The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use ...and other aspects related to their management.
We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban
The antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal.
There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban.
In this multicenter trial, the oral factor Xa inhibitor apixaban was compared with enoxaparin and warfarin for the treatment of acute venous thromboembolism. Apixaban was noninferior to enoxaparin ...and warfarin with respect to efficacy and superior with respect to safety.
Venous thromboembolism, with an annual incidence of 1 to 2 cases per 1000 persons in the general population, is the third most common cause of vascular death after myocardial infarction and stroke.
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Conventional treatment consists of a parenteral anticoagulant, such as enoxaparin, for at least 5 days, and warfarin begun during this time and continued for at least 3 months.
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Although effective, this regimen presents a challenge because enoxaparin requires daily subcutaneous injections, and warfarin therapy requires coagulation monitoring and dose adjustment.
Apixaban is an oral factor Xa inhibitor with a rapid onset of action and predictable pharmacokinetics that allow . . .
Apixaban for Extended Treatment of Venous Thromboembolism Agnelli, Giancarlo; Buller, Harry R; Cohen, Alexander ...
New England journal of medicine/The New England journal of medicine,
02/2013, Letnik:
368, Številka:
8
Journal Article
Recenzirano
Odprti dostop
When used for extended treatment after 6 to 12 months of anticoagulation therapy for venous thromboembolism, the factor Xa inhibitor apixaban reduced the risk of recurrent venous thromboembolism ...without increasing the risk of serious bleeding.
Venous thromboembolism, which includes deep-vein thrombosis and pulmonary embolism, is the third most common cause of vascular disease–related deaths.
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The mainstay of treatment is anticoagulation, and guidelines recommend therapy for 3 months or longer.
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Decisions about extending treatment are challenging. Although warfarin is effective for the prevention of recurrent venous thromboembolism, the inconvenience of laboratory monitoring and the dietary restrictions, coupled with concerns about bleeding, often lead to a reluctance to continue warfarin therapy beyond 6 to 12 months. Attempts to reduce the risk of bleeding by lowering the intensity of warfarin therapy have resulted in decreased efficacy without . . .
Abstract
Introduction
Despite a marked recent increase in the number of publications describing the incidence of venous thromboembolism (VTE) in Asia, and especially in mainland China, Hong Kong, ...Taiwan, Korea, Japan and Singapore, there remains a lack of consensus on the true risks, and trends over time, to inform appropriate clinical practice. The purpose of this systematic review was therefore to examine evidence about the incidence of symptomatic VTE in Asia.
Methods
Databases were searched for studies from Asia, published between January 1995 and February 2016, on the incidence of symptomatic VTE, deep vein thrombosis (DVT) or pulmonary embolism. Review of eligible studies was conducted independently by two reviewers. Data were extracted on incidence, predispositions and recurrence of VTE.
Results
One thousand nighty-five studies were identified, of which 73 were eligible for full text review and data extraction. Three population-wide estimates of VTE rates identified from Korea, Taiwan and Hong Kong reported annual incidences of 13.8, 15.9 and 19.9 per 100,000, respectively. Nine studies of Asian hospital registries or databases reported VTE rates ranging from 11 to 88 cases per 10,000 admissions. Population-based estimates of post-surgical DVT rates ranged from 0.15 to 1.35%. Age was a significant risk factor for VTE in all population groups.
Conclusion
Population-wide incidence estimates in Asia were approximately 15 to 20% of the levels recorded in western countries but have increased over time. It is anticipated this synthesis of evidence on the incidence of VTE and its predisposing factors will increase awareness about VTE in Asian populations.
In this clinical trial, apixaban, an oral factor Xa inhibitor, was shown to be superior to enoxaparin for the prevention of thromboembolism after hip replacement, without an increase in the risk of ...bleeding.
Patients undergoing hip-replacement surgery require effective thromboprophylaxis, and low-molecular-weight heparins, vitamin K antagonists, and mechanical methods are now standard therapies. Despite prophylaxis, however, subclinical deep-vein thrombosis develops in approximately 15 to 20% of patients soon after surgery, and symptomatic venous thromboembolism develops in 2 to 4% during the first 3 months after surgery.
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Practical limitations of current prophylactic techniques have stimulated a search for simpler methods. Low-molecular-weight heparins and fondaparinux require subcutaneous injection. Warfarin has a delayed onset of action and is relatively ineffective soon after surgery. Mechanical methods are cumbersome and relatively ineffective after hip surgery.
The development of . . .
Low-Dose Aspirin and Recurrent Thromboembolism
Results from the ASPIRE trial add evidence supporting the use of low-dose daily aspirin for preventing recurrent venous thromboembolism in patients who ...have had an initial unprovoked clotting episode.
Patients who have had a first episode of unprovoked venous thromboembolism are at high risk for recurrence after anticoagulant therapy is discontinued.
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Long-term treatment with a vitamin K antagonist is very effective in preventing a recurrence of venous thromboembolism while treatment continues
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but has not been shown to improve survival, is associated with a substantially increased risk of bleeding, and is inconvenient for patients.
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Consequently, many patients who have had a first episode of unprovoked venous thromboembolism discontinue anticoagulant therapy after 3 to 6 months despite recommendations to prolong therapy.
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Low-dose aspirin is a simple, inexpensive, and widely . . .
This noninferiority trial compared enoxaparin, a subcutaneously administered, low-molecular-weight heparin, with apixaban, an orally active inhibitor of factor Xa, for thromboprophylaxis after major ...knee surgery. Statistically, the noninferiority of apixaban was not demonstrated, but its use was associated with lower rates of clinically relevant bleeding.
