February 15th, 2011
Dabigatran for Patients with AFib: Putting the Updated Recs into Practice
Samuel Goldhaber, MD
CardioExchange welcomes Samuel Zachary Goldhaber, MD, Director of the Venous Thromboembolism Research Group and Medical Co-Director of the Anticoagulation Management Service at Brigham and Women’s Hospital in Boston. He answers practical questions from the CardioExchange editors about newly updated recommendations on the use of dabigatran in patients with atrial fibrillation, issued by the American College of Cardiology Foundation, the American Heart Association, and the Heart Rhythm Society.
Before pursuing elective cardioversion, should a patient be maintained on dabigatran for 3 weeks, or has the optimal duration changed? If the cardioversion succeeds, should the treatment last an additional 3 weeks after the procedure?
The guidelines remain the same for anticoagulation with planned elective cardioversion: 3 weeks of therapeutic anticoagulation before the procedure and at least 4 weeks of therapeutic anticoagulation after sinus rhythm has been achieved (Chest 2008; 133:546S). Dabigatran becomes therapeutic within 2 hours of administration.
For a patient with new-onset atrial fibrillation, does intravenous heparin have any role as a bridge to dabigatran?
When an asymptomatic patient presents with new-onset atrial fibrillation in the office setting, oral anticoagulation with dabigatran can be started without intravenous heparin. If the patient with new-onset atrial fibrillation is symptomatic, cardioversion may need to be performed imminently (if no thrombus is visualized on transesophageal echocardiography). In the symptomatic patient, there are two options:
- Begin therapy with intravenous heparin. (Cardioversion has not been extensively studied using dabigatran alone in patients with new-onset atrial fibrillation.)
- Begin therapy with dabigatran but without using intravenous heparin. (In the largest cardioversion experience to date, the stroke rate was low in dabigatran recipients, especially if they had been “cleared” first by transesophageal echocardiography; Circulation 2011; 123:131.)
How should a patient be transitioned on and off dabigatran from other antithrombotic agents (e.g., warfarin, enoxaparin, dalteparin, heparin)?
For patients switching from warfarin to dabigatran, give the first dose of dabigatran after the INR has declined to less than 2.0. In practice, this usually means withholding one or two doses of warfarin. For patients receiving parenteral subcutaneous anticoagulation, give the first dose of dabigatran just before the next scheduled injection of parenteral anticoagulation. For patients receiving intravenous heparin, give the first dose of dabigatran about 2 hours after discontinuing intravenous heparin.
If the patient experiences a bleeding complication while on dabigatran, is an antidote available?
There is no specific antidote for dabigatran-related bleeding. General supportive care and “tincture of time” usually work. In extreme circumstances, when confronted with a major, life-threatening hemorrhage, consider using recombinant factor VIIa or emergency hemodialysis.
If a patient has recurrent thromboembolic events while on dabigatran, what test should be performed to monitor the drug’s efficacy? Should a change in treatment be considered?
There is no clinically available test (such as INR, aPTT, or anti-factor Xa level) to monitor dabigatran’s efficacy. If a patient suffers a recurrent thromboembolic event, take a careful history to determine whether one or more doses of dabigatran were omitted. Dabigatran has a short half-life. If medication adherence was perfect, consider switching to another anticoagulation regimen.
For more of our coverage on dabigatran, check out the Dabigatran Resource Round-Up.
27 Responses to “Dabigatran for Patients with AFib: Putting the Updated Recs into Practice”
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If a patient who is taking dabigatran has to be taken to a surgical procedure, how long do we have to wait after the last dose of the drug?
Competing interests pertaining specifically to this post, comment, or both:
None.
If the surgery is completely elective, and if the patient is at low risk of stroke or other thrombosis, wait 3 half lives, and omit 3 doses of dabigatran. If the surgery is urgent, the maximal risk of bleeding should diminish as long as one dose of dabigatran is omitted.
That being said, in most cases, to adequately balance bleeding risk against clotting risk, omit the preoperative evening dose of dabigatran and the day-of-surgery dabigatran.–Sam Goldhaber, MD
Competing interests pertaining specifically to this post, comment, or both:
Clinical Research and Consulting for B-I
The guidelines for the above depend on renal function and the hemorrhagic risk of the surgery.. They are in the package insert. Also a PTT in the control range, particularly 32 or less, assures washout. One word of caution: the trough ECT and dabigatran level is naturally lower after the initial dose of dabigatran compared with the trough at steady state. The clinical significance of this fact is unclear, but potentially most important immediately after cardioversion.
