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Dabigatran: A Promising Alternative to Warfarin

On October 19, 2010, the FDA approved a long-awaited new drug, dabigatran, expected to replace warfarin (Coumadin) as a better way to prevent blood clots in susceptible patients. This provides an opportunity to re-visit several issues that we have addressed before, including Big Pharma tactics, drug approval by the FDA, deciding what is adequate evidence, applying science to clinical practice, and making individual health care decisions based on evidence that is sometimes incomplete.

Background

Patients with atrial fibrillation, artificial heart valves, deep vein thrombosis, pulmonary embolism, antiphospholipid syndrome, and people undergoing certain types of surgery are at risk of blood clots, embolism, and stroke. They are currently being treated with rat poison. Warfarin (Coumadin) is an anticoagulant originally intended to kill rats. It inhibits the vitamin K dependent synthesis of several clotting factors. It saves human lives but is a mixed blessing. It takes several days to achieve therapeutic levels. Patients must be monitored with frequent blood tests to ensure that their prothrombin levels stay between an INR (international normalized ratio) of 2 and 3. When starting out, this means blood tests every couple of days. For some patients, dosage fluctuates and requires frequent adjustments; others can eventually drop down to a monthly blood test. Warfarin interacts with a long list of other drugs that raise or lower its blood levels. It interacts with many foods, and patients have to modify their diet. It can cause serious bleeding complications; while preventing thrombotic strokes it can cause hemorrhagic strokes. It is taken once daily. There is an antidote, vitamin K, that can reverse its effects promptly.

Warfarin is the 11th most prescribed drug in the US. Its benefits clearly outweigh its risks, but we wish the risks were fewer. We have yearned for a better option: something safer, something that would not require monitoring with blood tests, something that foods wouldn’t interfere with, something that would not interact with every other drug in the book. And now it seems we have it: a direct thrombin inhibitor called dabigatran.

The Advantages of Dabigatran

Dabigatran is a pill taken twice daily as a fixed dose. It is immediately effective, versus the slow, several day onset for warfarin. No monitoring is required: no blood tests. It doesn’t interact with foods. It only interacts with a few drugs that affect levels of P-glycoprotein (such as rifampin, verapamil, and ketoconazole). Randomized controlled trials (RCTs) have shown that it is more effective than warfarin in reducing strokes and embolism and that it is less likely than warfarin to cause major bleeding complications. The difference is relatively small: the number of patients who would need to be treated (NNT) with dabigatran (rather than warfarin) to prevent one hemorrhagic stroke is approximately 370.

The Disadvantages of Dabigatran

It must be taken twice a day instead of once. Consistent timing of doses is important, because its effects wear off quickly compared to warfarin (its half-life is 12-17 hours vs. 20-60 hours for warfarin). It is more likely to cause dyspepsia (indigestion) and gastritis, and has a higher rate of major gastrointestinal bleeding (1.51% compared to 1.02% for warfarin). It costs about ten times as much as warfarin, around $200 a month.

Clinical Trials

The evidence has been consistently favorable and statistically significant. In the RE-LY trial, over 18,000 patients with atrial fibrillation were randomized to adjusted-dose warfarin treatment or dabigatran in two fixed doses (110 or 150 mg twice daily).In another trial, dabigatran and warfarin were compared in 2564 patients with venous thromboembolism. A meta-analysis of 3 trials showed that it was equivalent to injectable enoxaparin for preventing blood clots in patients undergoing elective hip and knee surgery.

Big Pharma and the FDA

Dabigatran has been available in Canada and Europe since 2008, and has been approved there for other indications like prevention of blood clots during surgery. The FDA has approved it only for atrial fibrillation. The FDA will inevitably be criticized for not approving it sooner, for costing lives by not making a better therapy available more quickly to US citizens. But it will be criticized for approving it too soon if post-marketing studies show unexpected problems. They can’t win.

