March 18th, 2011
Dabigatran Dialogue: Two Experts Answer Our Questions and Yours
Samuel Goldhaber, MD and Elaine Marie Hylek, MD, MPH
In a series of blog posts on CardioExchange, Samuel Goldhaber, Director of the Venous Thromboembolism Research Group in the Cardiovascular Division at Brigham and Women’s Hospital, has been guiding us on best practices around dabigatran. Recently, he teamed up with Elaine Hylek, Director of the Thrombosis and Anticoagulation Service at Boston University School of Medicine, for a live interview on the topic. An edited transcript is below, and the podcast is available as well.
Q: Are there patients that you definitely would or would not put on dabigatran?
SG: For patients with new-onset atrial fibrillation and a CHADS2 score ≥2, where anticoagulation is unequivocally recommended, dabigatran is my default choice, barring end-stage renal disease with a creatinine clearance <15. For patients who are already on warfarin and doing fine, I see no reason to rock the boat.
EH: Every patient should be informed about exciting and new advances in the field. That said, this drug does require some changes, compared to what patients are accustomed to with warfarin. For example, dabigatran is a twice-daily drug, it does not require monitoring, and there may need to be some education around fluctuating renal status. Also, the drug loses its potency when it is removed from the original bottle, so patients should not remove the tablets to place into a pill organizer or pill box.
Q: Let’s shift to some cases now. If a 70-year-old woman with hypertension, prior heart failure, and no other major issues is newly diagnosed with chronic atrial fibrillation in your office, how would you counsel her regarding warfarin versus dabigatran?
SG: I would discuss both drugs with her, but I would tell her that dabigatran (150 mg twice daily) is my preferred choice based on a rigorous, pivotal clinical trial (RE-LY). In that study, patients who took dabigatran (150 mg twice daily) had a 30% lower risk for stroke and a 60% lower risk for intracranial bleeding than those who took warfarin. I would emphasize the importance of adherence to dabigatran and note that it should always be taken with food.
EH: I agree with Sam and would also counsel her about the slightly higher risk for GI bleeding with dabigatran versus warfarin.
Q: There’s no clear test of adherence to dabigatran. If a patient reports being on this drug consistently for at least 4 weeks prior to cardioversion, would you consider it safe to cardiovert without transesophageal echocardiogram to rule out intracardiac clot?
SG: Performing a TEE and not detecting an intracardiac thrombus does not give the patient immunity against stroke during the cardioversion procedure and can, in fact, lead to a false sense of security. My preference is always to give the patient anticoagulation for 4 weeks prior to cardioversion rather than do a TEE/cardioversion. I have always told my patients receiving anticoagulation that the risk for stroke during cardioversion is about 1 in 1000. However, a posthoc analysis of the RE-LY trial was just published, showing that, regardless of whether you give dabigatran at 150 mg twice a day or warfarin, the rate of stroke within 30 days after cardioversion is, to me, amazingly high: 3 to 6 events in every 1000 patients cardioverted. Based on that information, I am certainly going to change the conversation I have with my patients about the risks of cardioversion.
EH: The RE-LY trial clearly demonstrated that dabigatran is a potent anticoagulant, but some clinicians may be uncomfortable with the lack of monitoring and thus may be hesitant to trust the drug’s effects. My sense is that if you have put someone on dabigatran for 4 weeks before a cardioversion, then you believe in the medication, you believe in the mechanism and in the coagulation pathway, and you believe in the results of the RE-LY trial. To then subject the patient to a procedure like a TEE is not necessarily sound. If the patient is absolutely certain they have taken the medication, then you have done all you can to prevent stroke in this setting.
Q: How would you recommend managing patients on dabigatran before and after noncardiovascular surgical procedures?
SG: Unless the patient is at very high risk for a stroke or bleeding event, I simply omit the dabigatran dose the afternoon or evening before the procedure and then omit both doses on the day of.
EH: The package insert also provides details about specific procedures for which you would want to hold dabigatran for longer — for example, those that require absolute hemostasis. Obviously, it would behoove the surgeon and proceduralist to consult that resource.
Q: Given the dangers of not being in the therapeutic range because of nonadherence, do you think that more-intensive or more-frequent counseling will be required for patients taking dabigatran, and if so, what sort of initial counseling and frequency of follow-up would you recommend?
