Stephan Moll, MD writes… The American Society of Hematology (ASH) has identified 3 things that physicians dealing with DVT, PE and blood thinners (anticoagulants) should avoid – published this week in the journal Blood [ref 1]. Read the rest of this entry »
Stephan Moll, MD writes…
On Oct 8th, 2013 the FDA approved a new drug to treat severe pulmonary hypertension. The drug is called Adempas® (riociguat). 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. 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
Stephan Moll, MD writes… A major international meeting about clotting and bleeding took place in Amsterdam, Holland, from June 29th to July 4th, 2013, the meeting of the International Society for Thrombosis and Haemostasis (ISTH). The clinically relevant highlights about blood clots and blood thinners are summarized below. None of the data presented at the meeting are immediately clinical practice changing. However, several presentations are noteworthy, as they indicate clinically relevant changes to come in the next few years.
A. New Oral Blood Thinner for DVT and PE
The major DVT and PE acute treatment trial (AMPLIFY trial) of the new oral blood thinner Eliquis (apixaban) was presented at ISTH. The drug is presently FDA-approved only for the treatment of irregular heart beat (atrial fibrillation), but not for DVT and PE. On the same day as the oral presentation, the New England Journal of Medicine published the full study (detailed discussion of study and result on Clot Connect here). Summary: Apixaban was as effective as warfarin and led to less major and clinically relevant bleeding than warfarin. Hopefully, the drug will be FDA approved soon – in next 6 months? – and clinically available. We will then have two new oral anticoagulant drugs for the treatment of DVT and PE to choose from –Xarelto (rivaroxaban) and Eliquis (apixaban).
B. Major Bleeding on the New Oral Blood Thinners
No reversal agent is presently available if major bleeding occurs in a patient treated with one of the new oral blood thinners, i.e. Xarelto, Pradaxa or Eliquis.
a) Pradaxa (dabigatran)
A reversal agent for Pradaxa (dabigatran) is in development. It is an antibody fragment directed against dabigatran, which can neutralize the drug’s blood thinning effect, referred to as “BI 655075”. Detailed data on this antidote, as studied in rats, were presented at ISTH. The reversal agent is now in a human volunteer phase 1 study (clinicaltrials.gov study number “NCT01688830”).
b) Xarelto, Eliquis and Edoxaban
To neutralize the blood thinning effect of Xarelto, Eliquis and edoxaban, a drug has been developed by the company Portola, that is an inactivated clotting factor X. It can bind to and, thus, remove the blood thinner from the circulation. The drug is called Andexanet (PRT4445). Data were presented at ISTH of an early clinical trial (phase 2). In the blood of human volunteers who took apixaban (Eliquis), the blood thinning effect of Eliquis was successfully and completely reversed by Andexanet, which was well tolerated. Further human volunteer trials reversing Xarelto and edoxaban with Andexanet are on the way.
c) Prothrombin Complex Concentrates (PCC)
PCCs are clotting factor concentrates that are being used to treat warfarin associated major bleeding. The products available in the U.S. are Bebulin, Profilnine and Kcentra. It is not known whether PCCs have any benefit when used to treat major bleeding in patients on one of the new oral blood thinners. At ISTH no patient data were presented and no clinical trial is ongoing testing whether PCCs are potentially beneficial in patients with major bleeding on one of the new oral blood thinners. Thus, it remains unclear whether PCCs have any benefit in the patient on a new oral blood thinner who has a major bleed. However, based on test tube and animal data, PCCs are part of the reversal strategy algorithm of a number of medical institutions.
d) Major Bleeding does not Equal Major Bleeding
The new oral blood thinners have a different bleeding pattern compared to warfarin: all three new oral blood thinners (dabigatran, rivaroxaban and apixaban) lead to less bleeds into the head (intracranial bleeds). Intracranial bleeds are the most feared of major bleeds. A presentation at ISTH showed that major bleeds on warfarin lead to a high rate of death if the bleed is intracranial, but that major bleed into the gastrointestinal tract rarely lead to death. This is helpful information when discussing the risk of bleeding with blood thinners with a patient.
