David A. Garcia

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.).

Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND VTE is a common cause of preventable death in surgical patients. METHODS We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations. CONCLUSIONS Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients.

Parenteral Anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

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.

Risk of Thromboembolism With Short-term Interruption of Warfarin Therapy

BACKGROUND Significant uncertainty surrounds the treatment of patients who must discontinue warfarin sodium therapy before an invasive procedure. In part, the uncertainty results from the lack of published information about the risk of thromboembolism associated with short-term warfarin therapy interruption. We aimed to assess the frequency of thromboembolism and bleeding within a large cohort of patients whose warfarin therapy was temporarily withheld for an outpatient invasive procedure. METHODS This prospective, observational cohort study was performed at 101 sites (primarily community-based physician office practices) in the United States. Enrollment was conducted from April 4, 2000, to March 6, 2002. The main outcome measures were thromboembolism or clinically significant hemorrhage within 30 days of warfarin therapy interruption. RESULTS A total of 1293 episodes of warfarin therapy interruption in 1024 individuals were included. The mean (SD) patient age was 71.9 (10.6) years; 438 (42.8%) were female. The most common indications for anticoagulant therapy were atrial fibrillation (n=550), venous thromboembolism (n=144), and mechanical heart valve (n=132). The most common procedures were colonoscopy and oral and ophthalmic surgery. Perioperative heparin or low-molecular-weight heparin was used in only 8.3% of cases overall. Seven patients (0.7%; 95% confidence interval [CI], 0.3%-1.4%) experienced postprocedure thromboembolism within 30 days. None of the 7 patients who experienced thromboembolism received periprocedural bridging therapy. Six patients (0.6%; 95% CI, 0.2%-1.3%) experienced major bleeding, whereas an additional 17 patients (1.7%; 95% CI, 1.0%-2.6%) experienced a clinically significant, nonmajor bleeding episode. Of these 23 patients who had bleeding episodes, 14 received periprocedural heparin or low-molecular-weight heparin. The duration of warfarin therapy interruption was variable; however, more than 80% of patients had warfarin therapy withheld for 5 days or fewer. CONCLUSIONS For many patients receiving long-term anticoagulation who need to undergo a minor outpatient intervention, a brief (< or =5 days) periprocedural interruption of warfarin therapy is associated with a low risk of thromboembolism. The risk of clinically significant bleeding, even among outpatients undergoing minor procedures, should be weighed against the thromboembolic risk of an individual patient before the administration of bridging anticoagulant therapy.

The new oral anticoagulants

Although their first application in clinical practice occurred in the 1940s, vitamin K antagonists remain the only form of oral anticoagulant medication approved for long-term use. Although the available vitamin K antagonists are highly effective for the prevention and/or treatment of most thrombotic disease, the significant interpatient and intrapatient variability in dose-response, the narrow therapeutic index, and the numerous drug and dietary interactions associated with these agents have led clinicians, patients, and investigators to search for alternative agents. Three new orally administered anticoagulants (apixaban, dabigatran, and rivaroxaban) are in the late stages of development and several others are just entering (or moving through) earlier phases of investigation. These novel anticoagulant medications are being studied for the prevention and treatment of venous thromboembolism, the treatment of acute coronary syndromes and the prevention of stroke in patients with atrial fibrillation. This review summarizes published clinical trial data pertinent to apixaban, dabigatran, and rivaroxaban.

Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists

Prothrombin complex concentrates (PCCs) are recommended as the treatment of choice in warfarin-related coagulopathy. However, the risk of thromboembolic complications associated with their use is not well defined. We performed a meta-analysis to estimate the rate of thromboembolic complications in patients receiving vitamin K antagonists (VKAs) treated with PCCs for bleeding or before urgent surgery. Medline and Embase databases were searched. Two reviewers performed study selection and extracted data independently. Studies providing data on incidence of thromboembolic complications in VKA-treated patients were eligible for the study. Weighted mean proportion of the rate of thromboembolic complications and the mortality rate were calculated. Twenty-seven studies (1,032 patients) were included. Seven studies used 3-factor, and 20 4-factor PCCs. Twelve patients had a thromboembolic complication (weighted mean 1.4%; 95% CI 0.8-2.1), of which two were fatal. The incidence of thromboembolic events was 1.8% (95% CI 1.0-3.0) in patients treated with 4-factor PCCs, and 0.7% (95% CI 0.0-2.4) in patients treated with 3-factor PCCs. Total mortality rate was 10.6% (95% CI 5.9-16.6). In conclusion, our results suggest there is a low but quantifiable risk of thromboembolism in VKA-treated patients receiving PCCs for anticoagulation reversal. These findings should be confirmed in randomised, controlled trials.

