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Why Pradaxa is not a bad drug

| Meds | May 23, 2012

It’s crazy out there in blood thinner land.

The novel blood thinning drug for patients with atrial fibrillation, dabigatran (Pradaxa) cannot get a break.

It’s all over the TV: Pradaxa = Bad drug.

Look at this image:

Why Pradaxa is not a bad drug

On the prestigious heart news site, theheart.org, an insignificant 113-patient study presented as a poster at a small symposium — by a researcher with ties to anti-coagulation clinics — gets attention because a few patients on dabigatran developed well-known complications. Though the author makes important points, namely, that blood-thinners should be used cautiously and patients should be well-informed about the risks and benefits, the study added nothing to what is already known about dabigatran.

Gosh. I can’t believe I feel a twinge of empathy for a Big Pharma company.

Here’s a news flash.

Dabigatran and rivaroxaban are blood thinners. They lower the risk of stroke, but increase the risk of bleeding. It’s the same for warfarin. When these two agents were compared to warfarin in huge randomized controlled clinical trials, they both looked favorable.

For my entire career, I have heard the downsides of warfarin. Now, we have two drugs that prevent more strokes than warfarin, don’t require blood checks, have no dietary interactions, minimal drug-drug interactions and are not used to poison rats. Do they worsen bleeding when one falls? Yes. So does warfarin.

Folks, of course it is better to not have a disease that increases the risk of stroke. That’s what I have been saying since I started this blog. Prevention is better. Go to bed on time, exercise every day that you eat, eat less, drink fewer irritants, don’t sweat getting a B+ and smile at your neighbor. I know; these are hard therapies with which to adhere.

But blood thinners are not bad medicines. They are medicines. They have risks and they have benefits. And the alternative: a patient can have the disease and its inherent risks.

John Mandrola is a cardiologist who blogs at Dr John M.

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  • http://www.facebook.com/people/Steven-Reznick/100000549195050 Steven Reznick

    Until we have an antidote for the drug , or can monitor serum levels and adjust dosage to limit bleeding risk it is a drug in which the complication of bleeding is life threatening to treat. Hemodialysis for bleeding is not a treatment that clinicians or patients should have to deal with. Yes warfarin has bleeding as a risk but in an emergency you can reverse it with currently available products.

    As for the reduction in strokes claim compared to warfarin there are numerous claims from major centers like the Mayo Clinic in Rochester that many of the patients in centers that didnt have first rate anticoagulation programs and clinics were not therapeutically anticoagulated with warfarin during the study resulting in more strokes. At places like Mayo where the INR was therapeutic they claim that warfarin did as well as dabagatrin in preventing strokes.

    As clinicians we all look forward to having anti coagulants that dont require monitoring with venipuncture or finger sticks, don’t require dietary alterations and medication dosage adjustment but not at the expense of more bleeding with prayer as good a therapeutic option as anything else you or the manufacturer currently have to offer to stop the bleeding. First do no harm sir !

    • LeoHolmMD

      A good point that many physicians are aware of. Patients…not so much. A study looking at mortality might help to resolve this issue. Really needs a closer look before it goes “blockbuster”.

    • http://twitter.com/drjohnm John Mandrola, MD

      As a cyclist (who has bumped his head) and an AF patient, I’ve thought about this issue a lot. What would have been the results if INRs could always be kept in range? Would the new drugs be better?

      I have a couple pilots and engineers with home INR monitors. They keep impeccable control of their INRs. Do the results of the clinical trials relate to these rare patients? Probably not.

      But these are the exceptions. For every dabigatran bleed, I bet the average community ER doctor sees 10 bleeds exacerbated by super-therapeutic INRs. That’s warfarin. That’s the real world.

      The only way I see warfarin management improving is if punitive government measures are enacted. Get the time-out and door-to-balloon time people on this and you would see better INRs. The problem with this approach though, is that healthcare givers can only play part of the role. The other part of good INR management requires effort from the patient. (Wait, Kevin, How do I strike that last sentence?)

      • MarylandMD

        “For every dabigatran bleed, I bet the average community ER doctor sees 10 bleeds exacerbated by super-therapeutic INRs.”
        Do you have data to back that up?  Even if it is true, what does it prove?  Given how many many patients are out there on Warfarin and how few are on Dabigatran, that may actually be evidence that Dabigatran is a more dangerous drug (especially if the market share for Dabigatran is less than 1/10th of the market share of Warfarin!).  Do we even have accurate numbers for market share at this time?