C. Performance of Clotting Tests on the New Oral Blood Thinners
The new oral blood thinners Xarelto, Pradaxa and Eliquis can influence thrombophilia lab results. This is important to realize when performing a clotting (thrombophilia) work-up in a patient who has had a DVT or PE and is on one of these drugs. This table shows how tests can be influenced. Caution is needed when interpreting thrombophilia test results to avoid wrong interpretations. The genetic tests for factor V Leiden and the factor II (prothrombin) 20210 mutation are not influenced by being on blood thinners.
D. D-dimer as a Predictor of Recurrent DVT and PE
The D-dimer is a protein in the blood that is typically elevated when a patient has an acute clot. It is also elevated in some patients who have a clotting tendency. A number of studies in the last few years have shown that the D-Dimer (tested on or off warfarin) helps predict, to some degree, which patient may develop another clot in the future if not on a blood thinner. Physicians sometimes use the D-dimer test result as one of the parameters to help decide whether a patient who had an unprovoked DVT or PE can come off blood thinners (if the D-dimer is negative/normal) or stay on blood thinners (if the D-dimer is elevated).
Several presentations at ISTH discussed the usefulness of the D-dimer in the prediction of recurrent DVT and PE. What is clear is that there are still several unknowns about the performance of D-dimer assays and how clinicians should use results for clinical decision-making.
a) What D-dimer assay does a lab use?
Different D-dimer assays have varying sensitivities to detect elevated D-dimer levels and are, thus, referred to as highly sensitive, intermediate-sensitive, and low sensitive [ref 5,6]. Before making any decisions on the results of a D-dimer test, a clinician should known what D-dimer assay his/her laboratory uses and what sensitivity the assay has.
b) Is the D-dimer useful in men as well as in women?
It appears that the D-dimer may not be helpful in men. (a) A summary of the REVERSE I and II studies confirmed that a negative D-dimer on warfarin is a predictor of a low risk of VTE recurrence in women. However, men have a higher risk of recurrence, no matter whether D-dimer is positive or negative. (b) The DODS study also showed that the D-dimer (obtained 4 weeks after having stopped warfarin) is not helpful in men to predict a low risk of recurrent VTE: even men with negative D-dimer have a high risk of recurrence. The DODS study also showed that women with a negative D-dimer have quite a low risk of recurrent VTE, particularly if the first VTE episode was hormone-associated.
c) Does the degree of positivity predict anything more than a simple positive/negative result?
Clinicians who use the D-dimer for clinical decision making on length of anticoagulation, often make decisions simply on whether the D-dimer test is positive or negative. This is because previous studies have evaluated the performance of the D-dimer assay in that manner. A study presented at ISTH showed that the degree of D-dimer positivity correlated slightly with the risk of DVT and PE recurrence: a doubling of the D-dimer result lead to an approximately 1.35 fold higher risk of recurrent DVT and PE in the patient not on warfarin.
d) Should clinicians use one D-dimer range, or age and gender-specific D-dimer cut-offs?
A study presented at ISTH used age and gender specific D-dimer cut-offs and showed that the D-dimer, if used in that manner, helped predict DVT/PE recurrence. May be at some point in the future clinicians should routinely use age- and gender-specific cut-offs.
E. IVC Filters in Patients with PE
One of the most relevant clinical studies presented at ISTH was the PREPIC II study. The study was done to assess whether placing an IVC filter (inferior vena cava filter; the IVC is the big vein in the abdomen) routinely in patients with acute PE (who also have a DVT) is beneficial. The idea behind the study is that such a filter may prevent further PEs coming from leg DVTs.
In the PREPIC II study patients with acute PE (who also had a leg DVT) were randomized to receive an IVC filter or no filter. A total of 399 patients were enrolled, 50 % of whom received a removable IVC filter, with the plan to remove it again within 3 months. Patients were routinely treated with blood thinners. Findings: (a) the risk of recurrent PE was low and was no different between the two groups: 3.5% in IVC filter group vs. 2.0% in no-filter group at 6 months; (b) filter complications were relatively low, occurring in 2.1 % of IVC filter patients; and (c) IVC filter removal was successful in 92.2 % of patients and failed in 7.8 %. Overall conclusion: There is no benefit of routinely placing an IVC filter in patients with acute PE.
