of 235 patients from four Asian countries were randomly assigned to edoxaban 30 mg qd, 60 mg qd or warfarin dose adjusted to international normalised ratio of 2–3 for three months. The primary endpoint was the incidence of centrally adjudicated all bleeding events (major, clinically relevant non-major and minor). Secondary endpoints included thromboembolic events, biomarkers of thrombus formation and all adverse events (AEs). The incidence of all bleeding events (95% CI) was 20.3% (12.9, 30.4) for edoxaban 30 mg, 23.8% (15.8, 34.1) for edoxaban 60 mg, and 29.3% (20.2, 40.4) for warfarin. A subgroup analysis suggested low body weight (≤60 kg) may affect the incidence of bleeding events with edoxaban. The incidence of study drug-related AEs was 22% for edoxaban 30 mg, 29% for edoxaban 60 mg and 33% for warfarin. No thromboembolic events occurred in any treatment group. In conclusion, this phase II study found a trend for a reduction in the incidence of all bleeding events in Asian AF patients with edoxaban 30 mg and 60 mg compared with warfarin. Adverse events were similar between the edoxaban 60-mg and warfarin groups and were lower with the edoxaban 30-mg group.ClinicalTrials.gov number: NCT00806624

scholarly journals Evaluation of Direct Oral Anticoagulant Prescribing in Patients With Moderate to Severe Renal Impairment

2021 ◽  
Vol 27 ◽  
pp. 107602962098790
Author(s):  
Clara Ting ◽  
Megan Rhoten ◽  
Jillian Dempsey ◽  
Hunter Nichols ◽  
John Fanikos ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Events ◽  
Increase Risk ◽  
Severe Chronic Kidney Disease ◽  
Dosing Strategies ◽  
Require Dose

Patients with renal impairment require dose adjustments for direct oral anticoagulants (DOACs), though there is uncertainty regarding their use in severe chronic kidney disease. Inappropriately dosed DOACs may increase risk of ischemic events when under-dosed, or risk of bleeding when over-dosed. The purpose of this study was to describe DOAC selection, dosing strategies, and associated clinical outcomes in patients with moderate to severe renal impairment at our institution. This was a single-center retrospective analysis of adult outpatients with moderate to severe renal impairment (estimated creatinine clearance <50 mL/min, including need for hemodialysis) who were prescribed a DOAC by a cardiologist between June 1, 2015 and December 1, 2018. Outcomes evaluated included the percentage of patients who received appropriate and inappropriate DOAC dosing, prescriber reasons for inappropriate DOAC dosing if documented, and incidence of thrombotic and bleeding events. A total of 207 patients were included. Overall, 61 (29.5%) patients received inappropriate dosing, with 43 (70.5%) being under-dosed and 18 (29.5%) being over-dosed as compared to FDA-labeled dosing recommendations for atrial fibrillation or venous thromboembolism (VTE). By a median follow-up duration of 20 months, stroke occurred in 6 (3.3%) patients receiving DOACs for atrial fibrillation, and VTE occurred in 1 (4.3%) patient receiving a DOAC for VTE. International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding occurred in 25 (12.1%) patients. Direct oral anticoagulants were frequently prescribed at off-label doses in patients with moderate to severe renal impairment, with a tendency toward under-dosing.

The NOACs: clinical pharmacology

ESC CardioMed ◽  
2018 ◽  
pp. 268-272
Author(s):  
Jeffrey Weitz
Keyword(s):  
Atrial Fibrillation ◽  
Vitamin K ◽  
Active Site ◽  
Randomized Clinical Trials ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Vitamin K Antagonist ◽  
Phase Iii ◽  
High Affinity

The limitations of vitamin K antagonists prompted the development of new oral anticoagulants that could be administered in fixed doses without routine coagulation monitoring. Focusing on thrombin and factor Xa because of their prominent roles in coagulation, structure-based design led to the development of small molecules that bind to the active site pockets of these enzymes with high affinity and specificity. Four non-vitamin K antagonist oral anticoagulants are now licensed: dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. In phase III randomized clinical trials that included over 100,000 patients these agents have proven to be at least as effective as vitamin K antagonists for prevention of stroke in patients with non-valvular atrial fibrillation and for treatment of venous thromboembolism, and to produce less bleeding, particularly less intracranial bleeding.

Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery

2012 ◽  
Vol 108 (11) ◽  
pp. 887-895 ◽  
Author(s):  
Shashank Rohatagi ◽  
Helen Kastrissios ◽  
Michelle Green ◽  
Michelle Green ◽  
Minggao Shi ◽  
...  
Keyword(s):  
Total Hip Replacement ◽  
Hip Replacement ◽  
Oral Absorption ◽  
Factor Xa ◽  
Compartment Model ◽  
Surgical Patients ◽  
Response Analysis ◽  
Total Hip ◽  
Replacement Surgery ◽  
Exposure Response

SummaryEdoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding.

Edoxaban Versus Enoxaparin for the Prevention of Venous Thromboembolism: Pooled Analysis of Coagulation Biomarkers From Stars E-3 and Stars J-V.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2260-2260
Author(s):  
Takeshi Fuji ◽  
Satoru Fujita ◽  
Shintaro Tachibana ◽  
Yohko Kawai
Keyword(s):  
Venous Thromboembolism ◽  
Factor Xa ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Bleeding Events ◽  
Double Blind ◽  
Once Daily ◽  
Treatment Groups ◽  
Post Operation ◽  
D Dimer

Abstract Abstract 2260 Introduction: Edoxaban is an oral, once-daily, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events. Two randomized, double-blind, double-dummy, phase III studies (STARS E-3 and STARS J-V) have been conducted to evaluate the efficacy and safety of edoxaban compared to enoxaparin for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) or total hip arthroplasty (THA). The objective of this pooled analysis was to investigate the effects of edoxaban on key coagulation biomarkers. Methods: Patients (N=1,326) undergoing TKA or THA in Japan and Taiwan were randomized to receive oral edoxaban 30 mg once daily (qd) or subcutaneous enoxaparin 2,000 IU twice daily (bid; equivalent to 20 mg bid) for 11–14 days. Edoxaban was initiated 6–24 hours after surgery and enoxaparin was initiated 24–36 hours after surgery, which is the standard of care in Japan. Blood samples were collected for coagulation biomarker measurements pre-operation, post-operation (pre-treatment, Day 0), Day 7 (prior to administration of the next dose) and completion day (Day 11–14). The primary efficacy outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE). The principal safety outcome was the incidence of major and clinically relevant non-major (CRNM) bleeding. Pharmacodynamic endpoints included key coagulation biomarkers such as D-dimer, prothrombin fragment F1+2 (F1+2) and soluble fibrin monomer complex (SFMC). Results: A total of 1,307 patients received at least 1 dose of edoxaban or enoxaparin. There were no clinically relevant differences in baseline characteristics between the treatment groups. The mean age was 68 years, mean body weight was 58.8 kg and 83% of patients were female. Overall, edoxaban significantly reduced the incidence of the composite of symptomatic and asymptomatic DVT and PE compared with enoxaparin (5.1% vs 10.7%, P<0.001). The incidence of major and CRNM bleeding events was 4.6% vs 3.7% in the edoxaban and enoxaparin groups, respectively (P=0.427). For both treatment groups, D-dimer and SFMC levels were reduced at Day 7 compared to post-operation/pretreatment levels, then increased slightly by Day 11–14. Levels of F1+2 also decreased by Day 7 in both treatment groups and further decreased by Day 11–14. However, for each coagulation biomarker, levels were significantly lower in the edoxaban group compared to the enoxaparin group at both Day 7 and Day 11–14. (Table, P<0.001). Conclusion: Edoxaban 30 mg qd is superior to enoxaparin 20 mg bid in the prevention of VTE events with significant reduction of D-dimer, F1+2 and SFMC following TKA and THA. Disclosures: Fuji: Daiichi Sankyo: Consultancy; Bayer: Consultancy; Century Medical: Consultancy; Showa Ikakogyo: Consultancy. Fujita:Daiichi Sankyo: Consultancy; Bayer: Consultancy. Tachibana:Daiichi Sankyo: Consultancy. Kawai:Daiichi Sankyo: Consultancy; Bayer: Consultancy; Toyama Chemical: Consultancy.