The first question “If the cardioversion succeeds, should the treatment (with dabigatran)last an additional 3 weeks after the procedure?” is inappropriate without mentioning the overall thromboembolic risk, since any antithromtic regimen depends upon CHA2DS2-VASc risk score. Successful cardioversion does NOT mean that anticoagulation is warranted just for at least 4 weeks. ESC guidelines on atrial fibrillation 2010. Do you agree?
Interesting topic, but I disagree-I believe anticoagulation IS warranted. I’m glad dabigatran is a viable option as an alternative to vitamin K antagonists for this purpose. Time (and hopefully some studies) will tell if it proves effective.
Regarding the question to anticoagulate or not, post cardioversion:
ACP 2008 guidelines, ACC/AHA 2006 atrial fibrillation guidelines: If no thrombus is seen on TEE, cardioversion is successful, and sinus rhythm is maintained, we recommend anticoagulation (target INR, 2.5; range, 2.0 to 3.0) for at least 4 weeks. –Grade 1B recommendation
There have been numerous studies that demonstrate there is an increased risk for thromboembolic events even in the absence of thrombi in the atrium seen on TEE prior to cardioversion. From what I understand, the two mechanisms thought to be at play are :
1) dislodgement of pre-existing emboli after cardioversion, and
2) formation of new thrombi following cardioversion.
The latter point has been given credence by several echocardiographic studies in post-cardioversion patients that show pooling of contrast in the atria, suggestion cardioversion leads to development of a thrombogenic milieu. The etiology of this is likely myocardial stunning from the cardioversion, which may last for weeks. The cause of myocardial stunning is not certain, but may be due to cytosolic calcium homeostasis, tachycardia-induced atrial cardiomyopathy, and/or atrial hibernation. Incidentally, ARBs have been shown to attenuate the stunning effect.
“ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation” (Circulation. 2006;114:e257-e354)
“Exclusion of atrial thrombus by transesophageal echocardiography does not preclude embolism after cardioversion of atrial fibrillation. A multicenter study” by Black et al. (Circulation. 1994;89:2509-2513)
“Antithrombotic Therapy in Atrial Fibrillation ” by DE Singer et al. (Chest. June 2008;133(6)suppl:546S-592S)
Four weeks post cardioversion is the minimum amount of time for anticoagulation. In the important Circulation 2011; 123:131 paper on dabigatran and warfarin stroke rates post cardioversion, I was surprised that the stroke rates are much higher for both dabigatran and warfarin than I had assumed. When I consent patients for elective cardioversion from AF, I have previously told them the stroke risk from cardioversion in about 1 in 1,000. Clearly, the stroke risk is higher, regardless of whether dabigatran or warfarin is used and regardless of whether the patient is first “cleared” witn transesophageal ECHO.–SZG
Concerning anticoagulation in pre and post CV in AF we have satisfactory evidence about warfarin efficacy and duration of therapy. Based only on the sub-study of the RE-LY trial should we presume a similar efficacy of dabigatran and adopt the same scheme of treatment?.
Competing interests pertaining specifically to this post, comment, or both:
None
The Circ 2011 paper on dabigatran and cardioversion is a rich database. I think this one substudy is enough for us to use the same procedures for dabigatran cversion as for warfarin cversion.–SZG
Guidelines suggest anticoag for ALL patients with afib duration at least 2 days. The CHADS score does not directly apply here. There is little data to support the specifics of this guideline, though the duration of post
cardioversion stunning ( whether electrical or pharmacological ) does correlate with the duration of antecedent afib.
Personally, for acute cardioversion I only defer anticoagand TEE when the onset of afib is clearly within 2 days and there is no substantial structural heart disease.
I believe the RE- LY data support cardioversion on steady state dabigatranfor at least 3 weeks without a TEE. I am comfortable cardioverting new afib on dabigatran for less than 3 weeks but more than 5 doses with a TEE. I have reservations about patients not yet at steady state with dabigatran.
Is it true that noncompliance and taking the medication intermittently may cause irreversible thrombin inhibition.and what do you do with patients whodevelop minor nosebleeds on the prescribed dose. Has the 150mgs dose once daily shown to be effective
A once daily dose of dabigatran 150 mg has not been studied. I would not think it would be effective unless the patient has end stage renal disease. But for end stage renal disease patients, the FDA approved dose is 75 mg twice daily and there is no approval for using 150 mg once daily for any patients.
Noncompliance with dabigatran exposes the patient to more clotting risk. I am not aware of any reliable evidence showing that intermittent dabigatran with periods of noncompliance promotes irreversible thrombin inhibition, which would paradoxically increase bleeding risk.
