Dabigatran (Pradaxa): Good news on safety but caution still warranted

Let’s talk about the new anticoagulants. Two recent studies involving dabigatran (Pradaxa) have shed new light on an important topic for patients with atrial fibrillation: the risk of bleeding versus the risk of stroke.

Dabigatran and rivaroxaban (and soon, apixaban) have been approved for the prevention of stroke in patients with non-valvular atrial fibrillation (AF). They are novel drugs that inhibit the body’s normal clotting system in a much different way than warfarin. And when compared to warfarin in head-to-head clinical trials, each of these agents fared well—with fewer strokes and less serious bleeding. In fact, their greatest benefit may be in safety. Across the board, patients on these drugs suffered fewer intracranial bleeding episodes–the most catastrophic sort of bleed.

But yet, the fear of bleeding persists. More specifically, one of the greatest fears with dabigatran (Pradaxa) is its lack of an antidote.

“What happens if the patient has a major bleed? There is no way to reverse the drug.”

It’s an appropriate concern. I get that. The trouble is that some have let the fear of future events–that have yet to happen—impair their view of the real data.

Here is where facts and science can help.

Before I tell you about the new studies, it’s worth mentioning some background on dabigatran. As most know, dabigatran was the first anticoagulant released in nearly 50 years. Until 2010, all we had to prevent stroke in patients with AF was warfarin. (Aspirin and other inhibitors of platelets are largely ineffective.) Let’s just say the initial enthusiasm over the first warfarin-replacement agent was robust. Sadly, irrational exuberance led to widespread overuse and misuse. Case reports chronicled stories of frail, elderly and kidney-impaired patients who suffered adverse outcomes with the new drug. Many of these patients should not have been prescribed the new drug.

So spawned the “Bad Drug” movement. I’ve written previously that dabigatran is not a bad drug; it’s simply a potent drug with benefits and risks. It must be used wisely and in well-educated patients—like all medical therapies. Again, balance: the risk of the drug (bleeding) versus the risk of not taking the drug (stroke).

Now to the facts:

A new study on the bleeding risk of dabigatran provides (more) reassuring evidence of its safety. (Sue Hughes nicely covers the story on theHeart.org.) Publishing in abstract form at the American Society of Hematology meeting in Atlanta, a group of investigators analyzed more than a 1000 major bleeding episodes in patients on either dabigatran or warfarin. The data came from a series of studies comparing dabigatran and warfarin, including the RELY trial.

The important question was: what happens when major bleeding occurs in patients on warfarin or dabigatran?

The results were surprising:

  • Mortality assessed at 30 days was lower in patients on dabigatran. (9% v 13%).
  • The overall use of blood products was similar in both groups.
  • Length of stay in the ICU was lower with dabigatran.
  • There were no differences in neurologic function.

This says something. Theoretical concerns are one thing; case reports another, but the actual analysis of real bleeding events provides far more valuable information. It’s powerful data. Skeptics of industry-sponsored studies should take note that such hard outcomes, like death, time in the ICU and amount of blood products given are hard to manipulate.

The conclusion here is clear. Despite the lack of an antidote, patients on dabigatran who suffer serious bleeding fared better than those on warfarin.

A quick note on equivalent neurologic outcomes: This finding also makes sense. Here is why: An intracranial bleed is often a catastrophe. An intracranial bleed on an anticoagulant is even worse. Ten times horrible is still horrible. Though warfarin can be reversed, the time it takes to accomplish this—hours—isn’t fast enough to impact outcomes. In other words, if you are unlucky enough to have bleeding in the brain, it’s unlikely that a reversal agent would matter. It’s the same with head trauma. Falling down and smashing your head is equally bad whether on warfarin or a novel anticoagulant.

Danger of using dabigatran for non-approved indications:

The second set of studies on dabigatran sound a strong word of caution to clinicians. We should not assume that the anticoagulant effect of dabigatran at doses used for atrial fibrillation works in patients with artificial heart valves or other clotting diseases.

Lisa Nainggolan of theHeart.org nicely summarized two case reports of clot-related events in patients with mechanical valves who were switched from warfarin to dabigatran. And then this week, we learn that Boehringer Ingelheim has stopped their investigation of the use of dabigatran in patients with mechanical aortic valves. The RE-ALIGN trial “did not achieve the desired results.” That’s telling.

The ‘off-label’ use of the novel anticoagulants is an increasingly relevant issue. I’ve seen it in the real world. Why, you ask? The convenience of these agents tempts us. A patient in the ER or your office has newly diagnosed AF. Both parties—patient and doctor–desire efficiency. Choice A involves the usual dance—shots for days until warfarin takes effect, or Choice B–take the new drug, of which there are free samples, and you are covered for stroke in one hour.

I worry about this sort of thinking. Case reports of clotting in patients with artificial valves and BI’s termination of RE-ALIGN should emphasize to doctors that what makes sense clinically doesn’t always hold true. AF patients with valvular heart disease were excluded from the clinical trials because they harbor a higher stroke risk. They are different.

