Dabigatran – Is It The Holy Grail We’ve Been Waiting For?

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Written By

Deborah A. Sturpe, PharmD, BCPS

Reviewed By

Jill S. Burkiewicz, PharmD, BCPS
Stuart T. Haines, Pharm.D., BCPS, BC-ADM

Citation

Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2010;361:1139-1151

Clinicians and patients alike have been anxiously waiting for an oral alternative to warfarin. That wait appears to be finally over. On October 19, 2010 dabigatran (Pradaxa®) was approved by the FDA and became the first oral direct thrombin inhibitor available in the United States. Unlike its predecessor ximelagatran, dabigatran doesn’t seem to cause liver toxicity. And unlike warfarin, dabigatran is administered as a fixed dose and requires no ongoing laboratory monitoring. Does this mean we have found the Holy Grail for anticoagulation therapy? Probably not. Currently, dabigatran is only approved for the prevention of stroke in patients with atrial fibrillation (A-Fib). Approval for the treatment of venous thromboembolism may be on the horizon, and studies are actively under way using the drug in a variety of other conditions commonly treated with warfarin. But for now, the use of dabigatran is (should be) limited to a relatively discrete population of patients. Let’s examine the literature.

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial was a phase 3, multicenter, international, randomized, controlled, non-inferiority trial that compared fixed dose dabigatran (at either 110 or 150 mg twice daily) with INR-adjusted dose warfarin (INR 2.0-3.0).1 Over 18,000 patients with A-Fib and at least one additional risk factor (previous stroke or transient ischemic attack, left ventricular ejection fraction < 40%, NYHA Class 2 or greater heart failure, age >=75, or age 65-74 with diabetes, hypertension, or coronary artery disease) were enrolled in the study. Overall severity of disease based on the CHADS2 scoring system was evenly represented between mild, moderate, and severe risk of thrombosis. Notable exclusion criteria included patients with severe heart-valve disorders, any condition that increased risk of hemorrhage (including history of gastrointestinal bleed in past year), blood pressure >180/100, recent or active malignancy, a specific indication for warfarin therapy other than A-Fib, and impaired renal function (CrCl < 30 mL/min). Thus the study population was not representative of the entire A-Fib population managed by many antithrombosis services. Nor were the study doses of dabigatran the same as the final FDA-approved doses. Although the 150 mg twice daily dose is recommended for those with CrCl > 30 mL/min, a dose of 75 mg twice daily for those with a CrCl of 15-30 mL/min was also approved.For this reason, we’ll only examine the data regarding dabigatran 150 mg twice daily vs. warfarin (INR 2.0-3.0).

Major efficacy and safety outcomes of RE-LY’s comparison of dabigatran 150 mg twice daily to warfarin (average time in INR range 64%) over a median two-year follow-up are as follows:

 

Drug favored

NNT or NNH

Event

per year

Stroke or systemic embolism (primary outcome)

D

NNT 172 for D

Hemorrhagic stroke

D

NNH 357 for W

Myocardial infarction

W

NNH 476 for D

Major bleeding (Hgb drop > 2 gm/dL; > 2 units blood needed; or critical organ bleeding site)

None

No difference

Life-threatening bleed (Hgb drop > 5 gm/dL; >4 units blood needed; intracranial; inotropes needed; or fatal)

D

NNH 286 for W

Major and minor bleeding (above plus all other bleeding)

D

NNH 58 for W

Gastrointestinal bleeding

W

NNH 204 for D

 

D = dabigatran      W = warfarin

In examining this data, dabigatran does offer an efficacy advantage over warfarin since statistical benefit was observed in the primary outcome despite the non-inferiority design of the study. Dabigatran is also less likely to cause life-threatening bleeding and hemorrhagic stroke. But of concern is the statistically higher incidence of myocardial infarction and gastrointestinal bleeding in the dabigatran group. Thus one benefit may quickly be erased by a harmful negative outcome. One must also consider if RE-LY’s outcomes were influenced by time spent in the therapeutic range (TTR) for those patients randomized to warfarin therapy. Wallentin, et al. conducted a pre-specified assessment of the RE-LY data to answer that question (TTR quartiles of <57.1%, 57.1-65.5%, 65.5-72.6%, and >72.6%)3, and the results for the lowest and highest quartiles are as follows:

