BROWSE ACTIVE INGREDIENT A-Z MEDICINES WITH BLACK TRIANGLE Pradaxa 110 mg hard capsules Last Updated on eMC 08-Mar-2016 View changes | Boehringer Ingelheim Limited Contact details +44 (0)1344 424 600+44 (0)1344 742579 - Pradaxa enquiries Before you contact this company: often several companies will market medicines with the same active ingredient. Please check that this is the correct company before contacting them. This site uses cookies. By continuing to browse the site you are agreeing to our policy on the use of cookies. Find out more here.Mr. Wilson, age 48, has severe aortic stenosis, and needs an aortic valve replacement. He finds no reason to quarrel with his doctor’s recommendation for a mechanical valve, understanding that it is more durable than a bioprosthetic valve. But when the doctor explains that he will need lifelong anticoagulation with warfarin, and then details the specifics of warfarin treatment, Mr. Wilson balks. “I don’t want to take warfarin” he tells his doctor.
“Aren’t there any other choices?” Mr. Wilson’s reaction is not uncommon. Warfarin, a vitamin K antagonist, has been used successfully in patients with mechanical heart valves to protect against thromboembolic complications, yet it has well known limitations, including the risk of serious bleeding, multiple food and drug interactions, and a requirement for lifelong international normalized ratio (INR) monitoring. The recent development of novel oral anticoagulants has thus been welcomed. One such anticoagulant is dabigatran etexilate, a direct thrombin inhibitor. Dabigatran received FDA approval in October 2010 for use in patients with atrial fibrillation, after the RE-LY trial showed that it is a clinically acceptable alternative to warfarin in this setting. When early animal studies showed promising results for dabigatran in preventing valve thrombosis, it was hoped that dabigatran might replace warfarin for patients with mechanical heart valves. But that hope has dimmed.
In this week’s NEJM, Eikelboom et al report the results of RE-ALIGN, a phase 2, prospective, open-label study designed to test a dagibatran dosing regimen for prevention of thromboembolic complications in patients with mechanical valves. The trial included patients in the immediate post-operative period (nearly 80% were in this group), as well as those who had undergone valve replacement at least three months earlier. Eligible participants were randomized to receive either dabigatran or warfarin for 12 weeks. The dabigatran dosing algorithm was based primarily on pharmacokinetic data from the RE-LY trial, and assumed that the risk of thromboembolism in patients with mechanical heart valves was similar to that of patients with atrial fibrillation. Starting doses were determined by creatinine clearance, and trough plasma levels of dabigatran were measured at pre-specified intervals. The target minimum trough plasma level was 50 ng/ml, as the RE-LY trial had shown increased thromboembolic risk below that threshold.
Appropriate INR targets were established for patients randomized to receive warfarin. The primary outcome of the study was trough plasma concentration of dabigatran. However, after 252 patients had been enrolled, an independent data safety monitoring board noted an excess of thromboembolic and bleeding complications in the dabigatran group, and the trial was terminated prematurely. The composite of stroke, transient ischemic attack, systemic embolism, myocardial infarction or death occurred in 15 patients (9%) randomized to dabigatran, compared to 4 patients (5%) randomized to warfarin. Major bleeding occurred in 7 patients (4%) in the dabigatran group and 2 patients (2%) in the warfarin group. There appeared to be no relationship between plasma levels of dabigatran and thromboembolic or bleeding events. The study authors raise the possibility that a different dosing regimen, one that produced a higher trough but lower peak, might have produced a better outcome. They also note that multiple coagulation pathways contribute to thrombus formation in patients with mechanical valves.
Differences in mechanism of action, they claim – warfarin inhibits the synthesis of coagulation factors VII, IX, X and thrombin, while dabigatran inhibits only thrombin – likely made warfarin more effective than dabigatran in this clinical setting. In an accompanying editorial, Dr. Hylek of Boston University School of Medicine raises several issues potentially contributing to the RE-ALIGN results, including the drawbacks of testing a fixed-dose regimen of dabigatran in the early postoperative period, when frequent individualized dose adjustments of warfarin are often necessary, as well as the limitations of transferring pharmacokinetic and dose information from one clinical setting to another. NEJM Deputy Editor John Jarcho emphasizes that the message from the RE-ALIGN trial is clear, namely, that “given the current evidence, dabigatran and other novel anticoagulants should not be used in patients with mechanical valves.” Tags: aortic stenosis, Dabigatran, INR, international normalized ratio, Mechanical Heart Valves, RE-LY trial, thromboembolic complications, warfarin Posted in From Pages to Practice |
This entry was posted on Wednesday, September 25th, 2013 at 5:00 pm and is filed under From Pages to Practice. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.Earn Free CME Credits by reading the latest medical news in your specialty. This article is a collaboration between MedPage Today® and: New oral anticoagulants (NOACs) may represent a major treatment advance for the prevention of thrombosis in patients with antiphospholipid syndrome with previous venous thromboembolism (VTE), European researchers suggested. The current mainstay of treatment of thrombotic antiphospholipid syndrome is vitamin K antagonists, primarily warfarin, but the narrow therapeutic window, the need for monitoring of the International Normalized Ratio (INR), and numerous interactions of vitamin K antagonists represent barriers to optimal management, according to Savino Sciascia, MD, PhD, of the University of Turin, and colleagues.