Advances in Atrial Fibrillation-related Stroke Prevention

2015 ◽  
Vol 9 (2) ◽  
pp. 122
Author(s):  
Pierre Amarenco ◽  
Werner Hacke ◽  
Bo Norrving ◽  
Natalia Rost ◽  
◽  
...  
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Anticoagulant Therapy ◽  
Stroke Prevention ◽  
Stroke Risk ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Haemorrhagic Stroke ◽  
Bleeding Events ◽  
Patients At Risk

In patients with atrial fibrillation (AF) the risk of stroke is substantially increased, especially in those who are elderly (over 75 years) or have risk factors such as previous stroke, heart failure or hypertension. Stroke outcomes are also generally much worse in those with AF. Current guidelines indicate that any patient with AF and risk factors for stroke should receive anticoagulant therapy to limit their stroke risk. Despite these established recommendations, only 50 % of patients at risk receive anticoagulation with a vitamin K antagonist (VKA) and only 50 % of those are within the therapeutic range, indicating lack of adherence to the guidelines. Withholding anticoagulant therapy is mainly left to an individual physician’s choice, as shown in the ongoing GARFIELD registry of AF stroke prevention practice. Many physicians fear the risk of intracranial haemorrhage (ICH) for which outcomes remain poor. Recent clinical studies have shown that the non-VKA oral anticoagulants (NOACs) (apixaban, rivaroxaban, dabigatran and edoxaban) significantly reduce the risk of ICH and other bleeding events, while having non-inferior stroke prevention to warfarin. Use of these drugs, limiting exposure to aspirin and alcohol and controlling blood pressure have been shown to minimise ICH risk in large clinical trials and meta-analyses. Recent data from the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation (ENGAGE AF)-TIMI 48 study showed that the factor Xa inhibitor edoxaban was non-inferior to well-managed warfarin for reducing all stroke risk, and significantly reduced haemorrhagic stroke, major bleeding, ICH and death. These findings further support the case for using NOAC therapy for stroke prevention in patients with AF and risk factors for stroke.

Randomized, Parallel Group, Multicenter, Multinational Study Evaluating Safety of DU-176b Compared with Warfarin in Subjects with Non-Valvular Atrial Fibrillation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 33-33 ◽  
Author(s):  
Jeffrey I. Weitz ◽  
Stuart J. Connolly ◽  
Satoshi Kunitada ◽  
James Jin ◽  
Indravadan Patel
Keyword(s):  
Atrial Fibrillation ◽  
Major Bleeding ◽  
Bleeding Event ◽  
Phase Iii ◽  
Fixed Dose ◽  
Bleeding Events ◽  
Treatment Groups ◽  
Parallel Group ◽  
Elevated Liver Enzymes ◽  
Major Bleeding Events

