Posts Tagged ‘Dabigatran’
Stephan Moll, MD and Damon Houghton, MD write … In patients with antiphospholipid syndrome (APS) who require anticoagulation for the treatment of DVT or PE, warfarin or a low molecular weight heparin have traditionally been used. A question that comes up is whether one of the new oral anticoagulants (DOACs) can be effectively and safely used instead.
It is not known at this point whether DOACs are equally, more or less effective as/than warfarin in patients with APS. Data from clinical trials directly comparing DOACs with warfarin are not yet available. Given the absence of data, no formal recommendations or guidelines exist on this topic. It is an individualized decision between a physician and patient with APS whether to use warfarin or a DOAC for the treatment of DVT or PE.
Several case reports and case series of patients with APS treated with a DOAC have been published. All data (from a total of 122 patients) have recently been summarized : Sixteen percent of patients had a recurrent clot on a DOAC. Given this relatively high rate of DOAC failure, the authors caution about the use of DOACs in APS. However, it is also known that warfarin has a high failure rate [references 2,3]. In addition, due to the nature of case report publications (potential bias; absence of control group), no strong or meaningful conclusion is possible as to how DOACs compare to warfarin or LMWH in the treatment of DVT and PE in patients with APS.
Several studies on APS and the use of DOACs are ongoing, with details available at clinicaltrials.gov:
- NCT02157272: A Prospective, Randomized Clinical Trial Comparing Rivaroxaban with Warfarin in High Risk Patients With Antiphospholipid Syndrome (TRAPS)
- NCT02295475: Apixaban for the Secondary Prevention of Thromboembolism Among Patients With the AntiphosPholipid Syndrome (ASTRO-APS)
- NCT02116036: Rivaroxaban for Antiphospholipid Antibody Syndrome (RAPS)
We discuss with patient with APS who needs to be on an anticoagulant:
- … that no solid data exist regarding the use of DOACs in APS, and that it is not known whether the DOACs are as effective as warfarin, less effective or more effective.
- … that some patients with APS develop new clots in spite of being on warfarin and that recurrent clots may also occur on a DOAC.
If we decide to use a DOAC, then our preference is typically a twice daily dosed anticoagulant (Eliquis® or Pradaxa®) rather than a once daily dosed drug (Xarelto® or Savaysa®), as the twice daily dosed drug leads to more steady drug levels throughout the day. The hypothesis is that this may lead to a more effective anticoagulant effect. However, this theory is unproven and whether this truly leads to a lower risk of anticoagulant failure in patients with APS is not known. A recent publication (case report plus discussion on drug pharmacokinetics/-dynamics) also suggests a twice daily rather than a once daily dosed drug in patients with APS if a DOAC is used [ref 4]. However, feasibility/practicality of once daily versus twice daily medication and, thus, patient preference, is also important to consider.
- Dufrost V et al. Direct oral anticoagulants use in antiphospholipid syndrome: Are these drugs an effective and safe alternative to warfarin? A systematic review of the literature. Curr Rheumatol Rep 2016;18:74.
- Crowther M et al. A Comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003;349:1133-8.
- Finazzi G et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS) J Thromb Haemost 2005;3: 848–853.
- Schofield JR et al. Dosing considerations in the use of the direct oral anticoagulants in the antiphospholipid syndrome. J Clin Pharm Ther. 2017 Jun 27. doi: 10.1111/jcpt.12582. [Epub ahead of print].
Disclosure: Dr. Moll has consulted for Janssen Pharmaceuticals and Boehringer-Ingelheim. Dr. Houghton has no disclosures.
Last updated: July 5th, 2017
Stephan Moll, MD writes… A publication in the New England Journal of Medicine today reports on the use of the Pradaxa® (Dabigatran) antidote Idarucizumab in patients on Pradaxa® who present with major bleeding or require urgent surgery [ref 1]. Read the rest of this entry »
Stephan Moll, MD writes (on Nov 7th, 2014)… A N Engl J Med publication this week [ref 1] reports on a new reversal agent (PER977 = Aripazine = ciraparantag) that may be effective against a number of different new oral anticoagulants. Read the rest of this entry »
Stephan Moll, MD writes… Apixaban (Eliquis®) was approved by the FDA this week (Aug 21, 2014) for the treatment of DVT and PE. The approval covers (a) acute DVT/PE management and (b) prevention of recurrent DVT/PE. Read the rest of this entry »
Stephan Moll, MD writes… Today the FDA approved Pradaxa (dabigatran) for the treatment of venous thromboembolism, based on the phase 3 RECOVER and RECOVER II trials. The dose is 150 mg twice daily for patients with a GFR > 30 ml/min. Due to the design of the RECOVER and RECOVER II trials, the drug is approved to be used in the patient with acute DVT or PE only AFTER 5-10 days of a parenteral anticoagulant have been given – not immediately from day zero onwards. The full package insert is here. The press release from Boehringer-Ingelheim is here. The FDA approval status of the four big new oral anticoagulants for the various indications is summarized in this table.
