Ammar Majeed

Management and Outcomes of Major Bleeding during Treatment with Dabigatran or Warfarin

Background— The aim of this study was to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin. Methods and Results— Two independent investigators reviewed bleeding reports from 1034 individuals with 1121 major bleeds enrolled in 5 phase III trials comparing dabigatran with warfarin in 27 419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran (n=627 of 16 755) were older, had lower creatinine clearance, and more frequently used aspirin or non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10 002). The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the warfarin group (13.0%; pooled odds ratio, 0.68; 95% confidence interval, 0.46–1.01; P=0.057). After adjustment for sex, age, weight, renal function, and concomitant antithrombotic therapy, the pooled odds ratio for 30-day mortality with dabigatran versus warfarin was 0.66 (95% confidence interval, 0.44–1.00; P=0.051). Major bleeds in dabigatran patients were more frequently treated with blood transfusions (423/696, 61%) than bleeds in warfarin patients (175/425, 42%; P<0.001) but less frequently with plasma (dabigatran, 19.8%; warfarin, 30.2%; P<0.001). Patients who experienced a bleed had shorter stays in the intensive care unit if they had previously received dabigatran (mean 1.6 nights) compared with those who had received warfarin (mean 2.7 nights; P=0.01). Conclusions— Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care, and had a trend to lower mortality compared with those who had major bleeding on warfarin. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00262600, NCT00291330, NCT00680186, NCT00329238 and NCT00558259.

Optimal Timing of Resumption of Warfarin After Intracranial Hemorrhage

Background and Purpose— The optimum timing of resumption of anticoagulation after warfarin-related intracranial hemorrhage in patients with indication for continued anticoagulation is uncertain. We performed a large retrospective cohort study to obtain more precise risk estimates. Methods— We reviewed charts of 2869 consecutive patients with objectively verified intracranial hemorrhage over 6 years at 3 tertiary centers. We calculated the daily risk of intracranial hemorrhage or ischemic stroke with and without resumption of warfarin; we focused on patients who survived the first week and had cardiac indication for anticoagulation or previous stroke. Using a Cox model, we estimated rates for these 2 adverse events in relation to different time points of resumed anticoagulation. The combined risk of either a new intracranial hemorrhage or an ischemic stroke was calculated for a range of warfarin resumption times. Results— We identified warfarin-associated intracranial hemorrhage in 234 patients (8.2%), of whom 177 patients (76%) survived the first week and had follow-up information available; the median follow-up time was 69 weeks (interquartile range [IQR] 19–144). Fifty-nine patients resumed warfarin after a median of 5.6 weeks (IQR 2.6–17). The hazard ratio for recurrent intracranial hemorrhage with resumption of warfarin was 5.6 (95% CI, 1.8–17.2), and for ischemic stroke it was 0.11 (95% CI, 0.014–0.89). The combined risk of recurrent intracranial hemorrhage or ischemic stroke reached a nadir if warfarin was resumed after approximately 10 to 30 weeks. Conclusion— The optimal timing for resumption of warfarin therapy appears to be between 10 and 30 weeks after warfarin-related intracranial hemorrhage.

Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy

BACKGROUND There is uncertainty regarding the efficacy and incidence of thromboembolic events in patients treated with prothrombin complex concentrates (PCC) for the emergency reversal of warfarin effect. METHODS During 2002 to 2010 we prospectively included 160 patients treated with PCC for emergency reversal of warfarin either for bleeding or because of the need of emergency surgery. A possible relationship to PCC was considered if objectively verified thromboembolism occurred within 7days of PCC administration. Efficacy was adjudicated as good if the bleeding was controlled promptly or if the surgeon did not report excessive perioperative bleeding. RESULTS We included 160 patients; 72% received PCC for bleeding. The median international normalized ratio (INR) before and after treatment with PCC was 3.5 (interquartile range [IQR] 2.6-5.4) and 1.4 (IQR 1.2-1.6). The mean dose of PCC was 1800IU (IQR 1200-2000). In addition to PCC, 74% of the patients received vitamin K and 34% received plasma. Six patients (3.8%; 95% confidence interval [CI], 1.4-8.0%) developed thromboembolic events (3 strokes, 1 myocardial infarction, 1 deep vein thrombosis, 1 splenic infarction), possibly related to PCC. The clinical efficacy was good in 146 (91%), moderate in 6 (4%), poor in 4 (2.5%) and non-evaluable in 4 patients. CONCLUSION The administration of PCC for the emergency reversal of warfarin may be associated with a low risk of thromboembolism. The contribution of an unmasked thrombotic process by cessation of anticoagulation or of activation of coagulation by the hemorrhagic event should also be considered.