Prevention of VTE in nonorthopedic surgical patients. Antithrombotic therapy and prevention of thrombosis, 9th ed

BACKGROUND VTE is a common cause of preventable death in surgical patients. METHODS We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations. CONCLUSIONS Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients.

Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial.

Context Vitamin K decreases the international normalized ratio (INR) in overanticoagulated patients who receive warfarin therapy, but its effect on clinical outcomes is less clear. Contribution Trial investigators detected no differences in the frequency of bleeding, thromboembolism, or death among overanticoagulated patients who received warfarin therapy and were randomly assigned to receive low-dose vitamin K or placebo. Caution The study was underpowered to detect differences in major bleeding. Implication Low-dose vitamin K corrects the INR in overanticoagulated patients who received warfarin therapy, but it has little effect on clinical outcomes. Withdrawal of warfarin may be all that is necessary to manage elevated INRs. The Editors Warfarin is a remarkably effective drug for primary and secondary prevention of arterial and venous thromboembolism. Among commonly used medications, warfarin is unique because its doseresponse characteristics are highly unpredictable, varying both among and within individuals over time. As a result, warfarin therapy requires ongoing monitoring using the international normalized ratio (INR), a value that reflects the degree to which warfarin has reduced coagulation factor levels and the coagulant potential of blood (1). For most indications, an INR range of 2.0 to 3.0 is targeted; INR values less than 2.0 are associated with an increased risk for thromboembolism, and INR values greater than 4.0 are associated with an increase in bleeding complications. The risk for bleeding, particularly intracranial bleeding, increases markedly as the INR exceeds 4.5 (13). Even in clinics dedicated to warfarin management, INRs are outside the therapeutic range one third to one half the time (4). When managing a patient with an INR greater than 4.5 who is not bleeding, clinicians generally either withhold warfarin treatment and allow the INR to decrease to the desired value or administer vitamin K (orally or intravenously) to more rapidly reduce the INR (1, 510). Small randomized trials have shown that a single dose of low-dose oral vitamin K (for example, 1 to 2.5 mg) effectively reduces the INR in otherwise-stable overanticoagulated patients within 24 hours of its administration; however, these studies were not large enough to determine whether low-dose vitamin K reduces bleeding without increasing the risk for thromboembolism (1115). A recent systematic review (16) supported this observation. To determine whether oral vitamin K is indicated in overanticoagulated patients who are not bleeding, we did a randomized trial in which we allocated oral vitamin K or placebo, 1.25 mg, to patients who presented with an INR of 4.5 to 10.0. The primary outcome measure was the frequency of all forms of bleeding events during the first 90 days. Our hypothesis that bleeding events would be reduced was based on our previously published, smaller studies of low-dose oral vitamin K administered to various patient groups. In these studies, we found a consistent and rapid decrease in the INR after low-dose vitamin K was administered (13, 15, 1722). Methods Study Patients We identified patients with INRs of 4.5 to 10.0 in participating outpatient anticoagulant therapy clinics. We screened patients as they presented for routine INR assessment and considered them for eligibility if they were receiving warfarin therapy with a target INR of 2.0 to 3.5, their most recent INR was between 4.5 and 10.0 in the past 24 hours, and they were not bleeding. We excluded patients if discontinuation of warfarin therapy was scheduled and if they were younger than 18 years, had a life expectancy less than 10 days, had an indication for acute normalization of their INR (such as imminent surgery), had a known severe liver disease, had a history of a major bleeding event within 1 month, had a known bleeding disorder, had received thrombolytic therapy within 48 hours, had a platelet count less than 50109 cells/L, could not take oral medications, had a known allergy to vitamin K, or could not return for laboratory or clinical monitoring. Study staff at each participating anticoagulant therapy clinic approached patients who met inclusion criteria for consent to participate. This study ran in parallel with a cohort study in which patients with INRs greater than 10.0 received oral vitamin K, 2.5 mg. Patients were otherwise identical to those enrolled in this study, and we followed them for similar outcome events. The results of the concurrent cohort study will be presented in a subsequent paper. Randomization and Treatment We instructed all eligible, consenting patients to withhold warfarin for 1 day and randomly assigned them to receive a capsule containing either vitamin K, 1.25 mg, or placebo. Randomization was done by using a computer-generated random-number table at the coordinating and methods center and was stratified by clinical center. Vitamin K capsules were compounded from 5-mg vitamin K tablets (Merck & Co., Whitehouse Station, New Jersey) by a commercial pharmacy with Health Canada approval (Clinical Trials Application control number 092635). Placebo capsules contained inert filler and were indistinguishable from the capsules that contained vitamin K. Random allocation of patients was accomplished when site-specific study personnel dispensed the next numbered study drug container at each clinical center; thus, patients, treating clinicians, and research