Abstract Introduction : The primary objective of this phase II study was to assess the safety of different dose regimens of DU-176b, an oral direct factor Xa inhibitor, in patients with non-valvular atrial fibrillation (AF). Methods : This was a randomized, parallel group, multicenter, multinational, double-blind DU-176b and open-label warfarin safety study in patients with AF (CHADS2 index ≥ 2). Patients were randomly assigned to receive either one of four fixed dose regimens of DU-176b (30 mg qd, 30 mg bid, 60 mg qd or 60 mg bid) or warfarin dose-adjusted to a target international normalized ratio (INR) of 2.0–3.0. for 12 weeks. Investigators, sponsor and study subjects were blinded to DU-176b dose but not to the identity of DU-176b vs. warfarin. Investigators adjusted warfarin doses based on INR values obtained in local laboratories. The INR was determined weekly for 4 weeks and every two weeks thereafter. The primary outcomes were the occurrence of centrally adjudicated major and/or clinically relevant non-major bleeding event, and elevated liver enzymes and/or bilirubin. Secondary outcomes included major adverse cardiovascular events (MACE), a composite of stroke, systemic embolism, acute myocardial infarction, hospitalizations due to cardiovascular condition or cardiovascular death, as well as all other adverse events, including all bleeding events. Results : A total of 1,146 patients were randomized. There were no clinically relevant differences between treatment groups with respect to the demographic data and baseline characteristics. Mean age was 65±8.7 years, 63.3% of patients had a CHADS2 index of 2 and 64.40% were warfarin naïve. The DU-176b 60 mg bid treatment arm was prematurely terminated during the study based on a recommendation by the Independent Data Monitoring Committee (DMC). A total of 180 patients were randomized to this group at the time. The incidence of major and clinically relevant non-major bleeding events was significantly higher in both the DU-176b 60 mg bid and 30 mg bid groups than in those given warfarin. The incidence of major and clinically relevant non-major bleeding events in the DU-176b 30 mg qd and 60 mg qd groups was similar to that in warfarin-treated patients. The time in therapeutic range (TTR) for warfarin-experienced patients was 50.1% and for warfarin naïve patients was 41.8%. There were no significant differences in the number (%) of subjects with persistently elevated ALT, AST, or bilirubin values across the treatment groups. The incidence of stroke was similar across treatment groups (Table). DU-176b 30 mg qd N=235 DU-176b 60 mg qd N=234 DU-176b 30 mg bid N=244 DU-176b 60 mg bid N=180 Warfarin qd N=250 Bleeding, n (%) (95% CI) Major+CR non-major 7 (3.0) (1.2–6.0) 11 (4.7) (2.4–8.3) 19 (7.8) (4.8–11.9)a 19 (10.6) (6.5–16.0)b 8 (3.2) (1.4–6.2) Major 0 (0) (0–1.6) 1 (0.4) (0–2.4) 5 (2.0) (0.7–4.7) 6 (3.3) (1.2–7.1)a 1 (0.4) (0–2.2) All 13 (5.5) (3.0–9.3) 19 (8.1) (5.0–12.4) 32 (13.1) (9.1–18.0) 33 (18.3) (13.0–24.8)b 20 (8.0) (5.0–12.1) Stroke, n (%) (95% CI) 1 (0.4) (0–2.3) 1 (0.4) (0–2.4) 2 (0.8) (0.1–2.9) 2 (1.1) (0.1–4.0) 4 (1.6) (0.4–4.0) Conclusions : DU-176b 30 mg qd and 60 mg qd dose regimens had a safety profile similar to warfarin in patients with AF. Patients treated with the DU-176b 30 mg bid or 60 mg bid regimens had more bleeding events than occurred with warfarin. These results suggest that the DU-176b 30 mg qd or 60 mg qd regimens are safe and well tolerated. A Phase III trial is needed to determine whether DU-176b will provide a suitable replacement for warfarin in AF patients. CR, clinically relevant. aP&lt;0.05, bP=0.002 to warfarin.

scholarly journals Safety and Efficacy of Apixaban in the Treatment of Atrial Fibrillation

2012 ◽  
Vol 6 ◽  
pp. CMC.S8204 ◽  
Author(s):  
Andrew Martin ◽  
Ralph Stewart
Keyword(s):  
Atrial Fibrillation ◽  
Effective Treatment ◽  
Randomized Trials ◽  
Factor Xa ◽  
Systemic Embolism ◽  
Bleeding Events ◽  
Safety And Efficacy ◽  
Narrow Therapeutic Range ◽  
Superior Efficacy ◽  
To Receive