It’s being marketed as Pradaxa by Boehringer Ingelheim. They stand to make obscene amounts of money before their patent runs out, but they had to spend obscene amounts of money to develop it. If they could not make a substantial profit they would have no motivation to create new drugs like this that may save a substantial number of lives. They were already aggressively advertising “Coming Soon” before the product was available on the market. There have been many discussions in the medical literature, some of which may well have been prompted by the manufacturer. It is to the company’s advantage to spread the word quickly, but it is also to the advantage of the provider and patient to learn when a better therapy is available. Big Pharma and advertising aren’t all bad.

Concerns

The FDA relied heavily on the results of one study to approve dabigatran for patients with atrial fibrillation. We try never to rely on one study, but in this case the study was particularly large, multi-center, well-designed, and supported by other related information. On the other hand, the study left some unanswered questions. It was open-label rather than double blind. The rate of complications with warfarin was higher in this study than was expected from the experience of previous studies. Might optimum control of INR have improved the warfarin results and lessened the apparent advantage of dabigatran? The average age of subjects was 71: might younger patients have different outcomes? The study lasted 2 years; might there be more adverse effects with longer use? A hazard ratio subgroup analysis indicated that warfarin was better than dabigatran for patients without hypertension and for patients in Europe: does this mean anything, or is it just noise in the data?

Real-world use is different from use in controlled studies. More people will be taking it, younger people, people with other co-existing health conditions, people who are taking other medications, people who may not comply with directions, people with different diets and lifestyles, people with different ethnicity or genetics, etc. As more people take it, rare adverse effects may become apparent. Post-marketing surveillance will be essential.

It has only been approved for patients with atrial fibrillation. Inevitably, doctors will prescribe it for off-label uses to include everything else that warfarin is used for. This is justifiable, but it would be nice to have pertinent studies. It is possible that the benefits may not be as great for other conditions as for atrial fibrillation.

The one-size-fits-all single dose may not be appropriate for every individual.

Conclusion

The Medical Letter has just reviewed the currently available information about dabigatran and concluded:

Fixed doses of the oral direct thrombin inhibitor dabigatran (Pradaxa) were at least as effective and safe as adjusted-dose warfarin in patients with non-valvular atrial fibrillation followed for a median of 2 years. Dabigatran, which does not require dose adjustment and close monitoring, could replace warfarin for this indication and probably others as well, particularly in patients with poor INR control. To what extent gastrointestinal adverse effects will limit its long-term use remains to be determined.

This does not fall under so-called “alternative medicine,” but dabigatran is an example of what “alternative” medicine should mean: a scientifically plausible, evidence-based alternative to warfarin.

Posted in: Pharmaceuticals

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29 thoughts on “Dabigatran: A Promising Alternative to Warfarin

  1. TsuDhoNimh says:

    Does the higher cost for the drug balance out if you take into consideration the cost of lab testing, and cost of hospitalization and treatment of complications of the drug?

  2. Shelley says:

    Interesting article. It should be noted that there is an alternative to lab testing in the form of a hand-held INR monitor. They’ve been around for at least a decade and allow the patient to easily track their INR and fluctuations in it on their own (a substantial advantage for younger patients and those who travel frequently).

    I’d also say that dabigatran sounds like an interesting alternative — but perhaps not for those who are well-stabilized on coumadin: There would be no advantages and you risk gastrointestinal problems. Just because something is NEW!! and IMPROVED!! doesn’t mean it is better for everyone.

  3. Calli Arcale says:

    Knowing my grandpa, if he hears about this, he’s gonna want to switch himself over. He always wants the latest. He’s been on Coumadin for, oh, probably fifteen years now following several episodes of DVT. My grandma is also on Coumadin after a series of strokes, but is very fragile for other reasons too; it’s possible she’d benefit more, but on the other hand, acid reflux disease runs strongly in the family — something that aggravates the stomach seems like a bad idea.

    Mind you, he could benefit from something that doesn’t interfere with food, because frankly his compliance in that area is terrible. He’s not supposed to drink alcohol, for instance, but he’s still a social drinker. And the holidays are approaching….

    I’m not terribly surprised this is so much more expensive; generic warfarin is one of the cheapest prescription drugs around. It’s quite possible the repeated blood tests exceed the difference in price, though. If you have a good health insurance plan, you might not care, but more and more people have insurance that leaves you paying more than just a $20 copay for an office visit; that can get spendy.