Detection of elevated INR by thromboelastometry and thromboelastography in warfarin treated patients and healthy controls

INTRODUCTION The diagnostic potential of whole blood viscoelastic tests thromboelastography (TEG®) and thromboelastometry (ROTEM®) to detect warfarin-induced INR elevation remains elusive. METHODS Viscoelastic tests were performed in 107 patients on warfarin and 89 healthy controls. Tests were activated by kaolin for TEG, and ellagic acid (INTEM) or tissue factor (EXTEM) for ROTEM. RESULTS Viscoelastic tests revealed significant differences in clotting profiles between controls and warfarin-treated patients. Compared with healthy controls, patients treated with warfarin had prolonged EXTEM clotting and TEG reaction time (p<0.001), both of which were also increased beyond the reference range. Increased INR values correlated with EXTEM CT (Spearman rho=0.87) and TEG R-time (rho=0.73). EXTEM CT had a sensitivity and specificity of 0.89 and 1.00, respectively, to detect elevated INR above 1.2 units, with a positive and negative predictive values (PPV and NPV) of 1.00 and 0.88, respectively. Similarly, TEG R-time had a sensitivity and specificity of 0.86 and 0.87, respectively, with a PPV of 0.89 and a NPV of 0.83. The corresponding receiver operator characteristic area under the curve was 0.99 (95% confidence interval [CI], 0.99 - 1.00) for EXTEM CT and 0.94 (95% CI, 0.91 - 0.97) for TEG R-time. CONCLUSIONS Tissue factor-activated viscoelastic testing (EXTEM) revealed individuals with warfarin-induced INR elevation accurately, while TEG - activated through the intrinsic pathway - still was of acceptable diagnostic value. Further studies are required to evaluate the diagnostic potential of viscoelastic tests in relation to standard laboratory tests in other mixed patient populations, where the PPV and NPV may be inferior.

Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate

Prothrombin complex concentrates (PCC) can rapidly normalise prolonged prothrombin time, induced by vitamin K antagonists (VKA). We conducted a multicentre retrospective study to investigate whether reversal of VKA coagulopathy with 4-factor PCC improves the survival of patients with VKA-related intracerebral haemorrhage as compared to plasma.We included 135 consecutive patients with VKA-related intracerebral haemorrhage treated either with plasma (mainly in Canada) or 4-factor PCC (The Netherlands and Sweden) for the reversal of VKA. Data on characteristics of the patients and the haemorrhage were collected. The volume of intracerebral haematoma was calculated from the first computed tomography (CT) scan. The unadjusted and adjusted odds ratio (OR) for 30-day all-cause mortality in both treatment groups was compared using logistic regression. Patients who received plasma (n=35, median 4 units) more often had diabetes, antiplatelet therapy, and intraventricular haemorrhage on the initial CT scans than patients who received PCC (n=100, median 22.5 IU/kg [interquartile range 20-26 IU], median of total dose 1,700 IU). The volume of intracerebral haematoma was larger in the plasma-treated group compared to the PCC-treated group (haematoma, mean 64.5 vs 36.0 cm³; p=0.021). The unadjusted OR for all-cause 30-day mortality in the PCC group was 0.40 (95% confidence interval, 0.18-0.87; p=0.021) compared to the plasma group. After adjusting for the haematoma volume, bleeding localisation and age, the effect of PCC on mortality became non-significant. In conclusion, treatment with 4-factor PCC for VKA reversal in patients with intracerebral haemorrhage does not seem to reduce the 30-day all-cause mortality compared to plasma.