Atrial fibrillation is a common arrhythmia that increases the risk of stroke and systemic embolism. Warfarin is a highly effective treatment in reducing this risk, but a narrow therapeutic range, drug and food interactions, required monitoring, and bleeding limit its use. We review Apixaban, an oral inhibitor of Factor Xa, which has been shown in large randomized trials to have superior efficacy in stroke reduction without an excess in bleeding events when compared with aspirin in those deemed unsuitable to receive warfarin, and demonstrates superior efficacy in reducing stroke and systemic embolism in addition to a reduction in bleeding events when compared to warfarin.

scholarly journals Comparative effectiveness of NOAC vs VKA in patients representing common clinical challenges: results from the GARFIELD-AF registry

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Virdone ◽  
J.C.L Himmelreich ◽  
K.S Pieper ◽  
A.J Camm ◽  
J.-P Bassand ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Renal Impairment ◽  
Elderly Patients ◽  
Vitamin K ◽  
Comparative Effectiveness ◽  
Bleeding Risk ◽  
Phase Iii ◽  
Considerable Proportion ◽  
The Impact ◽  
Anticoagulated Patients

Abstract Introduction Large phase III trials of non-valvular atrial fibrillation (AF) patients have shown a favourable risk-to-benefit ratio with Non-Vitamin K antagonist oral anticoagulants (NOAC) compared to Vitamin K antagonists (VKA). Although the results of these trials are directly applicable to many AF patients, important subsets of patients were under-represented. Thus, there remains uncertainty about the safety and effectiveness of NOAC therapy in common challenging scenarios. Purpose The main purpose of this study is to quantify and compare the impact of NOAC vs VKA in settings where clinical uncertainty still exists and represents a considerable proportion of AF patients in clinical practice. Methods The analysis was conducted in patients enrolled in the largest AF multinational prospective registry (the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation, GARFIELD-AF). We evaluated the effectiveness and safety of NOAC compared to VKA in three groups of patients representing common clinical challenges (CCC): 1) elderly patients (i.e. age ≥75), 2) increased bleeding risk (i.e. HAS-BLED ≥3 or prior bleeding), and 3) renal impairment (i.e. CKD stages II to IV). We applied a propensity score using an overlap weighting scheme to obtain unbiased estimates of the treatment effect within each CCC group. Weights were applied to Cox proportional hazards models to estimate the effects of the NOAC vs VKA comparison on the occurrence of death, non-haemorrhagic stroke/SE and major bleeding within 2 years of enrolment. Results Comparative effectiveness of NOAC vs VKA was assessed in 8607 elderly patients, 1711 with increased bleeding risk, and 4460 with renal impairment. The proportion of anticoagulated patients was low in patients with increased bleeding risk (59%), while in the other two CCC groups the corresponding proportion was close to the one in the overall population (72%). Among anticoagulated patients, NOAC were prescribed to 50–55% of patients in the CCC groups. Patients with a high risk of bleeding and impaired kidney function were less likely to be prescribed NOAC instead of VKA compared with the overall anticoagulated population (−5.4% and −4.7%, respectively). Propensity-weighted hazard ratios for all-cause mortality favored NOAC (vs VKA) in all three CCC groups: 0.86 (95% CI: 0.74–0.99) for elderly patients, 0.73 (0.53–1.00) for patients with increased bleeding risk, and 0.80 (0.65–0.98) for patients with renal impairment (Figure). Conclusion In the selected common challenging scenarios of AF patients, there were significant mortality reductions in favor of NOACs compared to VKAs. These observations suggest that NOACs are safe and effective in patients who are elderly, at increased bleeding risk, or renally impaired. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This study was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the GARFIELD-AF registry. The work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

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