Some Remaining Questions About Dabigatran

Yesterday’s approval of dabigatran (Pradaxa) has been long awaited in the cardiology community. Although just about everyone agrees that a good alternative to warfarin is highly desirable, there are many remaining questions about the drug as it prepares to enter the marketplace.

Here are a few questions raised by electrophysiologist John Mandrola on his blog:

  • In the RE-LY trial, dabigatran was used twice daily.  When not symptomatic, patients often find it difficult to remember their second daily dose.  Will compliance limit dabigatran’s effectiveness? Will once daily dosing work as well as twice daily?
  • In RE-LY, 12% of dabigatran patients reported GI discomfort (‘dyspepsia’). This was double the rate of warfarin. Will this be clinically significant?
  • Does dabigatran increase the risk of MI (heart attack)?  In RE-LY, patients in the dabigatran cohort were at slightly higher risk for MI.  In the 150mg (higher dose) dabigatran group the p-value barely reached statistical significance. (Translation: we don’t think dabigatran increases the risk of MI, but we are not quite sure yet.)
  • Dabigatran is cleared mostly by the kidneys.  Therefore, patients’ with chronic kidney disease (CKD), by virtue of higher blood levels of the drug. will be at increased risk for bleeding. Dosage adjustments will need to be made, and patients’ with severe kidney disease will not be candidates for dabigatran.  Outside of clinical trials, using renally-excreted drugs is challenging.  How will this sort out with widespread use of dabigatran?
  • Will dabigatran be useful in many other warfarin-treated diseases?  Things like mechanical valve protection, stroke prevention in LV aneurysms and hypercoaguable states (like Factor V Leiden)?  Probably the answer will be yes.  We’ll see.
  • But the real elephant-in-the-room will be cost.  Who will bear the brunt of the extra cost?  How much extra out-of-pocket cost will patients tolerate to free themselves from “rat poison,” and to reap the benefits of dabigatran’s improved stroke prevention and lower risk of intracranial bleeding?  (The cynic in me says not that much.)

Digging a bit deeper into the “real elephant-in-the room” issue of cost, electrophysiologist Westby Fisher in his blog had this to say:

…my bet is that it’s going to cost about ten times that of warfarin – I’d estimate $6 to $9 per day (another author suggested the anticipated cost of dabigatran in the United States, as calculated on the basis of its cost in Canada, would be approximately $7,000 to $9,000 per patient-year (four to five times the cost of warfarin, despite the increased physician and laboratory costs required to monitor the international normalized ratio [INR])). One researcher from the RE-LY trial countered:

It should also be kept in mind that total direct and indirect costs for management of anticoagulation with warfarin far exceed the cost of the drug. In a recent study, the direct costs during the first year of anticoagulation with warfarin in primary care were calculated at Swedish krona 16,244, corresponding to U.S. $2,230. This does not include expenses to patients for travel to the laboratory, lost time from work, or an accompanying caregiver.

Given its cost, I suspect it will be hard for insurers to swallow this drug at first and coverage may not be immediately available, but hopefully the superior convenience and stroke prevention will justify the drug’s initial price. Fortunately, other thrombin inhibitors will soon arrive to offer price competition to dabigatran’s exclusive first-to-market reign.

Finally, there’s another issue that is sure to come to the forefront soon. As Mandrola drolly observed:

It’s just a hunch, but the dabigatran launch will likely make the Multaq carnival look like a mere parish picnic.

I’ve written extensively about the overpromotion of dronedarone (Multaq) on this site in the past, but Mandrola is surely right. Pradaxa has clear blockbuster potential and it appears likely that Boehringer Ingelheim will heavily promote the drug. Much of that promotion, it should be noted, will be perfectly legitimate. But, as I wrote a few weeks ago, BI has already started preparing the market by using a soap opera star to promote awareness of AF, and it appears likely the company will rely (no pun intended) heavily on direct-to-consumer advertising.

And take a look at StopAfib.org, a “patient-driven” site for AF patients. The site makes the following claim:

We’re not pushing products or services, or selling things here, and we do not accept advertising.

But the site appears to be heavily dependent on industry funding (including, in addition to Boehringer Ingelheim, AtriCure, Bayer, Medtronic, and Sanofi) and since shortly before the September FDA advisory committee meeting the site has been incessantly and breathlessly promoting Pradaxa as a breakthrough for patients. A quick look at its Twitter feed shows that the organization has become a cog in BI’s marketing campaign to consumers. The site was a co-sponsor of the heavily promoted event with the soap opera star and of course was completely uncritical in its coverage of the event. This appears to be just a foretaste of what we will be seeing much more often going forward.

Update, 7:15 PM: Westby Fisher wrote to let me know that he had written about StopAfib.Org and its founder back in 2007. You can read his post here. If you read the whole post, and the comments, you’ll discover that there’s some ambiguity about the precise status of the site and its relationship to industry. My own belief is that unless the site is completely transparent and reveals all the details of its relationships with industry (including all dollars amounts) then it is impossible to take it seriously, except as a representative example of the pernicious nature of commercial influence.


Comments

  1. As mentioned, there are issues that remain unclear at the present time. The risk of MI is unknown, but I don’t believe that there was any correction for Type I errors in the analysis of secondary endpoints in RE-LY. Seems this was not a great concern to the FDA or the FDA reviewers.

    And dabigatran was most effective in populations who had poorly controlled INRs.

    What remains unknown is the best way to reverse the anticoagulant effects in a severe bleeding situation.

  2. Dan Hackam says

    John I think most misunderstand p values. When something has a p value of less than .05 it does not magically mean it’s the “truth”. That was connoted in what you wrote “we don’t think dabigatran increases the risk of MI, but we are not quite sure yet”. One has to take into account everything we know about this drug including earlier phase trials and, most importantly, ongoing studies in ACS patients. Ximelagatran was also (falsely) accused of increasing MI rates, but it actually reduced them in ESTEEM in a post-MI population (on top of aspirin and other therapies).

    It is remarkable how it’s become the case that p.05 means “no”. This is a complete misunderstanding of statistics as applied to clinical trials and experimentation.

  3. My last patient in Egypt with massive pulmonary embolism due to DVT , received Pradaxa 150 mg bd after successful thrombolysis, 10 days of heparin and after one month of warfarin he was complaining about weekly testing, put him on dibagatran, 3 weeks later he developed acute DVT and pulmonary embolism and had to be shifted to warfarin again, the patient weighed 130 Kg, I contacted Boehringer, they have no data on obese patients! Point of the story: stick to the currently approved indications, it is not going to replace Warfarin in most patients

  4. Our facility was a study site for RE-LY. I suspect that after use in a larger population in ‘real life’, outside of a trial, that the incidence of bleeding may be higher. Time will tell. But I’d be reluctant to be an early adopter of this medication.

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