 

HR (95% CI) for

Event

150 mg dabigatran vs. warfarin

(interaction for all quartiles)

Stroke or systemic embolism

 

 

     TTR < 57.1%

0.57 (0.37-0.88)

0.2

     TTR > 72.6%

0.95 (0.61-1.48)

 

 

 

 

Non-hemorrhagic stroke and systemic embolism

 

 

     TTR < 57.1%

0.54 (0.34-0.88)

0.076

     TTR > 72.6%

1.21 (0.74-1.98)

 

 

 

 

Intracranial bleeding

 

 

     TTR < 57.1%

0.53 (0.25-1.15)

0.89

     TTR > 72.6%

0.39 (0.18-0.34)

 

 

 

 

Major bleeding

 

 

     TTR < 57.1%

0.71 (0.52-0.96)

0.03

     TTR > 72.6%

1.16 (0.88-1.54)

 

 

 

 

Major gastrointestinal bleeding

 

 

     TTR < 57.1%

1.08 (0.70-1.66)

0.019

     TTR > 72.6%

2.00 (1.25-3.21)

 

 

 

 

Total bleeding

 

 

     TTR < 57.1%

0.89 (0.78-1.01)

0.15

     TTR > 72.6%

1.00 (0.89-1.12)

 

 

 

 

Stroke, systemic embolism, PE, MI, death, and major bleeding

 

 

     TTR < 57.1%

0.67 (0.56-0.80)

0.0006

     TTR > 72.6%

1.11 (0.91-1.35)

 

 

 

 

 

This data clearly suggests that as warfarin management improves, the advantage moves towards warfarin – particularly with regard to non-hemorrhagic stroke, systemic embolism, and gastrointestinal bleeding.

There may be other disadvantages to dabigatran. First, in the RE-LY trial, dabigatran was more likely than warfarin to cause dyspepsia (11.3% vs. 5.8%, p<0.001), and discontinuation rates were higher in the dabigatran group at both one and two years primarily due to serious adverse effects and gastrointestinal symptoms (15.5% vs. 10.2% at one year; 21.2% vs. 16.6% at two years).1 Second, although drug interactions are less likely with dabigatran as compared to warfarin, P-glycoprotein inhibitors and inducers can alter dabigatran levels.4 The clinical significance of these interactions is unknown as the RE-LY study did not include information about concurrent use of many of these drugs. Moreover, the population of patients taking a proton pump inhibitor in the RE-LY study did not appear to gain additional benefit from dabigatran as did other subgroups (which could simply be due to the small sample size, but further evaluation is warranted). Third, there is no reversal agent for dabigatran. Fourth, long-term effects of the drug are still unknown. And finally, there is the question of cost. A recent cost analysis published in the Annals of Internal Medicine suggested that dabigatran may be cost-effective when compared to warfarin if the 150 mg dose is priced at less than $13.70 per day5 (of note, recent news articles report the average wholesale price of both strengths of dabigatran to be $6.75 per day6). “Cost effectiveness” in this study was reported as $45,372 per quality adjusted life year gained.  However, information was not given regarding the estimated drug cost of warfarin – leading one to wonder if the cost of brand name Coumadin or generic warfarin (available for $4 per month a many community pharmacies) was used in the analysis. Further, the manufacturer of dabigatran has not released information about whether the drug will be available through a patient assistance program. In my opinion, that clearly leaves warfarin as the preferred drug for uninsured patients.  In our current healthcare system, it is often easier to help these patients access anticoagulation management programs than expensive medications.