Statistically, the noninferiority of apixaban was not demonstrated, but its use was associated with lower rates of clinically relevant bleeding.
The use of heparins, vitamin K antagonists, and mechanical methods to prevent venous thromboembolism after major joint surgery is now standard practice.
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Despite effective prophylaxis, subclinical venous thrombosis develops soon after surgery in 15 to 20% of patients who undergo hip replacement and in 30 to 40% of those who undergo knee replacement
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; symptomatic venous thromboembolism develops within 3 months after surgery in 2 to 4% of patients undergoing hip or knee replacement.
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Currently available prophylactic methods have practical limitations, since they require subcutaneous injection (the heparins) or careful dose adjustment (vitamin K antagonists) or tend to be . . .
Summary Background Low-molecular-weight heparins such as enoxaparin are preferred for prevention of venous thromboembolism after major joint replacement. Apixaban, an orally active factor Xa ...inhibitor, might be as effective, have lower bleeding risk, and be easier to use than is enoxaparin. We assessed efficacy and safety of these drugs after elective total knee replacement. Methods In ADVANCE-2, a multicentre, randomised, double-blind phase 3 study, patients undergoing elective unilateral or bilateral total knee replacement were randomly allocated through an interactive central telephone system to receive oral apixaban 2·5 mg twice daily (n=1528) or subcutaneous enoxaparin 40 mg once daily (1529). The randomisation schedule was generated by the Bristol-Myers Squibb randomisation centre and stratified by study site and by unilateral or bilateral surgery with a block size of four. Investigators, patients, statisticians, adjudicators, and steering committee were masked to allocation. Apixaban was started 12–24 h after wound closure and enoxaparin 12 h before surgery; both drugs were continued for 10–14 days, when bilateral ascending venography was scheduled. Primary outcome was the composite of asymptomatic and symptomatic deep vein thrombosis, non-fatal pulmonary embolism, and all-cause death during treatment. The statistical plan required non-inferiority of apixaban before testing for superiority; analysis was by intention to treat for non-inferiority testing. The study is registered at ClinicalTrials.gov , number NCT00452530. Findings 1973 of 3057 patients allocated to treatment (1528 apixaban, 1529 enoxaparin) were eligible for primary efficacy analysis. The primary outcome was reported in 147 (15%) of 976 apixaban patients and 243 (24%) of 997 enoxaparin patients (relative risk 0·62 95% CI 0·51–0·74; p<0·0001; absolute risk reduction 9·3% 5·8–12·7). Major or clinically relevant non-major bleeding occurred in 53 (4%) of 1501 patients receiving apixaban and 72 (5%) of 1508 treated with enoxaparin (p=0·09). Interpretation Apixaban 2·5 mg twice daily, starting on the morning after total knee replacement, offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding. Funding Bristol-Myers Squibb; Pfizer.
Objective To determine the efficacy and safety of the anticoagulant fondaparinux in older acute medical inpatients at moderate to high risk of venous thromboembolism. Design Double blind randomised ...placebo controlled trial. Setting 35 centres in eight countries. Participants 849 medical patients aged 60 or more admitted to hospital for congestive heart failure, acute respiratory illness in the presence of chronic lung disease, or acute infectious or inflammatory disease and expected to remain in bed for at least four days. Interventions 2.5 mg fondaparinux or placebo subcutaneously once daily for six to 14 days. Outcome measure The primary efficacy outcome was venous thromboembolism detected by routine bilateral venography along with symptomatic venous thromboembolism up to day 15. Secondary outcomes were bleeding and death. Patients were followed up at one month. Results 425 patients in the fondaparinux group and 414 patients in the placebo group were evaluable for safety analysis (10 were not treated). 644 patients (75.9%) were available for the primary efficacy analysis. Venous thrombembolism was detected in 5.6% (18/321) of patients treated with fondaparinux and 10.5% (34/323) of patients given placebo, a relative risk reduction of 46.7% (95% confidence interval 7.7% to 69.3%). Symptomatic venous thromboembolism occurred in five patients in the placebo group and none in the fondaparinux group (P = 0.029). Major bleeding occurred in one patient (0.2%) in each group. At the end of follow-up, 14 patients in the fondaparinux group (3.3%) and 25 in the placebo group (6.0%) had died. Conclusion Fondaparinux is effective in the prevention of asymptomatic and symptomatic venous thromboembolic events in older acute medical patients. The frequency of major bleeding was similar for both fondaparinux and placebo treated patients.
We performed a randomized dose-ranging study, double-blind for rivaroxaban doses and open-label for the comparator (low-molecular-weight heparin followed by vitamin K antagonists) to assess the ...optimal dose of rivaroxaban for the treatment of deep vein thrombosis. A total of 543 patients with acute deep-venous thrombosis received rivaroxaban 20, 30, or 40 mg once daily or comparator. Treatment lasted for 84 days. The primary efficacy outcome was the 3-month incidence of the composite of symptomatic venous thromboembolic complications and asymptomatic deterioration in thrombotic burden as assessed by comparison of ultrasound and perfusion lung scanning at day 84 with baseline. The main safety outcome was the composite of major bleeding and clinically relevant nonmajor bleeding. A total of 449 (83%) of the 543 patients could be included in the per-protocol population. The primary efficacy outcome occurred in 6.1%, 5.4%, and 6.6% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 9.9% of those receiving standard therapy. The main safety outcome occurred in 5.9%, 6.0%, and 2.2% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 8.8% of those receiving standard therapy. These results with simple fixed-dose oral regimens justify phase 3 evaluations (www.ClinicalTrials.gov no.NCT00395772).
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