Dabigatran hits the market...

****THIS IS NOT FOR ANTICOAGULANT THERAPY FOR DVT AND PE
but they think in the next 6 month***



Dabigatran Q&A: The who, when, and how for switching, starting, and stopping the new oral anticoagulant
November 3, 2010 | Shelley Wood

New York, NY - Dabigatran (Pradaxa, Boehringer Ingelheim) will be available in both Canadian and US pharmacies as of today for its newly approved indication: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the manufacturer, Boehringer Ingelheim, has announced [1]. The company has also said the drug will be priced at a "wholesale-acquisition" cost of $6.75 per day, lower than expected based on the up to $12/day price in markets where it is already approved for limited duration use after hip and knee surgery.
Dr Michael Ezekowitz

Physicians who've waited decades for an alternative to warfarin now have a host of questions about how to use the drug and in whom. heartwire put some of these to Dr Michael Ezekowitz (Lankenau Institute for Medical Research, Wynnewood, PA), co-principal investigator on the pivotal RE-LY trial.




heartwire: How do you switch a patient from warfarin [Coumadin, Bristol-Myers Squibb] to dabigatran?

Ezekowitz: Switching patients from Coumadin to dabigatran is relatively easy—all you have to do is measure the [international normalized ratio] INR. If the INR is 2 or less, you can switch the patient immediately to dabigatran. The patient needs to take the dabigatran twice daily, so what I recommend is that the first dose be taken first thing in the morning or at night, and usually we recommend that the patient take the medication either with food or something to drink.

H: How swiftly does dabigatran reach therapeutic levels?

E: Dabigatran becomes therapeutic within 30 minutes to two hours of oral administration, so it is pretty immediate.

H: What if a patient misses a dose?

First of all you want to encourage them never to miss a dose: they need to take it in the morning and in the evening very consistently. If they miss a dose, generally what we recommend is that if the dose is missed and the next dose is needed within the next six hours, they can wait until the next dose. So for instance, if the patient misses the morning dose then realizes at 3 o'clock in the afternoon that he missed a dose, then generally what we would recommend is that he take the next dose in the evening. However, if he realized at 10 am that he should have taken his dose at 8 am, it's perfectly okay for him to take the dose at 10 am.

H: How long do you need to wait after stopping dabigatran before surgery can be performed?

E: Generally, if it's elective surgery and the patient has normal kidney function, we recommend that he miss two doses of the drug. If the kidney function is abnormal, he should miss three and maybe four doses of the drug: in other words, two days' worth of the medication.

H: Do you have any insights into what compliance will be like, given the twice-daily dosing?

E: I think that patients and physicians need to be educated that it's important to take the drug twice a day, in the morning and in the evening. There are many medications that require twice-daily administration, and generally the adherence of the motivated patient is very good. But I think it's a matter of the education of the patient and the doctor.

H: What do you make of the FDA's decision to approve that untested 75-mg dose?

E: In the RE-LY trial, we did not test the 75-mg bid dosing. We tested a 110-mg bid dose, which was not approved. What the FDA did, and they did this unilaterally, frankly without our input, is that they modeled the kinetics of the drug against renal function, creatinine clearance, and then in the package insert made the recommendation that if the creatinine clearance was between 15 and 30 [mL/min], a reduced dose of the drug was recommended and that was 75 mg bid. I think what it does is it broadens the patient population that can be treated with benefit with the drug. So I think it's a good thing. Was it a surprise to us? To me, it was a complete surprise.

H: What do you make of the FDA's decision not to approve the 110-mg dose?

E: Initially, I was disappointed. . . . I thought that the option of having a lower dose might be of benefit. But on reflection, I think the label that was approved by the FDA was an outstanding label for the practicing physician, because it greatly simplifies the use of the drug. You use 150-mg bid in patients who have a creatinine clearance of 30 and higher and if their creatinine clearance is between 15 and 30, all you have to do is use the 75-mg bid dosing. So it's a very simple drug to use.

H: Are there any drug-drug interactions or contraindications that you want to highlight?

E: The only drug that is contraindicated is rifampicin, because it induces the p-glycoprotein enzyme and actually increases the removal of the drug by the gut from the blood via a complicated mechanism. But in all other respects, there are no other significant drug-drug interactions, and there are no warnings in the FDA label.

H: Do you have any advice for how to reverse a bleeding event?

E: If a patient bleeds, the first thing to do is to stop the medication, because the blood levels drop fairly rapidly after you stop the medication. The second thing is, you use general medical common sense and apply local measures to any area that may be bleeding, just as you would normally do. Generally, based on the results of the RE-LY trial, the bleed rates were lower in patients who were randomized to dabigatran, as compared with those randomized to warfarin, so that's what we generally do.

If the bleeding is catastrophic, which occurred in one patient in the 18 113 studied in the RE-LY trial, it is possible to dialyze the patient, because dabigatran is dialyzable. There is no specific antidote.

H: Do you have any insights into how insurers will cover this?