EH: Patients who alternate or skip doses of dabigatran won’t have the same buffer as they would on warfarin, because warfarin tends to remain in circulation for upwards of 36 to 40 hours. I would follow patients closely as they transition to dabigatran, especially if they have been on warfarin — at a minimum, I would see them once or twice in the first month and then maybe every 3 months for the next 6 months or so.
SG: We need the same type of collaborative engagement with patients on dabigatran as we have for patients on clopidogrel after coronary artery stent placement. Every clinician taking care of the patient — whether it be a cardiologist, primary care doctor, physician’s assistant, or nurse — needs to reminds him or her to take the dabigatran.
For more of our coverage on dabigatran, check out the Dabigatran Resource Round-Up.
15 Responses to “Dabigatran Dialogue: Two Experts Answer Our Questions and Yours”
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Dabogatran need not be taken with food. The AUC does not change, Cmax is delayed by about 2 hours. There is no known decrease in dyspepsia, but it is for this potential side effect reduction that some (including myself) recommend it with food, particulaly when starting the drug.
Beware of dabigatran’s renal excretion. The suggestion to hold only 2 doses before most surgical procedures holds if GFR exceeds 50.
The pericardioversion embolic rate in ACUTE was 0.5 to 0.8 %. RE-LY supports this with much greater numbers.
A big question: does RE-LY tip the balance for CHADS2 score 1 patients? I believe the risk-benefit considerations in the current guidelines (optional warfarin for CHADS2 of 1) weighed substantially on intracranial bleeding risk on warfarin. With a consistent reduction of ICBs with dabigatran ( and other factor 10A inhibitors), should we be more aggressive with CHADS2 1’s? How about the other risk stratification..CHADS- VASC? If the above 70 yo woman had no history of CHF? How bout no CHF and no HTN?
Dabigatran, with its lower stroke rate and lower intracranial bleeding rate compared with warfarin, will lower the threshold for anticoagulation to prevent stroke in AF patients. There are many borderline cases that can go “either way” with respect to anticoagulation. The efficacy and safety of dabigatran will ultimately increase the proportion of AF patients who receive indefinite duration anticoagulation.–SZG
While dabigatran is an exciting new therapeutic option in the field of thromboembolism, for the sake of transparency, it should be noted in the Transcript that both Dr. Goldhaber and Dr. Hylek have conflicts of interest involving Boehringer-Ingleheim, the manufacturer of dabigatran and sponsor of the Re-Ly study. Dr. Goldhaber has received research support from Boehringer-Ingleheim, and Dr. Hylek is on the Advisory board of the company. This is clearly stated in the author profiles, but one should NOT have to search for this information–In terms of your editorial policy, should be stated at the outset–Stephen Austin
Competing interests pertaining specifically to this post, comment, or both:
None
Great point here by Dr. Austin. The disclosures are indeed part of Drs. Goldhaber and Hylek’s profiles, but we at CardioExchange should make this information easier to see. We’ll be correcting that for future posts, thanks to this comment pointing out the usability issue. Much appreciated!
The problem with Dabigatran in the UK is likely to be cost. In the county I work in (Somerset, England) we have around 5000 patients with AF and a CHADS score of >1. A year of Dabigatran may cost around £700 ($1120) vs £125 ($200) for warfarin with monitoring.
Depending on the dose there may be fewer strokes or bleeding complications to offset the costs, but nonetheless the additional cost of dabigatran may be significant. We will have to look closely at the patients most likely to benefit in the current economic climate.
All new patients with preserved renal function and who take medication reliably, although perhaps desirable from the data, may not be economically viable. Who would the authors suggest benefit most? Who would they start with if they had a limited pot of money to dip into?
Competing interests pertaining specifically to this post, comment, or both:
I have accepted sponsorship from Boehringer-Ingelheim to attend a UK based conference later this year.
I’m more than a bit surprised by this UK assessment of cost. I thought the UK’s National Health Service has to pay for the cost of stroke care including long term nursing homes for stroke patients. If this is the case, I think that dabigatran will in the “big picture” be far more cost effective than warfarin.
On the other hand, we in the USA have heard that the UK is making drastic budget reductions in just about everything.