coordinators were unaware of treatment allocation. In 2 centers, we monitored the INR of outpatients in clinics or laboratories outside the clinical center. In such centers, we obtained consent for the study by telephone, and the study drug was shipped within hours to the patients home by using a courier service. In all cases, we confirmed receipt and consumption of the study drug on the day of randomization by telephone. In the remaining centers, in which patients were seen in person, consent and study drug administration occurred at the same time that the elevated INR was detected. Follow-up and Outcome Measures At enrollment, we advised patients to promptly seek medical evaluation if they developed signs or symptoms of bleeding or thromboembolism. At minimum, we assessed patients by telephone or in person on days 1, 3, 7, 14, 28, and 90 after randomization. Additional contact and INR sampling necessary to manage the patients anticoagulant therapy were done at the discretion of the patients physician. At each follow-up, we sought signs and symptoms of bleeding and thromboembolism and collected details about all such events. We asked patients a focused series of questions to help them recall these events. We reviewed and abstracted medical records of all suspected bleeding episodes, thromboembolism, and deaths. Our primary outcome measure was the frequency of bleeding events during the 90 days after randomization. We defined major bleeding as fatal bleeding, bleeding requiring transfusion of 2 or more units of packed red blood cells, bleeding resulting in a therapeutic intervention (such as endoscopy), or objectively confirmed bleeding into an enclosed space. We defined minor bleeding as bleeding resulting in a medical assessment that did not meet criteria as a major bleeding event. We defined trivial bleeding as all patient-reported bleeding events that did not result in a medical assessment. We combined all reported bleeding events (major, minor, and trivial) for this analysis. We chose to combine these events because our clinical experience suggested that reducing medically unimportant but bothersome bleeding, such as epistaxis, bruising, and menorrhagia, was a clinically important goal for our patients; patients with a minor or trivial bleeding event may be at greater risk for subsequent major bleeding; and the frequency of major bleeding was likely to be very low, calling into question the feasibility of a study powered to detect differences in major bleeding events. Secondary outcome measures included the frequency of major bleeding events, objectively confirmed venous or arterial thromboembolism, and death during the 90 days after randomization. We chose the 90-day period on the basis of our previous studies wherein we found a significant reduction in bleeding events (90 days) after the administration of similar doses of oral vitamin K (13). We hypothesized that low-dose oral vitamin K might influence a bleeding event during this extended period, because even small doses of this highly lipophilic drug might have an extended influence on INR control (and thus the risk for bleeding and thrombosis). In post hoc analyses, we examined the frequency of all bleeding and major bleeding events in the first 7 days and the number of clinical events in patients who were older than 70 years at enrollment. An independent adjudication committee, blinded to treatment allocation and not otherwise involved in the study, reviewed all bleeding events, thromboembolism, and deaths. Confirmation of venous thromboembolism required a nononcompressible venous segment on ultrasonography, an intraluminal filling defect on venography or computed tomographic pulmonary angiography, or a segmental (or larger) mismatch defect on ventilationperfusion lung scan. Arterial thromboembolism required either direct surgical visualization of thrombus; an intraluminal filling defect on angiography; or clear evidence of a new ischemic event on an objective test, such as electrocardiography, computed tomography, or magnetic resonance imaging. We advised clinics to reinstitute warfarin therapy once the INR was within the therapeutic reference interval after administration of the study drug. The clinicians who cared for the patients determined the warfarin dose when the drug was readministered. Target INR ranges for individual patients did not change as a result of the elevated INR that led to enrollment. Statistical Analysis Our primary analysis was an intention-to-treat comparison of the proportions of patien

Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial.

Aims The risk of stroke in patients with atrial fibrillation (AF) increases with age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding. We evaluated these outcomes in relation to patient age. Methods and results A total of 18 201 patients with AF and a raised risk of stroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to 2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or creatinine ≥133 μmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up. Of the trial population, 30% were <65 years, 39% were 65 to <75, and 31% were ≥75 years. The rates of stroke, all-cause death, and major bleeding were higher in the older age groups (P < 0.001 for all). Apixaban was more effective than warfarin in preventing stroke and reducing mortality across all age groups, and associated with less major bleeding, less total bleeding, and less intracranial haemorrhage regardless of age (P interaction >0.11 for all). Results were also consistent for the 13% of patients ≥80 years. No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes. Conclusion The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age. Owing to the higher risk at older age, the absolute benefits of apixaban were greater in the elderly.