        I suggest we stick with real data instead of made up numbers that confirm what we already believe…

  • John Bonnes

    My question is this, if you take pradaxa and get into an accident, have a huge laceration or something else where there is severe blood loss, how would you reverse it. I like Coumadin because if something goes wrong you can reverse it but I haven’t found anything that can reverse pradaxa yet. Yes, its nice for the convenience factor but what happens when your pradaxa patient comes into the ER who was involved in a major trauma?

    • http://twitter.com/drjohnm John Mandrola, MD

       Agreed.

      A conservative estimate of the numbers of patients enrolled in trials of non-reversible novel blood thinners is more than 50,000. That’s a lot of opportunity for trauma-related deaths. Overall, the signal was for lower mortality.

      My dad always advised me to deal with the present danger rather than potential future problems that have yet to develop. It’s like many other cardiac therapies in older patients: there is greater benefit but also greater risk.

      Other points: it’s true that major trauma centers can reverse warfarin faster than dabigatran wears off, by a matter of a few hours. Whether these few hours of delay impact overall outcomes is pure speculation. You hear about the man on dabigatran that sustained a massive brain bleed after a fall. What you don’t know is how he would have fared on warfarin. In clinical trials, AF patients at higher risk of stroke did better on dabigatran.

      My rule is that if a patient is too frail for warfarin, they should not be on the new blood thinners.

      Ultimately, the decision comes to balancing the risks and benefits of either treatment. This is where the well-informed doctor comes in. My job isn’t to mandate a therapy. My job is to educate and advocate–so that a patient can make the best decision for them.

  • MarylandMD

    Can you say Raxar, Ketek, Avandia, Actos, Posicor, Vioxx, Bextra, Celebrex, Baycol, Darvon, Meridia, and Zelnorm?

    The early studies always look great, especially the ones sponsored by the drug companies!  It’s what we find out when the drug is used for years on many thousands of real patients that will tell us whether this drug will really be safe and effective.  I care too much about my patients to jump on a medication that has been out for less than 2 years in the US.  Let some other doctors’ patients be the unpaid guinea pigs for the drug companies.  My group has an excellent anticoagulation program that has had very very few complications from Warfarin therapy, so I do not see the need to change.

    • http://twitter.com/drjohnm John Mandrola, MD

       Good point about post-market surveillance of drugs. And I respect skepticism.

      AF increases the risk of stroke. Stroke is disabling and often life-altering or ending. All agree that warfarin reduces this risk. Approximately 6000 patients were enrolled in clinical trials supporting warfarin’s benefit–that’s combining all trials. These are the facts.

      Here’s another: The RELY trial studied 18,000 patients, of which 12,000 received dabigatran. Patients on dabigatran suffered fewer strokes and less intracranial bleeding than those on warfarin. What’s more, a trend for lower mortality was noted with dabigatran. Though the trial was sponsored by a pharma company, it’s hard to fudge hard end-points. You would have to be posit downright dishonesty and fraud. I’m more optimistic than that. Lastly, the other two non-warfarin anticoagulants, rivaroxaban and apixaban have shown remarkably similar data.

      Sometimes what’s new is no better than what’s old. Other times it is. And yet others, we aren’t sure.

      Yes, by all means, be skeptical, be vigilant, be mindful of past experience. But also, be learned of science and open-minded to the benefits of therapeutic advances. Do this for your patients; do it for you.

      As an older doctor, I constantly fight the urge to cling to my old dogmas–lest I become a Luddite. An awful fear of mine.

      I don’t claim to know the answers on the new anticoagulants. I discuss the results of clinical trials with patients, focusing on the areas of uncertainty, including post-market performance. Together, we come to a shared best decision.

      My favorite part about the new blood thinners: these conversations.

      • MarylandMD

        I used to be more trusting of industry-sponsored research, but after Vioxx and Avandia, I feel that such trust borders on recklessness.  ”Fool me once, shame on you–fool me twice, shame on me,” as the old saying goes.  Until the raw data for ALL studies of a drug up for FDA approval are shared and independently analyzed, I will not believe what industry tells me, and I will wait until the drugs are tried in the real world and data that can’t be filtered by the drug company is available.  While some doubt the benefits of the new anticoagulants are as great compared to Warfarin as the studies suggest, I am much more concerned about side effects, complications and drug interactions.  They are often what make or break a drug, and they seem to be what the drug companies are especially good at hiding behind a fog of statistical tricks.  So even if it is “hard to fudge hard end-points,” it may not matter.  But don’t think that just because it is hard it is beyond the capabilities of the drug companies and their statisticians!