Please keep us updated on CardioExchange about UK cost considerations for prescription drugs and for other health care payment policies.–SZG
I agree with Stephen Austin and hope this kind of blog is not going to Change CardioexChange in its pattern it still preserves. Dr. Goldhaber and Dr. Hylek have sent two messages for practice: The drug loses its potency when it is removed from the original bottle and it should always be taken with food.
Lets get the major issues settled beforewe get into cost.I have not heard the most important questiions about dabigatran ansered,
1 For the millions on coumadin, how/when does one start dabigratin. I It is dangerous to let a high risk senior stop coumadin with out coverage with heparin until dabigatran is therapeutic .Do you just cancel coumadin and start dabigatran in full dose or wait a few days or what
2 Do we stop dabigratin a day or many days pre op. How long is dabigatin impacting clotting after it is cancelled.
3 What are the major drugs, food ,etc that impact dabigatran
The answers from the previous post are well delineated in the package insert. I firmly believe that anyprescribing physician should be very familiar with its content.
There are of couse” gray”areas…these are the issues which I find most important to discuss in a forum like this. I have touched on some before : (1) the 75 mg bid dose FDA approved despite lack of robust clinical data, (2) the acceptance by the FDA of a 2.5 increase in AUC with drug interactions (P- GP inhibitors..like dronedarone and keto and amio ): no dose adjustment recommended in USA (even with GFR borderline). In cases where GFR is borderline and there is a P-Glycoprotein inhibitor, I have checked a trough PTT…data suggest it should be less than 3x ULN.
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I have spoken for BI on 6 occasions. Prior posts have indicated this I have read over 300 pages from FDA documents. I am in regular contact with the company, and have challenged them in some areas. Nevertheless, we should never be in denial of latent biases.
One of the drawbacks of warfarin is it’s teratogenicity. Has Dabigatran been tested in pregnancy?
Competing interests pertaining specifically to this post, comment, or both:
NONE
Dabigatran has not been tested in pregnancy. Nor has any other novel anticoagulant. And I don’t think we’ll see any testing in pregnancy because of the fear of litigation. Only if there is some sort of Federal Government Immunity granted, as there is for vaccine testing, can I imagine novel drug testing in pregnancy.
The problem that Dr. Retta raises is important because current anticoagulation options for pregnant women are limited and have a lot of drawbacks. There is a large unmet need for improvement.
But, for now, I don’t see any drug testing of pregnant women in the “anticoagulation pipeline.”–SZG
Class C. Don’t overdose pregnant rats. Hopefully, they will test it, as well as rivaroxaban. This would particularly be good if/when drugs are used for DVT or prophylaxis thereof. Dabi is approved for this in Europe: .RECOVER and rivaroxiban: EINSTEIN. I don’t know re prosthetic mechanical valve
trials. I have used off label dabi for DVT..could not take warfarin and could not afford injectables. Curious re Sam Goldhaber’s view re DVT use.
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speak for BI
I’ve had a lot of requests to prescribe dabigatran for off label use in DVT. So far, I’ve held off, because I’ve found reasonable alternatives. I’m waiting for the information about the dabigatran DVT trials to be submitted to the FDA for FDA review. One wonders why the efficacy for dabigatran compared with warfarin was both noninferior and superior for stroke prevention in AF in RE-LY but only noninferior for recurrent venous thromboembolism (VTE)in RE-COVER. Is there a fundamental difference in the two disease states of AF and VTE for which dabigatran provides a “new window”?–SZG
The European EMA has permitted the use of dabigatran (and rivaroxaban) only in the primary prevention of VTE in elective knee/hip surgery.
Being a Belgian pharmacist, I can only speak for what I see in region where I work: our surgeons nor our anesthesiologists prescribe the drug.
I’m afraid that Belgian physicians in general will keep on prescribing the longer acting phenprocoumon (preferred to warfarin in the Belgian setting because there are no warfarin clinics nor facilities to support self-management of patients).
I do have one small question: are there any new insights of the small increase in myocardial infarctions as reported in the RE-LY trial? Do you think this to be clinically significant for a certain subgroup of your patient, significant enough so that you will take this into account?
PS: I’ve heard that the bottles will not be distributed in Europe; only the blisters.
Competing interests pertaining specifically to this post, comment, or both:
none
The reassuring aspect of RE-LY with respect to myocardial infarction is that vascular death and total death rates trended downward with dabigatran compared with warfarin. We await further data from other trials.–SZG