Jack Ansell

Apixaban versus warfarin in patients with atrial fibrillation.

BACKGROUND Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).

The Perioperative Management of Antithrombotic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

This article discusses the perioperative management of antithrombotic therapy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). The primary objectives of this article are the following: (1) to address the perioperative management of patients who are receiving vitamin K antagonists (VKAs) or antiplatelet drugs, such as aspirin and clopidogrel, and require an elective surgical or other invasive procedures; and (2) to address the perioperative use of bridging anticoagulation, typically with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). A secondary objective is to address the perioperative management of such patients who require urgent surgery. The recommendations in this article incorporate the grading system that is discussed in this supplement (Guyatt G et al, CHEST 2008; 133:123S-131S). Briefly, Grade 1 recommendations are considered strong and indicate that the benefits do (or do not) outweigh risks, burden, and costs, whereas Grade 2 recommendations are referred to as suggestions and imply that individual patient values may lead to different management choices. The key recommendations in this article include the following: in patients with a mechanical heart valve or atrial fibrillation or venous thromboembolism (VTE) at high risk for thromboembolism, we recommend bridging anticoagulation with therapeutic-dose subcutaneous (SC) LMWH or IV UFH over no bridging during temporary interruption of VKA therapy (Grade 1C); in patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, or low-dose SC LMWH over no bridging during temporary interruption of VKA therapy (Grade 2C); in patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest low-dose SC LMWH or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH (Grade 2C). In patients with a bare metal coronary stent who require surgery within 6 weeks of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C); in patients with a drug-eluting coronary stent who require surgery within 12 months of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C). In patients who are undergoing minor dental procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure and co-administering an oral prohemostatic agent (Grade 1B); in patients who are undergoing minor dermatologic procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C); in patients who are undergoing cataract removal and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C).

American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy

### Mechanism of Action of Coumarin Anticoagulant Drugs Warfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the carboxylation of glutamate residues to γ-carboxyglutamates (Gla) on the N-terminal regions of vitamin K–dependent proteins (Figure 1).1–6 These proteins, which include the coagulation factors II, VII, IX, and X, require γ-carboxylation by vitamin K for biological activity. By inhibiting the vitamin K conversion cycle, warfarin induces hepatic production of partially decarboxylated proteins with reduced coagulant activity.7,8 Figure 1. The vitamin K cycle and its link to carboxylation of glutamic acid residues on vitamin K–dependent coagulation proteins. Vitamin K1 obtained from food sources is reduced to vitamin KH2 by a warfarin-resistant vitamin K reductase. Vitamin KH2 is then oxidized to vitamin K epoxide (Vit KO) in a reaction that is coupled to carboxylation of glutamic acid residues on coagulation factors. This carboxylation step renders the coagulation factors II, VII, IX, and X and the anticoagulant factors protein C and protein S functionally active. Vit KO is then reduced to Vit K1 in a reaction catalyzed by vitamin KO reductase. By inhibiting vitamin KO reductase, warfarin blocks the formation of vitamin K1 and vitamin KH2, thereby removing the substrate (vitamin KH2) for the carboxylation of glutamic acids. Vitamin K1, either given therapeutically or derived from food sources, can overcome the effect of warfarin by bypassing the warfarin-sensitive vitamin KO reductase step in the formation of vitamin KH2. Carboxylation promotes binding of the vitamin K–dependent coagulation factors to phospholipid surfaces, thereby accelerating blood coagulation.9–11 γ-Carboxylation requires the reduced form of vitamin K (vitamin KH2). Coumarins block the formation of vitamin KH2 by inhibiting the …

Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors

The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug–drug interactions and less food‐drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Am. J. Hematol. 2012.

The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement

Summary.  Background: Heparins and warfarin are currently used as venous thromboembolism (VTE) prophylaxis in surgery. Inhibition of factor (F) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit–risk profile. Objectives: To evaluate the safety and efficacy of apixaban, a potent, direct, oral inhibitor of FXa, in patients following total knee replacement (TKR), and to investigate dose–response relationships. Patients/methods: A total of 1238 patients were randomized to one of six double‐blind apixaban doses [5, 10 or 20 mg day–1 administered as a single (q.d.) or a twice‐daily divided dose (b.i.d.)], enoxaparin (30 mg b.i.d.) or open‐label warfarin (titrated to an International Normalized Ratio of 1.8–3.0). Treatment lasted 10–14 days, commencing 12–24 h after surgery with apixaban or enoxaparin, and on the evening of surgery with warfarin. The primary efficacy outcome was a composite of VTE (mandatory venography) and all‐cause mortality during treatment. The primary safety outcome was major bleeding. Results: A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis. All apixaban groups had lower primary efficacy event rates than either comparator. The primary outcome rate decreased with increasing apixaban dose (P = 0.09 with q.d./b.i.d. regimens combined, P = 0.19 for q.d. and P = 0.13 for b.i.d. dosing).A significant dose‐related increase in the incidence of total adjudicated bleeding events was noted in the q.d. (P = 0.01) and b.i.d. (P = 0.02) apixaban groups; there was no difference between q.d. and b.i.d. regimens. Conclusions: Apixaban in doses of 2.5 mg b.i.d. or 5 mg q.d. has a promising benefit–risk profile compared with the current standards of care following TKR.

Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion.

Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence.

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data

BACKGROUND Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

Aging and the anticoagulant response to warfarin therapy.

OBJECTIVE To assess the effect of aging on the anticoagulant response to warfarin. DESIGN Retrospective cohort study. SETTING A university hospital outpatient anticoagulation clinic. PATIENTS All patients (n = 530) monitored in the anticoagulation clinic over a 10-year period (1980 to 1990). The 530 study patients had a mean age of 61.5 (+/- 14.7) years (age range, 12 to 90 years). The patients were stratified into four age groups: younger than 50 years (n = 97); 50 to 59 years (n = 107); 60 to 69 years (n = 149); and 70 years or older (n = 177). MEASUREMENTS For each patient, a dose-adjusted mean prothrombin time ratio was calculated by dividing the mean prothrombin time ratio by the mean daily warfarin dose. RESULTS Older patients were more likely to be female (P less than 0.001), to have more medical problems (P less than 0.001), to be taking more medications (P less than 0.001), and to weigh less than younger patients (P less than 0.001). Across age groups, there were no significant differences in the use of medications that potentiated or inhibited the anticoagulant effects of warfarin. The prothrombin time ratio, when adjusted for dose, was significantly increased in older patients (P less than 0.001). The increased anticoagulant response to warfarin seen with increasing patient age persisted even after simultaneously controlling for relevant demographic and clinical variables in a multivariate model. Other factors significantly associated with an increased sensitivity to warfarin included use of a medication with a potentiating interactive effect with warfarin, female gender, and overall medication use. Increased body weight and duration of warfarin use exceeding 6 months were found to be inversely related to anticoagulant response. CONCLUSION The anticoagulant response to warfarin is exaggerated with advancing age. This finding emphasizes the need for close monitoring of older patients treated with warfarin therapy.

Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management (ISAM)

AbstractBackground/objectivesExpert oral anticoagulation management is the key to good outcomes and is performed variably in different health care systems throughout the world. We set out to assess the quality of anticoagulation management in five countries in patients receiving vitamin K antagonists (VKAs) for stroke prophylaxis in chronic non-valvular atrial fibrillation (NVAF), and to compare the anticoagulation management practices in these countries.Methods and resultsThis was a retrospective, multi-centre cohort study in the United States, Canada, France, Italy, and Spain. About 1,511 patients were randomly recruited from representative practices (routine medical care (RMC) in the US, Canada, and France; anticoagulation clinics in Italy and Spain) and data pertaining to their oral anticoagulation care were abstracted from their medical records. The predominant anticoagulant in use was warfarin in the US, Canada, and Italy; acenocoumarol in Spain; and fluindione in France. Documentation of care was poor in the US, Canada, and France, countries where RMC was studied. Percent INRs or time-in-therapeutic range was greater in the two anticoagulation clinic samples compared with the RMC samples.ConclusionOral anticoagulation care varies considerably from country to country. Findings suggest that anticoagulation clinic care (ACC) may provide better outcomes as assessed by international normalized ratio (INR) time-in-range. Physicians tend to under treat more than over treat. Finally, documentation of care is often inadequate. Condensed Abstract Oral anticoagulation management (routine medical care or anticoagulation clinic care) was retrospectively assessed in 5 countries using a uniform, structured assessment tool. Major management differences were detected, especially between anticoagulation clinic care and routine care. Documentation was often a problem in the latter setting. Less time in therapeutic INR range was noted in routine medical care. Findings suggest that anticoagulation clinic care may provide better outcomes as assessed by international normalized ratio (INR) time-in-range. Physicians tend to under treat more than over treat. Finally, documentation of care is often inadequate.

Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation

Background— In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). Methods and Results— The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53–1.00) and 0.88 (95% CI, 0.57–1.35) (Pinteraction=0.078), for mortality were 0.91 (95% CI, 0.74–1.13) and 0.91 (95% CI, 0.71–1.16) (Pinteraction=0.34), and for major bleeding were 0.50 (95% CI, 0.36–0.70) and 0.75 (95% CI, 0.58–0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. Conclusions— The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers’ and patients’ predicted quality of international normalized ratio control. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.