F. Bleeding Risk Scores
At least 7 risk scores exist to assess a patient’s risk for bleeding on warfarin. Using bleeding risk scores could potentially be a helpful tool when making decisions about length of anticoagulation therapy. Most scores were developed from studies of patients with irregular heart beat (who are often older than patients with DVT and PE). At ISTH there were 2 presentations that compared these scores to predict major bleeding in DVT/PE patients. They showed that the scores perform suboptimally and do not well predict major bleeding. Further research is needed to optimize existing bleeding risk scores or create a new one that accurately assesses and predicts the risk of major bleeding in DVT/PE patients on warfarin. Furthermore: as the pattern of bleeding is different with the new oral blood thinners, warfarin bleeding risk scores may not accurately predict major bleeding on these new drugs anyway. A new bleeding prediction risk score specific for the new oral blood thinners may have to be developed.
G. Interesting/Relevant Ongoing Clinical Studies
a) ALIFE-2 study
(www.ALIFE2study.org). “Anticoagulants for living fetuses in women with recurrent miscarriage and inherited thrombophilia”. The primary objective of this randomized international, multi-center study is to evaluate the efficacy of low molecular weight heparin (LMWH) in women with recurrent miscarriage and inherited thrombophilia. Women will either receive once daily prophylactic-dose LMWH or no pharmacologic intervention. The study has been enrolling since Jan 2013.
b) HIGHLOW study
(http://www.studies-obsgyn.nl/Highlow). “Evaluation of efficacy and safety of intermediate dose LMWH versus fixed low dose LMWH in pregnant women with a history of previous VTE”. This is a randomized, open-label trial. Patients receive either intermediate dose LMWH (nadroparin; not routinely available in the U.S.), adjusted to actual body weight during pregnancy, or fixed low-dose LMWH, i.e. nadroparin 2850 IU, the standard dose for prophylaxis of DVT/PE. The study has been enrolling since April 2013.
Disclosure: I have consulted for Janssen, Boehringer-Ingelheim, Daiichi.
Last updated: Aug 12th, 2013
Stephan Moll, MD writes…
An important study (called AMPLIFY trial) was published today in the New England Journal of Medicine [ref 1]. In a large study of patients with acute DVT or PE, Eliquis (apixaban) was as effective as warfarin and caused less major bleeding. Read the rest of this entry »
Dr. Stephan Moll writes… Skyla® is a new intrauterine device (IUD) birth control option, approved in February 2013 by the FDA. Skyla® is like a small version of the Mirena® IUD; it releases low doses of the hormone progestin to help the IUD prevent pregnancy. It has the following features: Read the rest of this entry »
Beth Waldron, Clot Connect program director, writes…
If you’ve experienced deep vein thrombosis (DVT) or pulmonary embolism (PE), a recurrence of a blood clot in the future is a concern. Diagnosing a recurrent clot can be a challenge because it is sometimes difficult to tell if symptoms are the result of a new clot or the signs of chronic damage from the initial clot.
- Around 40% of patients with DVT develop long-term pain and swelling, known as post-thrombotic syndrome. Such pain and swelling can fluctuate, and be particularly pronounced after standing for prolonged periods of time or being overly active.
- Around 4% of patients with PE develop long-term shortness of breath, known as pulmonary hypertension.
How do healthcare professionals know when symptoms are the result of a past blood clot or due to a new clot? Read the rest of this entry »
Stephan Moll, MD writes….
The pharmaceutical company Portola reported today (May 8th, 2013) on the findings of their human volunteer study of their blood thinner antidote PRT4445 (ClinicalTrials.gov Identifier: NCT01758432 – medical details of the study design are here, study NCT01758432. This dug is in early development. In the study, healthy volunteers who had taken the new oral blood thinner Eliquis (Apixaban) received the reversal agent. The study showed a “rapid and sustained and dose-related reversal” of the blood thinning effect of Eliquis” and “no serious adverse events”. Read the rest of this entry »