In contrast, NOACs have fewer drug interactions and do not interact with food or alcohol, providing stable anticoagulant intensity, the authors wrote online in Rheumatology. This group of agents includes dabigitran etexilate (Pradaxa), a direct thrombin inhibitor, and the direct factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis) and edoxaban (Savaysa). In an online review in Rheumatology, Sciascia and colleagues examined the evidence for the use of NOACs in antiphospholipid syndrome, with attention to their safety profile. They reported that the largest study involving NOACs in patients with antiphospholipid syndrome was a trial of 35 patients with previous VTE who had poor anticoagulation control with vitamin K antagonists. Patients in that study were treated with rivaroxaban, and the data appeared to support the use of a NOAC for secondary thromboprophylaxis for patients with antiphospholipid syndrome with previous VTE who require a target INR of 2 to 3.
But use in patients with previous arterial thrombosis or in those who require a target INR above 3 "is still a matter of discussion," the authors wrote. With regard to laboratory monitoring, the utility of currently available tools to monitor coagulation with vitamin K antagonists are not ideal for the NOACs, the authors noted. Activated partial thromboplastin time and prothrombin time may be appropriate for qualitative but not quantitative assessments of activity. However, testing for lupus anticoagulant among patients receiving these anticoagulants "would appear to be unreliable," Sciascia and co-authors wrote. Although the Taipan/Ecarin ratio has been found to sensitive for the detection of these antibodies, "in our experience, false-positive results were seen with all types of lupus anticoagulant testing, suggesting that they cannot be used diagnostically for patients receiving NOACs," they added. In patients with renal impairment, the NOACs should either be avoided or dosages reduced because they are in part eliminated by the kidneys, and impaired renal function may significantly affect NOAC blood levels.
Patients with hepatic disease were excluded from phase III clinical trials of NOACs, and labeling restrictions apply when rivaroxaban, apixaban, and dabigatran are used in patients with impaired hepatic function. Although NOACs have fewer drug interactions than vitamin K antagonists, the use of potent P-glycoprotein inhibitors such as systemic ketoconazole, cyclosporin, and dronedarone is not recommended with dabigitran. Similarly, concomitant use of inhibitors of both P-glycoprotein and CYP3A4 with direct factor Xa inhibitors is generally contraindicated due to decreased exposure and effect. In addition, NOACs do have interactions with antiplatelet agents and nonsteroidal anti-inflammatory drugs -- drugs that may also be used in patients with VTE histories -- with a consequent increase in bleeding risk. Carbamazepine, rifampicin, phenobarbital, and phenytoin reduce the plasma concentration of both rivaroxaban and dabigatran, and simultaneous use should therefore be avoided.
Clarithromycin, amiodarone, and quinidine may increase dabigatran levels, and concomitant use warrants close clinical monitoring for bleeding, especially in high-risk patients such as those who are older than 75 or have low body weight or creatinine clearance of 30 to 50 mL/min. The overall risk of bleeding complications with NOACs at therapeutic doses is comparable with that of vitamin K antagonists, with lower rates of intracranial hemorrhage in the studies of patients with atrial fibrillation, the authors noted. Management of bleeding associated with the NOACs is similar to that with vitamin K antagonists. "Importantly, special attention should be paid to time since the last dose of NOACs and the concomitant use of other medications that can potentially increase the bleeding risk (antiplatelet agents and NSAIDs) or interfere with NOAC metabolism," they wrote. "Currently, supportive strategies are the mainstay for the treatment of bleeding with NOACs, and include discontinuation of the drug, mechanical compression, surgical hemostasis measures, and administration of transfusion support;