Management of rivaroxaban or apixaban associated major bleeding with prothrombin complex concentrates: a cohort study

There is uncertainty regarding the effectiveness and occurrence of thromboembolic events in patients treated with prothrombin complex concentrates (PCCs) for the management of major bleeding events (MBEs) on rivaroxaban or apixaban. We investigated the effectiveness of PCCs given for the management of MBEs in patients on rivaroxaban or apixaban. Between 1 January 2014 and 1 October 2016, we prospectively included patients on rivaroxaban or apixaban treated with PCCs for the management of MBEs. The effectiveness of PCCs was assessed by using the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria for the assessment of the effectiveness of major bleeding management. The safety outcomes were thromboembolic events and all-cause mortality within 30 days after treatment with PCCs. A total of 84 patients received PCCs for the reversal of rivaroxaban or apixaban due to a MBE. PCCs were given at a median (interquartile range) dose of 2000 IU (1500-2000 IU). Intracranial hemorrhage (ICH) was the most common site of bleeding requiring reversal (n = 59; 70.2%), followed by gastrointestinal bleeding in 13 (15.5%) patients. Management with PCCs was assessed as effective in 58 (69.1%) patients and ineffective in 26 (30.9%) patients. Most patients with ineffective hemostasis with PCCs had ICH (n = 16; 61.5%). Two patients developed an ischemic stroke, occurring 5 and 10 days after treatment with PCC. Twenty-seven (32%) patients died within 30 days after a MBE. The administration of PCCs for the management of MBEs associated with rivaroxaban or apixaban is effective in most cases and is associated with a low risk of thromboembolism. Our findings are limited by the absence of a control group in the study.

A benefit-risk assessment of dabigatran in the prevention of venous thromboembolism in orthopaedic surgery.

Dabigatran etexilate is a novel orally administered anticoagulant that exerts its action through reversible direct thrombin inhibition. This anticoagulant has been approved for prophylaxis against venous thromboembolism (VTE) after hip or knee arthroplasty, and in a few countries also for atrial fibrillation. This article reviews the efficacy and safety of dabigatran for the prophylaxis of VTE-indication compared with data on the most common current regimen with low-molecular-weight heparin (LMWH), specifically enoxaparin.Alternative prophylactic agents are also discussed. The results regarding efficacy and safety are very similar for dabigatran and LMWH. Bleeding and gastrointestinal reactions are the most frequently reported adverse events with a comparable incidence on LMWH and are probably the result of surgery and anaesthaesia. No adverse event that is specific for dabigatran has been observed in these studies, although dyspepsia has been reported as significantly more frequent than warfarin in long-term studies on other indications. The fact that dabigatran has no antidote has so far not been a problem in patients undergoing orthopaedic surgery. The use of the lower dose of dabigatran (150 mg) appears beneficial to reduce the risk of bleeding in patients over 75 years of age and in those with moderate renal impairment to avoid drug accumulation. The convenience of oral administration is an advantage for dabigatran over LMWH, particularly for extended prophylaxis up to 1 month after surgery. In conclusion, the benefit-risk profile of dabigatran is favourable for use as prophylaxis against VTE after major orthopaedic surgery with its convenient oral administration without need for laboratory monitoring and a low risk of bleeding or other adverse events.

ABO Blood Group and Risk of Thromboembolic and Arterial Disease A Study of 1.5 Million Blood Donors