Disclosures: I have been a consultant for Boehringer-Ingelheim, Daiichi, and Janssen.
Last updated: April 7th, 2014
Stephan Moll, MD writes… On Dec 19th the FDA accepted the application by Bristol-Myers Squibb (BMS) and Pfizer for review of Eliquis (apixaban) for the treatment of DVT and PE. The press release of BMS is here. The goal date for a decision by the FDA is August 25, 2014. Read the rest of this entry »
Stephan Moll, MD writes…
Interesting publication this week in Circulation: “Management and outcomes of major bleeding during treatment with dabigatran or warfarin” (Majeed A et al; published online Sept 30,2013; full publication is here). The management and prognosis of major bleeding in patients treated with dabigatran or warfarin was compared, pooling data of the major bleeds that occurred in 5 phase III dabigatran trials. 1,121 major bleeds occurred in 27,419 patients treated with warfarin or dabigatran.
The noteworthy findings:
- Patients with major bleeding on dabigatran (Pradaxa) do not fare worse than patients with major bleed on warfarin (regarding 30 day mortality). They may actually fare a little better, as evidence by a shorter stay in the intensive care unit. That is reassuring when discussing the choice of the anticoagulant (warfarin versus dabigatran) with a patient.
- There were (as we already knew from previous publications) significantly less intracranial bleeds on dabigatran than on warfarin; however, there were more GI bleeds on dabigatran (supplemental table 1). This is noteworthy, as many would view an intracranial bleed as more worrisome and detrimental than a gastrointestinal bleed.
- Warfarin reversal is done suboptimally in clinical practice: In patients with major bleeding on warfarin, (i) only 30 % of patients received vitamin K and (ii) only 1.2 % of patients received a prothrombin complex concentrate (PCC); 30 % received FFP. This is noteworthy, as guidelines (ACCP 2012) suggest that in case of major bleeding on warfarin PCCs be given rather than plasma (FFP); and vitamin K should be standard of care in warfarin reversal. The observation in this Circulation publication reflects that reversal of warfarin therapy is often suboptimally done, even though appropriate tools exist, i.e. vitamin K and PCCs (see also Clot Connect’s Kcentra discussion here).
Disclosure: I have consulted for Boehringer-Ingelheim.
Last updated: Oct 2nd, 2013
Stephan Moll, MD writes…
1. Pradaxa (Dabigatran)
- Today, August 28th, 2013, it was announced that the FDA is reviewing the application by Boehringer-Ingelheim to get Pradaxa (dabigatran) approved for use in patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) – details here.
- At present, in the US, Pradaxa is only FDA-approved for prevention of stroke and other arterial clots in patients with irregular heart beat.
2. Eliquis (Apixaban)
- On July 11th , 2013 the company making Eliquis applied for FDA approval of their drug for DVT and PE prevention after hip and knee replacement surgery – details here.
- The company has not yet filed for approval of the drug for DVT and PE treatment.
- At present, in the US, Eliquis is only FDA-approved for prevention of stroke and other arterial clots in patients with irregular heart beat.
3. Xarelto (Rivaroxaban)
- Xarelto is, at present the only one of the new oral anticoagulants that is FDA-approved for the treatment of DVT and PE. It is also approved for (a) DVT and PE prevention after hip and knee replacement surgery, and (b) for prevention of stroke and other arterial clots in patients with irregular heart beat.
- This new oral anticoagulant by the Japanese company Daiichi is not FDA-approved at this time and no FDA review of data is pending.
Disclosure: I have consulted for Janssen, Daiichi, Boehringer Ingelheim.
Last updated: Sept 1st, 2013
Stephan Moll, MD writes… A major international coagulation conference, the bi-annual meeting of the International Society for Thrombosis and Haemostasis (ISTH; www.isth.org), took place in Amsterdam, Holland, from June 29th to July 4th, 2013. The clinically relevant highlights about thrombosis and anticoagulation are summarized below. Read the rest of this entry »
There is a lot of appropriate interest and excitement today about one of the four new oral anticoagulants in development – Apixaban (Eliquis). Data from the large ARISTOTLE trial were published today in the NEJM, showing that in patients with atrial fibrillation Apixaban was more effective in preventing stroke and systemic thromboembolism, caused less major bleeding, and resulted in lower mortality than warfarin in patients with non valvular atrial fibrillation [ref 1]. This is good news. Read the rest of this entry »