So is dabigatran the Holy Grail we’ve been waiting for? For me, it’s not even close. The first consideration is affordability, since in my opinion inability to access the drug eliminates any need to even have a debate about dabigatran vs. warfarin. And even in patients who can afford the drug’s cost, I would only recommend it for those patients who closely meet RE-LY’s inclusion and exclusion criteria AND meet all of the following characteristics:

  1. Normal renal function (since the FDA-approved 75 mg dose was not studied in RE-LY and no outcome data is available in other published clinical trials)
  2. Low gastrointestinal bleed risk (due to the higher incidence in the dabigatran group and the lower efficacy trend observed in patients on proton pump inhibitors)
  3. Inability to gain good INR control on warfarin and/or lack of access to routine INR testing.

Otherwise, I feel there are simply too many unknowns about this new therapy compared to our standard of care. Warfarin remains the best bet for most patients! What do you think?

Comments

8

<p>I reviewed the RE-Ly study myself and I wasn't impressed. I was actually very disappointed because this new drug&nbsp;was widely promoted to bring an end to warfarin. I work at a rural government hospital and acquisition cost of dabigatran will be an issue. Also, it is currently only approve for use in Afib patients while warfarin has so many indications.</p> <p>I am not giving up hope yet on Dabigatran.</p>

<p>First of all, I'd like to extend many thanks to Dr. Sturpe for a great review.&nbsp;</p> <p>I do agree with the general overtone that both Dr. Sturpe and some others have come to agree on about the limitations regarding dabigatran regarding costs, side effects, etc. However, we must remember, in the patient population where this drug is indicated and safe it will provide an invaluable advantage to those patients who don't want to restrict their Vit. K diet and want to go back to living that "normal life" where they can eat whatever they want. I couldn't tell you the amount of patients I saw working in the coumadin clinic this past summer (as a student) who were on pill regimens with 10+ pills, but really only cared about stopping one of them... the coumadin.&nbsp;</p> <p>Overall, great review... I look forward to seeing more literature and actually seeing this drug clinically to form a more "practice based" opinion.&nbsp;</p>

<p>Great review and I agree with everyone so far that this is not the "warfarin-killer." As with most new drugs, cost will be the deciding factor. Those who can afford, or&nbsp;are willing to pay the large co-payment will choose dabigatran. The luxury of eating all the greens you want and not having to get your INR checked will come at a price, and many people will pay for that. However, the majority will prefer to pay $4 for their warfarin and let their insurance company pick up the tab for the INR monitoring. Dabigatran will be a reasonable choice for a) those who can afford it, b) people who are unstable on warfarin (despite best efforts to improve INR stability), and c) people at low risk of GI bleed.</p> <p>In my mind, this all gets more interesting once other agents become available (rivaroxaban). We will go from 1 primary agent of choice to 3 or 4 options. Then what? Comparative data will take awhile, and this will all get much more complicated. Until then...warfarin remains option #1</p>