        I am very open-minded to the benefits of therapeutic advances.  AFTER they have been properly vetted.

  • LeoHolmMD

    Welcome to the new “war on drugs”. I am suspicious that these law firms, who are spending an enormous amount on advertising, are actually being hired as negative PR firms from drug competitors. Nothing works like negative attacks, right? Patients will be afraid, doctors will be afraid, and the alternative drug will be prescribed, all with total disregard to evidence or actual risk which may be quite small. The anticoagulation market has exploded and competition is through the roof. Note that in many of the law firm commercials there is a disclaimer (in micro print of course) that the cases may be referred out. Why would a law firm advertise to gain business for someone else? Where is all this money coming from? Very suspicious. Of course, attorney client privilege will keep us from ever finding out.

  • Aaron Johnston

    I will chime in my perspective as an emergency doctor.
    Certainly warfarin/coumadin is potentially reversible and when we see people bleeding with elevated INR we can mitigate this to an extent with PCC’s. That being said severe bleeding events in coumadin-ized patients like massive GI bleeds, intracranial haemorrhages, and major trauma bleeds are not suddenly halted as the octaplex is given. Anti-coagulated patients with severe bleeding tend to do poorly even when managed well, and measured coagulation profile is restored to ‘normal’.While dabigatran is not a panacea for AF, neither is octaplex (or alternate PCC) a panacea for critical bleeding patients on coumadin. RELY seems to show a reduction in major bleeding events for dabigatran vs coumadin and I think these are the events we really care about. In spite of the availability of a reversal agent for coumadin, reversal is not all that successful for severe/major bleeding events and perhaps the more important issue is to decrease the incidence (? prevalence) of those events all together.

    Whenever medications are prescribed side effects will occur. On my last shift I saw a patient with hypoglycaemic seizure post insulin, complete heart block post verapamil dose increase, and a lady with a broken hip who fell in the night after taking imipramine as a sleep aid. Every medicine offers a trade off between some benefit and the risk of adverse side effects. If less people die major bleeding deaths on dabigatran vs coumadin it may indeed be a better medication, even though the bleeding deaths that do occur are uncomfortable for us, because there is less that we can do for the individual patient.

    It is not as simple as good/bad…

    Aaron Johnston
    http://www.emergsource.com

  • http://www.bytehead.org/blog/ Bryan “bytehead” Price

    I’m on Pradaxa now.  I do NOT miss the monthly (or more frequent) run to the doctor’s office for a blood test.  I do NOT have to worry about if I eat a spinach salad over a lettuce salad (and can almost completely lose track of what I am eating), I don’t have wild swings even as I was making sure my diet was consistent, I now don’t freeze at 70, nor think it’s perfectly fine out at 90+.  You would have thought I was born in Florida.  I was about done with coumadin as far as the side effects were going.  Not that Pradaxa doesn’t have some side effects (just as I was getting over the side effects of hydralyzine…), but I can live with those.

  • http://profile.yahoo.com/KNZ22VMISM6D26MXSJ4PKMGXXM James

    I am a Hematologist from Wisconsin. The Wisconsin Alumni Research Foundation (WARF) was the dominant building on the west side of campus in Madison thanks to coumadin. That being said I want to pose a dilemma that hasn’t been discussed, cost. The direct anti-thrombins cost as much as 100 times as much as coumadin. Is the Pharma claimed benefit enough to provide quality year of life benefit of <$50,000 or as I have heard lately <$100,000 compared to coumadin? I haven't been able to pose that question to my drug rep because I don't have one. Thankfully they can't call on Hematologists yet. I am a bit concerned as one of the direct anti-thrombins is being tested to prevent VTE in cancer patients. This would be a goldmine for Pharma!

  • SaraJMD

    I think the elephant in the room may be the entire industry that has built up around warfarin and INRs, including coumadin clinics and the host of laboratory solutions for frequent lab testing. If these new drugs really pan out, a whole bunch of billable services go by the wayside. The fact that there are competing financial interests in different healthcare market sectors is part of why Pradaxa generates such interesting discussion — do we need a new, expensive drug, or do we need even more frequent and comprehensive warfarin monitoring? Neither is a zero-cost proposition.

    • MarylandMD

      I think we should be very careful with assertions like this.