  4. Harriet Hall says:

    @TsuDhoNimh,

    The cost may balance out; we’re not sure yet because we only have opinions and estimates so far. And the cost will likely decline, especially when the patent runs out and generic versions are marketed.

    @Shelley,

    You say there would be no advantages for someone stabilized on Coumadin. Yes, there would, and I listed them above. The research indicates that for every 370 patients who switched, one would avoid a stroke. And don’t forget the advantages of not having to get blood tests, restrict diet, avoid interacting drugs, and readjust Coumadin levels after every change in other medications.

    I have a personal interest in this subject, because I take Coumadin (for antiphospholipid syndrome). My hematologist’s office uses the handheld devices, and I don’t like them. They require a finger stick that I find more painful than venipuncture. They have repeatedly failed, giving an “error” message and requiring another stick. Once, when a second device was used after the second stick, it also gave an “error” message. I would rather go to my regular lab and get a reliable venipuncture.

    Despite all these considerations, I haven’t decided whether I will want to switch. I have been very well stabilized on Coumadin and only have to get a blood test once a month. I generally prefer to wait a couple of years after any drug goes on the market, to see if problems arise.

  5. Toiletman says:

    Why don’t they sell an extended release one instead of making it necessary to take it twice daily? Hmmm I guess to milk the patent.

  6. Peter Lipson says:

    The cost does appear to balance out (citation).

  7. cloudskimmer says:

    Dr. Hall,
    It’s great for people who have no mobility problems to go in for a venipuncture, but for elderly people, going in a couple of times a week can be impossible. My mother was able to get a visiting nurse through Medicare, but the time ran out, and so her blood goes untested. She also has trouble remembering to take her medication, and her risk for falls makes me wonder if she should be taking coumadin at all. The nurse was very good, and since the reading is very fast, if it doesn’t register the first time, she could always squeeze out another drop of blood. And for an elderly, anemic person, I was concerned about the amounts removed during venipuncture.

    My mother probably won’t go on the new drug because it is wildly expensive, and she is now in the coverage gap, so has to pay full cost for her prescriptions. She certainly can afford it, and I will ask her Doctor during our next visit. When I think that 25% of that cost goes to advertising, it makes me mad every time I read a magazine. Other developed countries mandate affordable prescriptions (about 7 pounds in England–$12) but in the U.S. we still pay outrageous fees for huge drug company profit margins. And a lot of the research is done at universities; drug companies don’t bear the full cost of a new drug, do they? Will Canadians and Europeans be getting dabigatran for an affordable price? What will they pay?

    My big worry with blood thinners is that elderly people aren’t steady on their feet and a fall could cause uncontrollable hemorrhage. At what point is that risk greater than that of a blood clot? How can these risks be determined and a reasonable decision be made? (By the Doctor and patient, of course; I don’t want the Orwellian ‘solution;’ though that eventually triumphs when no one cares about the patient any more, and they don’t get treatment.)

    Why does the needle stick have to be taken from the finger? Can’t you get a drop of blood from your thigh or arm instead for a less painful sample?

  8. Woody says:

    One additional potential disadvantage of dabigatran would be the lack of an effective antidote, unless there is one available that I missed in your summary. Even though serious bleeding complications are less common with dabigatran, it still is an anticoagulant, and I suspect bleeding complications would still be serious in the setting of significant trauma. At least with coumadin you can reverse the anticoagulation predictably with vitamin K.

  9. ConspicuousCarl says:

    > Toiletmanon 16 Nov 2010 at 12:21 pm
    > Why don’t they sell an extended release one instead
    > of making it necessary to take it twice daily? Hmmm
    > I guess to milk the patent.

    I was going to write a longer detailed post to explain how confused you are, but I guess it is sufficient to say that making time-release pills does not represent a magical time-traveling act of reducing the cost of research done years before the first sale.

  10. Toiletman says:

    Why so angry? And what has that to do with my post and ad-hominem attacks are never nice. As if research costs would be an argument for that. They will already make enough money within the regular 10 years. Maybe it is a cultural thing but I personally think that patient benefit is more important than additional profits. And yes, I am talking of additional profits because this drug is very very likely to be successful and make enough profit especially because of the big European market, where drugs are usually covered by one’s insurance or state healthcare givers.