E: The point is that dabigatran is much better than Coumadin in the sense that the risk of intracranial bleeding is reduced by about 60%. There will be a cost differential, and I'm not sure what the status is with respect to reimbursement—you will have to ask the company about that. [Editor's note: a cost-efficacy analysis was reported earlier this week by heartwire.]

H: Any specific recommendations for patients who have received a drug-eluting stent and are already taking both aspirin and clopidogrel?

E: About 8% of the patients who were in the RE-LY trial were being treated with clopidogrel; the use of clopidogrel at study entry was not a contraindication. As far as triple therapy is concerned, we don't have data yet from the RE-LY trial on patients who were on triple therapy over the course of the trial; however, for the study as a whole, there was a bleeding advantage in favor of dabigatran over warfarin, particularly when it came to intracranial hemorrhages, so I doubt very much that dabigatran would be a disadvantage, compared with warfarin, for triple therapy. But this is a question that really needs to be definitively addressed at some point.

H: Do you have any insights into who could or should be switched off warfarin to this drug and any patients who shouldn't?

E: Well, the decision to switch the patient from warfarin to dabigatran rests with the patient's doctor and the patients themselves. There is a clear advantage to using dabigatran: you have a 34% reduction in stroke, a 60% reduction in intracranial bleeds, and fewer bleeds in general. The patients who are contraindicated are those patients who have a creatinine clearance of less than 15—those are patients who are generally headed toward dialysis—and also patients who have mechanical heart valves, were not entered into the trial and should not be treated with dabigatran. All the rest are certainly candidates for dabigatran therapy, and I anticipate that the uptake of the drug will be very rapid.

H: The major barrier will be the price, would you agree?

E: The issue of cost is of course very important for all elements of healthcare and the proportion of the cost of the drug . . . that is borne by insurance companies and Medicare will obviously be key with respect to patients. That is a question that unfortunately, at this early stage, I don't have direct knowledge of.

H: Do you know of any trials looking at the use of dabigatran in patients with mechanical heart valves?

E: Yes, I understand it is one of the priorities of the company and that they are organizing a trial that will involve mechanical heart valves in patients who also have atrial fibrillation.

This Q&A was prepared in collaboration with theheart.org's forum moderator and blogger, Dr Melissa Walton-Shirley.
Ezekowitz disclosed working "with all the companies that make or are trying to make oral anticoagulants." He received research funding from Boehringer Ingelheim and is also on its speaker's bureau, although he noted that he has not yet given a talk about dabigatran.

« Previous heartwire article
Simple stroll down the hall can reveal which surgery patients are at highest risk
Nov 2, 2010 16:00 EDT Next heartwire article »
Go, team! Outcome gains seen with cardiologist-GP collaborative care early post-HF discharge
Nov 3, 2010 11:30 EDT
Source

1. Boehringer Ingelheim. Boehringer Ingelheim's Pradaxa available in US pharmacies starting Wednesday, November 3 [press release]. November 1, 2010. Available here.


Related links

* Pradaxa prescribing information
* Dabigatran for stroke prevention in AF passes cost-effectiveness test
[Thrombosis > Thrombosis risk; Nov 01, 2010]
* Canadian update to the AF guidelines: Role for dabigatran already in place
[Arrhythmia/EP > Arrhythmia/EP; Oct 26, 2010]
* FDA approves dabigatran for stroke prevention, embolism, in AF patients
[Arrhythmia/EP > Arrhythmia/EP; Oct 20, 2010]
* Oral anticoagulants REDEEMed? Daily dabigatran "safe" with dual antiplatelets after MI
[Site Structure > Homepage; Nov 19, 2009]
* RE-LY: Post hoc analysis confirms benefit of dabigatran relative to warfarin at all INR levels
[HeartWire > Medscape Medical News; Nov 17, 2009]
* RE-LY: Oral antithrombin dabigatran outshines warfarin in atrial fib
[Brain/Kidney/Peripheral > Brain/Kidney/Peripheral; Aug 30, 2009]



Your comments


Dabigatran Q&A: The who, when, and how for switching, starting, and stopping the oral anticoag



# 1 of 14

November 3, 2010 10:33 (EDT)



karl kaos

converting from dabigatran to warfarin
Since the rate of discontinuation of dabigatran due to adverse events exceeded 20% at 2 years in the RE-LY study, patients may need to be switched to warfarin. According to the package insert labeling, when converting from dabigatran to warfarin the starting time of warfarin needs to be adjusted based on creatinine clearance:
• For CrCl >50 mL/min, start warfarin 3 days before discontinuing dabigatran
• For CrCl 31-50 mL/min, start warfarin 2 days before discontinuing dabigatran.
• For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing dabigatran.
• For CrCl <15 mL/min, no recommendations can be made.


# 2 of 14

November 3, 2010 10:40 (EDT)



David Cohen

Very helpful
Thanks very much for posting this very practical dialog. This addresses many of the nitty gritty questions that are hard to glean from the trial and is an outstanding service to the community of practicing physicians


# 3 of 14

November 3, 2010 11:23 (EDT)



Christopher Cannon

Superb
This is a TERRIFIC primer on the use of this important new drug. A+ to Dr. Ezekowitz and to theheart.org!


