Archive for the ‘Pradaxa – dabigatran’ Category
Stephan Moll, MD and Damon Houghton, MD write … Antiphospholipid syndrome (APS) is an acquired clotting disorder. Patients with APS may have DVT or PE that requires treatment with blood thinners. Warfarin (Coumadin®, Jantoven®), and sometimes the injectable heparin drugs (enoxaparin = Lovenox®; dalteparin = Fragmin®; tinzaparin = Innohep®; etc.), have traditionally been used in patients with APS. A question that comes up is whether one of the new oral blood thinners (apixaban = Eliquis®; dabigatran = Pradaxa®; edoxaban = Savaysa®; rivaroxaban = Xarelto®) can be used instead of warfarin or a heparin drug. These drugs are collectively referred to as direct oral anticoagulants (DOACs).
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.
Multiple cases of patients with APS treated with a DOAC have been published. All of these (i.e. a total of 122 patients) have recently been summarized [ref 1]: Sixteen percent (i.e. one of every 6 patients) had a recurrent clot on a DOAC. As this is a high rate of DOAC failure, the authors caution about the use of DOACs in APS. However, two things need to be considered: (a) it is also known that warfarin has a high failure rate [references 2,3]; and (b) due to the nature of case report publications (potential bias; absence of control group), no strong or meaningful conclusion is really possible as to how DOACs compare to warfarin in the treatment of DVT and PE in patients with APS
Several studies on APS and the use of DOACs are ongoing. Details of the following studies can be found 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)
This is what we discuss with the patient with APS who needs to be on a blood thinner:
- I highlight 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.
- I discuss the fact 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 to use a twice daily dosed blood thinner (Eliquis® or Pradaxa®) rather than a once daily dosed drug (Xarelto® or Savaysa®). The thought behind this is that a twice daily dosed drug leads to more steady drug levels throughout the day and that this may lead to a more effective blood thinning effect. However, this is a theory unproven, and whether this truly leads to a lower risk of recurrent clots than being on a once daily drug is not known. A recent publication of a case report with discussion of drug metabolism also favors a twice daily rather than a once daily dosed drug in patients with APS [ref 4]. Ultimately, the most effective medication is likely the one that is taken as prescribed; therefore, a patient’s preference regarding the feasibility and practicality of a once daily versus twice daily medication is also an important consideration.
- 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…. Today (Jan 8th, 2015) the FDA approved yet another new oral blood thinner, Savaysa (edoxaban), for the treatment of DVT and PE. The drug was also FDA approved today for stroke prevention in patients with irregular heart beat (atrial fibrillation). The FDA press release here (link). Read the rest of this entry »
Stephan Moll, MD writes (on Nov 7th, 2014)… A publication this week in the New England Journal of Medicine reports on a new reversal agent (PER977 = Aripazine = ciraparantag) that may be effective against a number of different new oral anticoagulants [ref 1]. 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) the longer-term 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 DVT and PE. Thus, two of the new oral blood thinners are now FDA-approved for the treatment of DVT and PE: Xarelto (rivaroxaban) and Pradaxa (dabigatran). Due to the design of the clinical trials that lead to the FDA approval, Pradaxa should NOT be given immediately when DVT or PE are diagnosed, but rather after 5-10 days of treatment with an injectable blood thinner (into the skin or a vein; such as Lovenox = enoxaparin; Fragmin = dalteparin; Innohep = tinzaparin; or heparin). A Clot Connect summary of the FDA approval status of the four big new oral blood thinners for the various indications is in this table. Pradaxa’s full medication package insert is here. Today’s press release from Boehringer-Ingelheim about the FA approval is here.
Disclosures: I have been a consultant for Boehringer-Ingelheim, Daiichi, and Janssen.
Last updated: April 7th, 2014
Stephan Moll, MD writes…
The injectable low molecular weight heparins (LMWH; e.g. enoxaparin = Lovenox; dalteparin = Fragmin; tinzaparin = Innohep) are the preferred blood thinners in the pregnant patient. Warfarin is to be avoided as it can cause malformations of the fetus and can lead to bleeding in the unborn.
Regarding breastfeeding: the low molecular weight heparins (listed above) and warfarin are safe in the woman who is beastfeeding.
Rivaroxaban (Xarelto), dabigatran (Pradaxa) and apixaban (Eliquis) should not be used during pregnancy or while breastfeeding.
A detailed summary about the safety of each blood thinner during pregnancy and while breast-feeding, based on the ACCP 2012 guidelines [ref], can be found here.
Bates SM, Greer IA, Middeldorp S et al. VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141(2)(Suppl):e691S–e736S.
Disclosure: I have consulted for Janssen and Boehringer-Ingelheim.