    @article author: Are there any reliable informations about the developing costs and how much of their capital is used for research and advertisement respectively?

  11. Harriet Hall says:

    @cloudskimmer,

    I wasn’t suggesting that the home testing devices are not a great idea for most people. I was only expressing my personal preference. In this, as in the pros and cons of treatment decisions, it is always important to consider the individual patient – “holistically.”

    @toiletman,
    I don’t have any information about developing costs and use of capital.

    To extend your argument, why not make every drug in an extended release form so that no drug is required more than once a day? There are many good reasons why this is not done: financial, technical and regulatory reasons. It simply is not practical. And extended release makes it impossible to quickly stop a medication if problems arise.

  12. ConspicuousCarl says:

    Toiletman:

    Anyone who wants financial information can just do a google search for the company name and net income or profit.

    Boehringer Ingelheim’s net income in 2009 was 15%, which was a step of from 12% the year before.

    You can look at more detailed reports to determine how much was advertising, but I personally tend to think that they are already trying to optimize their budgets vs. profit, and the end result was 15%. That’s higher than average, as most businesses typically make less than 10%, but it was also abnormal even for them.

    And nothing changes the impracticality of proposing that one-a-day pills will somehow mean that the seller doesn’t need as much money in total.

    If you don’t like “ad hominem” attacks, why don’t you try dropping them yourself? You vilify a whole bunch of people with your financially-implausible assertion. Instead of accusing them of milking sick people, your FIRST reaction should have been that which was your second reaction here–admitting that you don’t know how much money is involved in the entire process.

  13. Shelley says:

    @HarrietHall,

    I’m also personally interested in this as my husband has been on coumadin for nearly 20 years. He has a hand-held monitor and has seldom had the problems you mention, but he has been using a monitor at home for 10 years or so so he’s well accustomed to it. It has given him the opportunity to learn how his body responds to diet changes (when traveling etc) and allowed him to check his INR when on the road. He’s also been extremely stable on coumadin – so that helps a great deal

    I didn’t see a reference for the reduction in strokes, but I will go back and try to find the source for that article — I’m simply suggesting that we have long-term studies on coumadin. It works, and if someone is stable on it (they’ve got the bugs worked out in terms of diet and other medications), there might not be good reasons for changing.

  14. RE extended release and profits: I thought this was a well-known way to try to game the system. Get a drug approved as short release, then when the patent is about to expire get approval for the XR version. It doubles the patent protection for what is essentially the same drug.

    This has nothing to do with whether profits are immoral or who should be absorbing what costs or whether advertising is a net benefit. Just … isn’t deliberately withholding an XR formulation a recognized strategy? If so, why all the hate for toiletman?

  15. ConspicuousCarl says:

    “I thought / if so”

    Sometimes yes, sometimes no. In this case, you don’t know, and neither did he. So that’s one reason. He hates unknown people for uncertain reasons, I hate specific people for specific reasons. I am not sure why you might think my method is worse than his.

    However, Toiletman’s assertion was not just that there could be an all-day version (which he doesn’t know for sure), he implied that it would cost people less, which is silly and insulting for the reasons I already provided.

    And then even if you were right that the general claim applies to this case, proposing a shortened patent protection arrangement is an equally bad idea for reducing costs because then the manufacturer will just have to charge even more during whatever period they are able to sell it, and when politicians or activists complain as they always do, the manufacturer will be able to show all of the numbers to justify their pricing, as they always can.

  16. I didn’t propose a shortened patent protection system. What the deliberate-withholding hypothesis suggests to me is that rewarding companies with extended patent protection if they release an XR version early could be beneficial to patients.

    Say company A gets 10 years of patent protection for Drug A-SA and at year 9.5 gets 10 more years of patent protection for Drug A-XR. Patients then get 10 years of high-priced, inconvenient medication followed by ten years of a choice between high-priced and convenient and low-priced and inconvenient.