# 4 of 14

November 3, 2010 11:59 (EDT)



Weiss Robert

Price
The monthly price is about $250. This will take many patients in the doughnut hole where they will stop the drug. Is a $4/month drug + INRs safer than a $250/month drug that patients may be financially forced to miss?


# 5 of 14

November 3, 2010 12:09 (EDT)



Guess Who

Just in time information--THANKS!
I'm a patient who is extremely happy to come off warfarin after 5 years with a-fib (converted). Yesterday, I was just about to go on 150mg b.i.d., and my physician did not have any startup information. I had a hard time finding any information about converting from warfarin, as the pradaxa.com site was quirky yesterday (it's fixed today--click on "full prescribing information" button to get the package insert information). My INR had just been measured as 3.0, so it was fortunate that I was able to find the full information on my own so that I could wait until my INR drops below 2.0 to begin with dabigatran. But, other prescribing practitioners, pharmacists, and patients might not have been able to find this information easily. So, you have performed a real service as regards converting from warfarin and other helpful information. Again, THANKS! (Steve Goldstein, Ph.D.)


# 6 of 14

November 3, 2010 12:34 (EDT)



roberto hoffman

monitoring
How do you know this drug is working as antithrombin as needed ? I know you don t need to check often for the INR as with coumadin but perhaps you want sometimes to know how is it working Is the D Dimer helpful ?


# 7 of 14

November 3, 2010 02:06 (EDT)



Joseph Catapano

DVT? NVAF ?
Any studies about Dabigatran for DVT and/or pulmonary embol?
What is the exact definition of valvular atrial fibrillation?


# 8 of 14

November 3, 2010 06:30 (EDT)



vern chichak

vka
if the vitamin dependent clotting factors are 2, 7 9, and 10 and coumadin is initiated, won't it take as long as the longest half life of these clotting factors to see a therapeutic effect and therefore still take several days to get to a inr of 2-3?, the reversal of the anticoagulant effect is much more rapid as all of the clotting factor ie 2, 7, 9, and 10 are present except for the final carboxylation step which requires vit k. please let me know the reference for the tinimg of the initiation of coumadin as it relates to stopping dabigatran and starting coumadin?


# 9 of 14

November 3, 2010 09:37 (EDT)



mori krantz

Freedom of choice?
It will be interesting to watch the clinical development programs for factor Xa inhibitors like Apixaban, and Rivaroxaban (recent trial suggests non-inferiority in Afib to warfarin). Dabigatran, a direct thrombin inhibitor, may become one of a number of choices for our patients.


# 10 of 14

November 4, 2010 02:08 (EDT)



Nabil Kamas

To Joseph Catapano
First of all, a big thank you to heartwire and Dr. Melissa Walton-Shirley and especially to Dr. Ezekowitz for this great set of useful information. For Mr. Joseph Catapano: The RE-Cover trial is investigating the role of Dabigatran in acute VTE (DVT/PE). And valvular AF is simply atrial fibrillation on top of heart valve defects.


# 11 of 14

November 4, 2010 09:47 (EDT)



Aaron Doonan

Should we use this in the setting of triple therapy?
The RE-LY trial showed a significant increase in MI in the high-dose group as compared to warfarin. Until the mechanism of this is elucidated (or hopefully refuted entirely), I doubt that prescribing this drug in patients with known CAD that have had PCI requiring clopidogrel or prasugrel would be advisable.

However, I don't know if the relatively small subgroup taking clopidogrel had the same increase in MI as those patients not taking it. I wonder if the addition of clopidogrel would "protect" these patients from the increase in MI seen in the entire patient population...


# 12 of 14

November 4, 2010 10:16 (EDT)



D Hackam

dabigatran, warfarin and MI in RE-LY
Warfarin has a 50-year track record for preventing MI (going back to the 1960s and studies from Scandinavia, and much more recent studies like ASPECT-2, WARIS, APRICOT, etc). The head-to-head comparison with dabigatran showing increased rates of MI in the dabigatran group was not placebo-controlled, so it cannot be said that dabigatran increases MI, just that it lacks the protective effect of warfarin on MI rates. We need more data on the efficacy of adding antiplatelets to dabigatran and I believe this will come from forthcoming studies in ACS patients.


# 13 of 14

November 4, 2010 11:15 (EDT)



Abdulmalik Abdulrahman

Use of dabigatran in STEMI.
In case of ACS (STEMI)in patient taking dabigatran is it possible to give thrombolytic therapy?


# 14 of 14

November 4, 2010 01:58 (EDT)



Denis Rochon

Cost with really dictate the outcome of Dabigatran...
A study just came out in Canada,http://www.ncbi.nlm.nih.gov/pubmed/20663051?dopt=AbstractPlus
stating that the direct and indirect cost for managing long term warfarin use is $5.60/day which is a SHARED cost(patient,lab work for INR,society) and now we see with this post that Dabigatran's $6.75/day will be strictly the patient's cost.
The other thing is the "No antidote" what if an EMERGENCY procedure is needed,stat, or a person is involved in a car accident and is bleeding internally, how do you apply PRESSURE???(not measure).