      I am a family doc in a large multispecialty group so I am not enmeshed in the upper echelons of the medical-industrial complex.  That being said, I have not seen or heard of any organized “Coumadin Clinic Industry”.  Seriously, is there such a thing?  Generally, a “Coumadin Clinic” is a small part of a hospital’s outpatient offerings to meet a need for the community physicians.  While it MAY be a revenue stream, it is also a well-recognized liability risk.  Do Coumadin clinics across the country band together to lobby congress and the FDA?  Do they coordinate lobbying efforts with the lab industry?  If they do, how much money are we talking about, and how does it compare to the pharmaceutical industry, one of the very biggest sources of lobbying and political money in the US?

      In our practice we have an organized anticoagulation program that is centrally supervised and run at the individual practices by RNs and LPNs.  Each visit (or call) with the anticoagulation nurse is reviewed and signed by the patient’s PCP.  The program keeps our patients under good control with very few complications.  I am quite proud of what our group does in helping our patients and taking a load off the PCPs.  I earn some fractional RVUs for every patient visit that I supervise, so you could say I have a financial interest in Warfarin continuing as the medication of choice for anticoagulation.

      Despite my “financial interest” I say this with complete honesty: I would drop our anticoagulation clinic in a heartbeat if I could.

      The time, effort, headaches, and worry I put into managing my patients on Coumadin isn’t worth the tiny amount of money that I make for managing those patients.  I am confident my group would say the same thing.  I put a lot into Coumadin management because I care deeply about my patients.  I feel it is my duty to protect my patients from the devastating strokes or PEs that could injure or kill them.  I truly dislike Coumadin and dream of the day when I write my last prescription for that damned medication with its narrow therapeutic window.

      If the new anticoagulants do pan out I will be almost as happy as the drug companies that will make all the money off of them.  I am voicing my concerns in this thread partly out of a hope that someone here can address them and convince me that the new medications are worth gambling with my patients lives and health (and my reputation as a physician who provides quality care).  So far, all I have heard is that I should trust the industry-sponsored study data.  Well, I’m sorry, but that’s not good enough.  I have been burned before.

      So let’s not poo-poo the critics as just vested interests fighting for their share of the health care dollar.  That is at least an extremely unfair portrayal of some of us, and it borders on being a smear.

      • MichelleMLS

        As a Medical Laboratory Scientist of 40 years, I would be remiss in failing to succinctly state that it is imperative any medication involved in the complicated clotting processes must be monitored. ASPIRIN, NSAIDS, COUMADIN, PRADAXA:  all can cause unexpected and life-threatening bleeding. For any entity to assert that “testing is not necessary” is inane…and has proven extremely dangerous for the patient placed on the anti-coagulant therapy!

        An A-Fib patient for the past 8 years, I’ve grown to despise my daily dose of Coumadin and it’s myriad interactions…however, with routine testing it is relatively easy to maintain that golden standard INR of 2.0–3.0 . Do I enjoy the extra testing required before and after I travel or enjoy some “forbidden” food? Certainly not. Do I enjoy that monthly veinipuncture that affects both my bank account and my time? Of course not. However, to presume the “new generation” of anti-coagulants need no monitoring is placing the patient in a horribly precarious situation.

        I must take brand Coumadin in order to maintain a relatively stable INR. Some patients appear to do well on generic Warfarin. The cost difference between these two will make you cringe. I often feel as if I should simply eat out of a D-Con box! However if the patient’s INR continues to be erratic and unstable, the patient should simply be placed on Coumadin and monitored accordingly. As to the cost of these “new generation” anti-coagulants:  they are even more ridiculous!  Further, those patients prescribed Pradaxa present to the ER as frequently as Coumadin/Warfarin users–if not more so–with severe bleeding complications.

        I cannot in good conscience accept the blanket statement of non-monitoring for any anti-coagulant. The danger is too great for the patient, even if he or she follows the dosage and administration guidelines perfectly. An anti-coagulant is just that:  the names and chemical compositions have changed, but their actions–and their serious complications–have not.

  • http://www.litigationandtrial.com/ Max Kennerly

    The problems with Pradaxa are two-fold: it has no reversal agent, and doctors often don’t know it has no reversal agent. An increased bleeding risk would not necessarily be cause for liability or to pull it from the market, but the Pradaxa label doesn’t warn either patients or doctors of that. Doctor prescribes it thinking it’s an easier version of warfarin, patient starts to have bleeding problem, patient goes to hospital… then patient dies from internal bleeding while frustrated emergency medicine, internal medicine, and neurosurgery physicians try to figure out what the hell they can do to stop it. Warfarin, in contrast, has several antagonists that all work quite well.

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