    Alternate scenario.
    Company A gets 10 years of patent protection for Drug A-SA. At any time they may introduce Drug A-XR and have patent protection for it from the time of its introduction until 10 years after A-SA has expired. This would give them up to twice as many years of patent protection for A-XR as under the usual system. In that extreme case, for the first ten years patients would be able to choose between high-priced and convenient and high-priced and inconvenient (a choice they don’t have in the usual system). For the second ten years they would have the usual choice: high-priced and convenient vs low-priced and inconvenient.

    Another alternate scenario:
    There is no A-XR formulation. A-SA is expensive and inconvenient for ten years and inexpensive and inconvenient thereafter.

    Like I said, it’s not about anybody being evil. If an unintended consequence of patent-protection laws is that useful innovations are withheld, maybe we want to look at that. Or not. Whatever. But under the current system, whenever a new drug is introduced that has to be taken at inconvenient intervals, the pharmaceutical company is always going to be subject to the suspicion that at the last minute they will discover that actually it’s possible to make an XR version. Which of course you will want to pay a lot extra for because the SA version is so bloody inconvenient.

    This might be completely unfounded for any given drug, but the suspicion will always be there because it’s realistic.

  17. Toiletman: Why don’t they sell an extended release one instead of making it necessary to take it twice daily? Hmmm I guess to milk the patent.

    ConspicuousCarl: Toiletman’s assertion was not just that there could be an all-day version (which he doesn’t know for sure), he implied that it would cost people less, which is silly and insulting.

    No, he didn’t imply that a once-daily XR formulation would cost anyone less than taking a twice-daily SA formulation twice. He implied that patent extensions were a motivator. Re-read what he wrote. ‘Milk the patent.’ Not ‘Bilk the patient.’

    No, none of us knows for sure, for this particular drug. But we all know it happens.

  18. qetzal says:

    I think there’s some truth to both sides of the argument. It’s pretty clear that drug companies will sometimes introduce extended release (XR) formulations near the time that their underlying patent on the drug substance is running out. Obviously, they’re hoping to maintain market share by convincing patients to switch to the new patented XR formulation, rather than go with the suddenly much cheaper short-acting (SA) generic.

    However, it’s also true that developing an XR formulation can be far from trivial. Developing the SA formulation first will usually get the drug to market substantially quicker. Of course, that allows the drug company to start selling that much sooner, but it also helps patients who get to benefit from the new drug sooner as well.

    So yeah, BI may well be taking a deliberate strategy to try to milk as much profit as they can. But in the end, that’s what they’re supposed to do – earn as much profit for their investors as they legally and ethically can.

    Besides, I wouldn’t say that simply going from twice daily to once daily dosing was that much of a convenience factor. Once the drug substance goes generic, BI might be able to get some premium for an XR formulation, but I doubt it would be very much unless there are more substantial benefits than just convenience.

  19. Xplodyncow says:

    Here’s the industry’s spin on how much money goes into R&D (see, e.g., p. 12):

    What goes into the cost of prescription drugs?

  20. BillyJoe says:

    Harriet,

    “I generally prefer to wait a couple of years after any drug goes on the market, to see if problems arise.”

    I see, let other’s take the risk while you just get the benefits :D

    On the other hand, if everyone decided to wait a couple of years….

  21. WilliamLawrenceUtridge says:

    I have a far, far greater issue with the dishonesty that goes into the marketing and research on a drug than I do with the cost. Drug companies are large and expensive for a variety of reasons and asking them to develop drugs but not make a profit is unreasonable.

    Of course, I’m young, healthy, live in Canada (try our health care, it’s great!) and have very good insurance, so…

    But still, let’s say I personally spent 10 years of my life, oh, writing a book. Because of time off of work, and I self-published, the total cost was on the order of $100,000 to produce 5,000 volumes. Am I going to sell them at $20 each, or release them as a PDF on the internet, or sell electronic versions at a discounted rate? If I sell them at $25 I gain a modest profit of $20,000 and doubtless that will be taxed. $20,000 (less taxes) for 10 years of my life. And what about my wife? She’s put up with the time taken to write this book, not to mention sinking a considerable amount of our money into it. And my kids, who have been wearing second-hand clothes and doing without team sports. Do I owe more to my audience who loves my book (particularly at $25 per book) or my family who actually helped me write it? How many people would try for $30, or $40 per book, perhaps producing special editions, alternate covers, illustrated versions, etc. in an effort to get something back for all that time spent?