Last updated: Jan 23rd, 2014
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. Read the rest of this entry »
Stephan Moll, MD writes… This week (Sept 1st 2013) the New England Journal of Medicine published the phase 3 clinical trial of the new oral blood thinner edoxaban compared with warfarin in the treatment of DVT and PE [ref 1]. It showed that edoxaban was as effective as warfarin and led to less clinically relevant bleeding.
- Edoxaban is one of the new oral blood thinners (anti-Xa anticoagulant) that does not require routine m0nitoring for its blood thinning effect and does not interact with vitamin K in the diet like warfarin.
- At this point it is not FDA approved for any indication.
- It is dosed once daily.
- It reaches its peak blood thinning effect within 1 to 2 hours of oral intake.
- Its half-life is 9-11 hours, which means that it is mostly out of the system in 48 hours after stopping it.
- 35 % of the drug is cleared by the kidney, which means that it needs to be dose reduced or avoided in patients with significant impairment of kidney disease.
- This is a randomized, double-blind study.
- All patients received initial therapy with open-label enoxaparin into the skin (subcutaneous) or intravenous heparin for at least 5 days, before edoxaban or warfarin were started.
- Edoxaban was dosed 60 mg once daily. The dose was reduced to 30 mg once daily in patients with impaired kidney function or a body weight less than 60 kg (132 pounds).
- Length of treatment with blood thinners was 3 to 12 months.
- A total of 8292 patients were enrolled (4143 into the edoxaban treatment arm, 4149 into the warfarin arm).
- Recurrent DVT or PE occured in 3.2 % of patients in the edoxaban group and 3.5 % in the warfarin group. Conclusion: edoxaban is not worse than warfarin.
- “Clinically relevant bleeding” occured in 8.5 % of patients in the edoxaban group and 10.3 % in the warfarin group. Conclusion: edoxaban is better than warfarin from a bleeding point of view.
- “Major bleeding” was the same in both groups, 1.4 % in the edoxaban group, 1.6 % in the warfarin group. Conclusion: edoxaban is not worse than warfarin in respect to major bleeding.
The study concludes that edoxaban (a) is as effective as high quality standard therapy with warfarin, and (b) causes less clinically relevant bleeding.
My perspective – Edoxaban compared to the other new oral blood thinners
- This table lists the key differences of the 4 new oral blood thinners in the treatment of VTE.
- Edoxaban is the 4th of the big new oral blood thinners. Its development lags behind the other 3 drugs, which are, at least for the irregular heart beat (atrial fibrillation) indication, already FDA-approved and on the market. For DVT and PE treatment, only rivaroxaban (Xarelto) is FDA-approved; Xarelto is, therefore, the only one of the new oral blood thinners I would use at this time for DVT and PE treatment.
- The main downside of the edoxaban study design is that edoxaban was not started right off the bat once the diagnosis of VTE was made in a patient, but that patients were first treated for at least 5 days with la ow molecular weight heparin (LMWH) blood thinner into the skin or i.v. heparin before edoxaban or warfarin were started. This is similar to the dabigatran study design. The Xarelto and Pradaxa studies, on the other hand, gave the new oral blood thinner immediately after diagnosis, without the need for initial LMWH. Thus, from a clinical-practical point of view, treatment of an acute DT or PE with edoxaban would be more cumbersome (cost of LMWH; teaching of self injections) than treatment with Xarelto or Eliquis.
- Edoxaban is given once daily. This is more convenient for patients than a twice daily regimen, such as with Pradaxa and Eliquis.
- It is good to see data of DVT and PE trials on these various drugs published and the drugs making their way through the FDA approval process and, hopefully, eventually onto the market. It is good to see data on a variety of different patients treated with these drugs, as there are a number of different types of patients which we need to learn more about as to how they fare on the new oral blood thinners: patients who are obese, have kidney impairment, have large PEs, have cancer, etc. The data published in today’s New England Journal of Medicine are a very helpful addition to our knowledge-base.
- HOKUSAI-Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;Sept 1.
- Agnelli G et al. Oral Apixaban for the Treatment of acute venous thromboembolism. N Engl J Med, 369:799-808.
- The Einstein Investigators: Oral Rivaroxaban for symptomatic venous thromboembolism. New Engl J Med 2010;363:2499-510.
- The Einstein Investigators: Oral Rivaroxaban for the treatment of symptomatic pulmonary embolism. New Engl J Med 2012;366:1287-97.
- Schulman s et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52.
Disclosure: I have consulted for Janssen, Boehringer-Ingelheim and Daiichi.
Last updated: Sept 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, as far as I know, for any indication.
Disclosure: I have consulted for Janssen, Daiichi, Boehringer Ingelheim.
Last updated: Aug 28th, 2013
What topics do you need to discuss with your physican or anticoagulation clinic pharmacist or nurse when you are considering starting Pradaxa (Dabigatran)? A structured, bulleted checklist may be helpful for the discussion, to make sure that all relevant points are addressed. A suggested list is here. Read the rest of this entry »