Background— ABO blood groups have been shown to be associated with increased risks of venous thromboembolic and arterial disease. However, the reported magnitude of this association is inconsistent and is based on evidence from small-scale studies. Methods and Results— We used the SCANDAT2 (Scandinavian Donations and Transfusions) database of blood donors linked with other nationwide health data registers to investigate the association between ABO blood groups and the incidence of first and recurrent venous thromboembolic and arterial events. Blood donors in Denmark and Sweden between 1987 and 2012 were followed up for diagnosis of thromboembolism and arterial events. Poisson regression models were used to estimate incidence rate ratios as measures of relative risk. A total of 9170 venous and 24 653 arterial events occurred in 1 112 072 individuals during 13.6 million person-years of follow-up. Compared with blood group O, non-O blood groups were associated with higher incidence of both venous and arterial thromboembolic events. The highest rate ratios were observed for pregnancy-related venous thromboembolism (incidence rate ratio, 2.22; 95% confidence interval, 1.77–2.79), deep vein thrombosis (incidence rate ratio, 1.92; 95% confidence interval, 1.80–2.05), and pulmonary embolism (incidence rate ratio, 1.80; 95% confidence interval, 1.71–1.88). Conclusions— In this healthy population of blood donors, non-O blood groups explain >30% of venous thromboembolic events. Although ABO blood groups may potentially be used with available prediction systems for identifying at-risk individuals, its clinical utility requires further comparison with other risk markers. # CLINICAL PERSPECTIVE {#article-title-45}Background— ABO blood groups have been shown to be associated with increased risks of venous thromboembolic and arterial disease. However, the reported magnitude of this association is inconsistent and is based on evidence from small-scale studies. Methods and Results— We used the SCANDAT2 (Scandinavian Donations and Transfusions) database of blood donors linked with other nationwide health data registers to investigate the association between ABO blood groups and the incidence of first and recurrent venous thromboembolic and arterial events. Blood donors in Denmark and Sweden between 1987 and 2012 were followed up for diagnosis of thromboembolism and arterial events. Poisson regression models were used to estimate incidence rate ratios as measures of relative risk. A total of 9170 venous and 24 653 arterial events occurred in 1 112 072 individuals during 13.6 million person-years of follow-up. Compared with blood group O, non-O blood groups were associated with higher incidence of both venous and arterial thromboembolic events. The highest rate ratios were observed for pregnancy-related venous thromboembolism (incidence rate ratio, 2.22; 95% confidence interval, 1.77–2.79), deep vein thrombosis (incidence rate ratio, 1.92; 95% confidence interval, 1.80–2.05), and pulmonary embolism (incidence rate ratio, 1.80; 95% confidence interval, 1.71–1.88). Conclusions— In this healthy population of blood donors, non-O blood groups explain >30% of venous thromboembolic events. Although ABO blood groups may potentially be used with available prediction systems for identifying at-risk individuals, its clinical utility requires further comparison with other risk markers.

The oral thrombin inhibitor dabigatran: strengths and weaknesses.

Since the quest for a better replacement of warfarin started several decades ago and new compounds were brought forward to clinical trials, the concept of an ideal anticoagulant frequently became presented in lectures and articles. We have here reviewed strengths and weaknesses of the oral thrombin inhibitor dabigatran in terms of pharmacokinetics and clinical data. When strengths clearly exceed the weaknesses for any characteristic, the drug fits into the concept of an ideal anticoagulant in that domain. It is evident that dabigatran does not accomplish that concept for all characteristics but it reaches well above warfarin. We believe it is unlikely that any drug will fulfill all criteria for the ideal anticoagulant. Laboratory testing for dabigatran will not be discussed in any detail in this article, which is instead the focus of other articles from this issue of Seminars in Thrombosis & Hemostasis.

Bleeding events with dabigatran or warfarin in patients with venous thromboembolism

Dabigatran was as effective as warfarin for the acute treatment of venous thromboembolism in the RE-COVER and RE-COVER II trials. We compared the incidence of bleeding with dabigatran versus warfarin in pooled data from these studies. The localisation, bleeding severity, and the impact of key factors on the incidence of bleeding, were compared between the dabigatran and warfarin treatment group. Altogether, 2553 patients received dabigatran and 2554 warfarin, each for a mean of 164 days. The incidence of any bleeding event was significantly lower with dabigatran (hazard ratio [HR] 0.70; 95% confidence interval [CI], 0.61-0.79), as was the incidence of the composite of MBEs and clinically relevant non-major bleeding events (HR 0.62; 95% CI, 0.50-0.76). The incidence of major bleeding events (MBEs) was also significantly lower with dabigatran in the double-dummy phase (HR, 0.60; 95%CI, 0.36-0.99) but not statistically different between the two treatment arms when the entire treatment period is considered (HR 0.73 95% CI, 0.48-1.11). Increasing age, reduced renal function, Asian ethnicity, and concomitant antiplatelet therapy were associated with higher bleeding rates in both treatment groups. The reduction in bleeding with dabigatran compared to warfarin was consistent among the subgroups and with a similar pattern for intracranial, and urogenital major bleeding. In conclusion, treatment of venous thromboembolism with dabigatran is associated with a lower risk of bleeding compared to warfarin. This reduction did not differ with respect to the location of bleeding or among predefined subgroups.