    Drug companies are not evil for wanting to make a profit, particularly given a limited amount of time during which they can make a real profit that pays for the R&D costs. Of course, they also have to pay for the marketing, for which I have less sympathy. We have made it a habit to vilify drug companies – not without justification – but without them we wouldn’t have drugs.

    Life is complicated; “Big Pharma is evil” is certainly a simple answer, but ignores the fact that if a drug isn’t successful, it can bury the company. And the fewer companies that exist, the fewer new drugs that are developed. Arthur Allen’s Vaccine (ISBN 9780393059113) has some interesting information on the time and costs that go into making new vaccines – a large part of which is to offset expected litigation from the nutters (and justified individuals who experience the rare, but real side effects of vaccines, plus the few who have side effects unrelated except by time). Good book.

  22. BillyJoe
    “On the other hand, if everyone decided to wait a couple of years….”

    Even in medicine*, it seems some people are early adopters, early majority, late majority, laggards, etc. IMO – I believe that each segment of the population offers some benefit to the process. Early adopters tend to be more enthusiastic and that enthusiasm can carry them through some of the annoyances or concerns of dealing with a new product. Late majority and laggards, tend to be more skeptical and that skepticism can provide manufacturers with the motivation to improve their product enough to fit a broader audience.

    This is something I have been thinking about lately. Currently there is a newer technology for synthetic bone grafts that may offer a easier surgery for my son. Among plastic surgeons, the opinions seem somewhat split. Our surgeon would like to wait to see how the early adopter are doing over many years before using the material himself. Some surgeon and parents feel that science (and the FDA) offers enough information on what the long term results of the product will be to take advantage of the less painful surgery, quicker recovery times with the new product.

    *Although in medicine this might be determined by risk/benefit to the individual patient as much a patient personal preference.

  23. weing says:

    Nice review Harriet. I went for a drug company sponsored dinner last week and the information I received was as you have so nicely summarized it. The steak was great too. No, I haven’t prescribed it. I usually wait a number of months before prescribing a new drug like this.

  24. SDR says:

    Dr. Hall, thanks for writing this, if only for bringing the existence of dabigatran to my attention n.

    As an EMT in an area with many geriatric patients, I treat those who take Coumadin regularly, including treating the problems that as a physician you are aware come with the use of any blood thinners (uncontrolled hemorrhaging from injuries, GI bleeds, other hidden internal bleeding after trauma, etc).

    Thanks to you, if during assessment a patient mentions they take dabigatran I will be more prepared for these possible complications of which I might otherwise not be aware. As this drug becomes more commonly prescribed, I will be able to provide much better patient care to those who take it.

  25. BillyJoe says:

    micheleinmichigan,

    Well, I was joking, and didn’t expect Harriet to answer (as she hasn’t)

    I realise not everyone’s going to wait 2 years before trying it. There are, as you say, early enthusiasts and the late laggards and there probably always will be.
    Still, if the sceptical message gets out there….

  26. weing says:

    @BillyJoe,

    I follow the principle of not being the first nor the last one to prescribe a new drug. I recall Osler recommending the use of new drugs as soon as they come out, before they stop working.

  27. BillyJoe says:

    weing,

    Well, as long as you remember that in order not to be first, someone else, of necessity, has to be first. Your “not first” policy is absolutely dependent on people doing what you fundamentally disagree with.

    Doesn’t that worry you just a little bit? ;)

  28. BillyJoe – Oh, I see you even had a smiley face. It seems I’m often either taking people seriously when the are joking or thinking people are joking when they are serious. Must go in for maintenance on my social humor detection device.

  29. weing says:

    BillyJoe,

    There is an alternative approach. First, try the new med on the family cat. If it looks OK, try it on the dog. If it passes that test, try it on your mother-in-law. If still fine, try it on yourself first before starting a patient on it. :)

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