<p>Excellent review but would also point out:</p> <ol> <li>Lancet article focuses on time in range by center (cTTR) and not individual time in range (iTTR) even though the latter is reported in the paper, it just is not emphasized or included in the table. &nbsp;The top 50% of patients (by iTTR) in rely actually had better outcomes than did either dabigatran arm (see&nbsp;<a href="http://clotcare.org/warfarin_vs_dabigatran.aspx">http://clotcare.org/warfarin_vs_dabigatran.aspx</a>).</li> <li>Why iTTR rather than cTTR? &nbsp;Because a good cTTR may mask the fact that iTTR values are widely variable and several recent reports have shown that event rates are several times higher in the 1/4 to 1/3 of patients with the lower iTTR values. &nbsp;For example, two recent articles by Dan Witt and his group (Blood 2009; 114:952-6 and J Thromb Haemost 2010; 8:744-9) reported a cTTR of about 65% but that was because a minority had iTTRs of 100% while the mean TTR for the remaining majority was &lt; 50%; and these patients had about 3 times the major event rate. &nbsp;Available data suggest that patients with an iTTR below some threshold (perhaps an iTTR &lt; 60%) may receive more harm than benefit from warfarin therapy. &nbsp;I believe that we should identify such patients and do what we can to improve their INR control or consider stopping warfarin or maybe even change to dabigatran if we must.</li> <li>40% of RE LY patients were on ASA at the start of the study and 20% took ASA throughout the trial. &nbsp;We know that ASA increases bleeding risk with warfarin and, based on prior data from ximelagatran studies, it is reasonable to suspect that ASA may have reduced the MI rate with dabigatran.</li> <li>We need to change how we manage warfarin. &nbsp;It appears to be feasible to reduce major events in warfarin patients by at least 50% while greatly improving the efficiency of management for both patient and clinician. &nbsp;We and 3 other groups have reported on combining patient self-testing with online management in achieving such results. &nbsp;We have been managing warfarin the same old way for more than 30 years and it is cumbersome, wasteful, and dangerous. &nbsp;We should adopt moden methods that can routinely achieve an iTTR of &gt; 75% while virtually eliminating INRs &lt; 1.5 or &gt; 5 and do so with 10 min/wk for patient self-testing and creating a virtual clinic visit and &lt; 10 min of clinician time/month.</li> <li>Vitamin K restriction (as suggested in a prior comment) only serves to make the INR unstable. &nbsp;We encourage patients to eat a healthy amount of vitamin K (or take a daily vitamin K supplement) and to just be consistent in the types of food that he/she eats.</li> <li>Do we really want to use an anticoagulant with an effect that we can neither monitor nor reverse?</li> </ol> <p>Best wishes, "Henry the contrarian" :)</p> <p>&nbsp;</p> <div>&nbsp;</div> <p>&nbsp;</p>

<p>Well said Deb - where is the efficacy data for a 75mg dose when those patients were clearly excluded from RE-LY?&nbsp;</p> <p>The hype reminds me of when Chantix first came out... and then phase IV data became available.</p>

<p>The drug has great potential however as stated above there are still a lot of unanswered questions. Is there a need to monitor this drug (even though the company states there is no need)? One has to take into consideration that AUC and bleeding rates correlate, the drug's serum level correlates directly with affects on coagulation parameters, it is 80% renally elimnated as unchanged drug and clearance is determined by renal function, it is unstudied in patients with creatinine clearnace less than 30ml/min (although approved by FDA for such patients). Also there is a lack of flexibility of dose adjustments due to only two dosage strengths. Practioners may not want to rush and place every afib patient on warfarin until we have some more answers.</p> <p>.</p>

<p>I agree with the points made...</p> <p>The one outstanding question I have is related to adherence. With the short half-life of dabigatran and the need for consistent BID dosing the providers in my practice, including myself, are curious how adherence was assessed. Typically, my warfarin patients are an adherent bunch b/c the monitoring factor encourages a sense of accountability. The reduction in stroke from RE-LY is impressive, but they didn't (at least from what I've reviewed thus far) address adherence rate and if their population was "freakishly adherent"; I wonder if "realworld adherence" (paricularly when patients hit the Medicare gap or have to hold off getting the prescription due to the high copay/cash price) would&nbsp;make the margin&nbsp;less impressive? I agree that the apparent benefits don't outweigh the risks/cost.</p> <p>I don't get the sense from the family medicine providers I work with, that this is a medicine they are going to gravitate toward.</p> <p>Thank you for providing such a great venue to discuss ambulatory care topics!!!</p>

<p>Great review, found it to be very helpful. Also will be interesting to see&nbsp;whether&nbsp;rivaroxaban or apixaban (direct factor Xa inhibitors)&nbsp;if approved will become&nbsp;the new&nbsp;"warfarin killers". Both are&nbsp;have been studied or are being studied in some&nbsp;similar indications as dabigatran...would also be interesting to see how these two compare (direct thrombin inhibitors vs. direct factor Xa inhibitors).</p>

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