I have one patient who had a nosebleed with dabigatran. But he also takes aspirin and Plavix for a drug-eluting stent. Nosebleeds are often due to a bleeding site that needs to be cauterized by an ENT doctor. And antiplatelet agents such as aspirin or Plavix are much more likely to cause nosebleeds than anticoagulants such as dabigatran or warfarin.–SZG
Question:
85 y.o. F S/P inferior wall MI with >50% EF on IV heparin develops Afib with RVR and CHF on day 2, fails DC cardioversion, on cardorone and b-blocker. Rate controlled and CHF resolved but remains Afib. Would you
recommend Dabigatran for this patient?
She has persistent AF and has a high risk of stroke. Dabigatran overall should reduce the stroke risk by about 30% compared with warfarin. Dabigatran should reduce the risk of intracranial bleed by about 60% compared with warfarin. As an elderly female, dabigatran has a higher risk of GI bleed than warfarin. But, a stroke or intracranial bleed is usually much more devastating than a GI bleed.
So, yes, I’d prescribe dabigatran for this patient.–SZG
If GFR by CG less than 15: no. If GFR stable and > 30: I would discuss it as preferable, but not a strong preference ( may be a cost issue). If GFR 15 -30: FDA approved but not clinically studied: here for now I go with warfarin. In any case, if afib persists after 6 gm or so of amio: shock without TEE (if therapeutic anticoag maintained throughout). If DES…use a lower” European” aspirin dose and hopefully” triple therapy” minimized to 6 to 8 wks total.
Those who note the increased GIB rate with dabigatran and this patient’s other risks for GIB: age and antiplatelet therapy…also note that stroke and intracranial bleediing are lower with dabigatran (and I would use a PPI dosed about 12 hrs after clopidogrel, albeit data quite poor). Nevertheless, this was the type of patient for whom the 110 mg bid dose would have been reasonable, despite FDA rejection.
Competing interests pertaining specifically to this post, comment, or both:
Speaker for BI
sorry..although changing one’s mind is unusual in these forums…I would probably avoid dabigatran if the above patient is on dual antiplatelet therapy. Very few of RE- LY patients were on both asa and clopidogrel.
Competing interests pertaining specifically to this post, comment, or both:
same
For patients like the above mentioned with coronary artery disease, the increased risk of coronary events observed in RE-LY (dabigatran 150mg vs warfarin HR=1.38, p=0.048)should be taken in consideration?
Competing interests pertaining specifically to this post, comment, or both:
none
There was a slightly higher MI rate with dabigatran than with warfarin. However, the vascular death and overall death rates trended lower with dabigatran. So, I’m comfortable with dabigatran based upon the published data to date.–SZG
The FDA mandated review found 4 more MIs. The recalculated nominal p value was 0.12. There were no more revascularization procedures in the dabigatran arm. The MI rate in the dabig group was comparable to lower than seen in other afib trials with warfarin.
More data should come forth with trials using dabig in ACS situations.
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speaker for BI
have u seen major prolongations of INR with Dabigatran?
Any serious GI bleeds and hematuria?
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SNY/BMS speaker
The INR can go sky high (to 4, for example) with dabigatran or with any direct thrombin inhibitor. But here’s the catch: the INR is meaningless except for warfarin. (Therefore, the INR should never be measured if a patient’s taking dabigatran.)
I’ve personally not encountered any GI bleeds or hematuria with dabigatran. Then again, the drug’s only been available since November 1, 2010.–SZG
Yes…a potential problem..as PT and INRs are often checked and those unfamiliar with dabigatran have on occasion given FFP. I have seen INRs even higher than 4. There is great variation of INRs on DTIs with some reported dependence on the lab’s reagents and the ISI.
We would not check an INR for a patient on argatroban, bivalirudin, or desirudin because we know the INR will be elevated and clinically meaningless. For the same reason, the INR should not be checked for patients on dabigatran.–SZG
Can patients with ectasia of coronary arteries and no occlusive disease be given Dabigatran to prevent thrombi in the ectatic segments ?
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No
Other than stroke prevention for patients with atrial fibrillation, dabigatran has no other FDA approved indication. And I would not prescribe off label dabigatran to prevent thrombi in the ectatic segments of coronary arteries.–SZG
As we know, patients with certain genetic determinats make them more sensitive to coumadin. Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 and of a key pharmacologic target of warfarin, vitamin K epoxide reductase, contribute to differences in patients’ responses to various warfarin doses. Are there any studies to determine if some patients are more sensitive to pradax than others?
Based on available data, there is no reason to suppose that dabigatran (Pradaxa) metabolism varies to a clinically important extent based upon genetic determinants. However, this is an emerging field of interest and the pharmacogenetics of dabigatran will, I’m certain, be studied for many years to come.–SZG
And see the blog discussion on Dabigatran at http://www.ghthomas.blogspot.com.