In the case of potent new clot-blocking drugs, following the evidence base makes good sense. Take note here, of all people, you know that I am not advocating for always following a protocol. Medicine does not work this way. All I am saying is that these drugs warrant caution. They make me think more, not less.

It’s often said in medical journals: “More research is needed.”

Yes. For sure.

The learning continues. This is good.

JMM

Full disclosure: I have no financial relationship with any of the manufacturers of the novel anticoagulant drugs. It’s just me.

Comments

  1. Skeptical Scalpel says

    It’s a nice discussion about bleeding as a side effect of the drug. But we surgeons have been concerned about dabigatran from the beginning for another reason.

    If a patient on dabigatran presents with a GI bleed, a subdural hematoma or other significant trauma, there is no way to save him because there is no way to tell how anticoagulated the patient is and no reversal agent as opposed to warfarin.

  2. jane says

    I have a question about the supposed uselessness of aspirin in AF. Most of the studies used low-dose aspirin and achieved only modest reductions in stroke rates, but the available data on high-dose aspirin showed much larger reductions, according to a meta-analysis a few years ago. In the big apixaban vs. aspirin study, where the dose of aspirin or placebo aspirin was up to the individual physician, I recall that the 7% of the aspirin group who got high-dose aspirin (3 or 4 baby aspirin per day) had noticeably lower events than the ca. 92% who got 1 per day. Interestingly, the people who were getting apixaban and “high-dose” placebo aspirin also seemed to do better than those who got apixaban and low-dose placebo aspirin; had the former group had the same stats as the latter group the difference between apixaban and aspirin in the “high-dose aspirin” subgroup would not have been impressive. The study authors did not see fit to tell us whether either of these apparent differences was statistically significant. There seems to be good evidence that high-dose aspirin offers no extra preventive benefit in people without AF, but is it possible that it has other mechanisms of action in people with AF that make it, as limited data suggest, closer to warfarin in potency than low-dose aspirin?

    • says

      I am not familiar with any contemporary study showing that aspirin–at any dose–effectively prevents stroke in AF. North American guidelines suggest aspirin is better than nothing, but European guidelines are much more doubtful.

  3. Pete Capozzoli says

    As you said Dr John, when major bleeding occurs in patients on warfarin or dabigatran, mortality assessed at 30 days was lower in patients on dabigatran. (9% v 13%).
    I am trying to balance that against what Skeptical Scalpel said.

    My question: If a patient has a bleed and is on dabigatran and you know when the last dose was as a baseline, depending on the age and history of the patient, wouldn’t you have an idea of how fast they would clear the dabigatran and therefore, an idea of how to proceed? And anyway, wouldn’t you have to assume you would have to apply the same protocol to clear the dabigatran as quickly as possible, no matter what the level of anticoagulation?

    Lastly, you (Dr. John) said: “Though warfarin can be reversed, the time it takes to accomplish this—hours—isn’t fast enough to impact outcomes. In other words, if you are unlucky enough to have bleeding in the brain, it’s unlikely that a reversal agent would matter.”

    So there are 3 scenarios:
    1) The patient has a serious bleed/trauma and dies as a result before any medical care can be applied (anticoagulation not an issue).
    2) The patient survives long enough to be treated, but worsens so quickly that neither warfarin nor any other anti-coagulant could be reversed anyway (all anticoagulants would be an issue).
    3) The patient remains relatively stable and there is enough time (3-4 hours?) to reverse the warfarin. In that situation, depending on the time the patient took their last dose of dabigatran (could be 12 hours prior), it might be as much as 15-16 hours since the last dose of dabigatran before the warfarin would have been reversed anyway(3-4 hours), if they had been on warfarin. You can’t assume the patient took their dabigatran in the last hour is my point.

    So, with all these scenarios, for afib patients on anticoagulation, how many patients on dabigatran have GI or cranial bleeds that could be saved (no matter what anticoagulation they were on) ? I bet the number is less than the amount of people that are spared having a stroke because they are on dabigatran versus warfarin. The study shows 9% dabigatran versus 13% warfarin mortality in these bleed situations. Maybe it is because there are so few scenarios where reversal would have mattered anyway AND… again, there are statistically few that are in a trauma or major bleed situation on dabigatran anyway.

    I’m not a doctor, but it seems common sense would dictate that the drug that works better to prevent strokes and has fewer intracranial bleeds, plus for whatever reason, patients fare better when there IS a major bleed… then that drug would be preferable.

  4. Skeptical Scalpel says

    Pete, I appreciate you comments, but your statement “And anyway, wouldn’t you have to assume you would have to apply the same protocol to clear the dabigatran as quickly as possible, no matter what the level of anticoagulation?” is flawed.

    There is no protocol to clear the dabigatran. There is no antidote, no reversal possible. The only way it is cleared is via the kidneys with time.

    This is from a review published in the November 2012 issue of the Journal of Trauma: “With normal CrCl (980 mL/min) and maintenance of
    adequate diuresis, the drug’s effect will be approximately 50%
    of its peak 12 hours to 14 hours from the last dose. Anticoagulation
    effects will be minimal by 24 hours. The drug’s
    half-life increases to approximately 19 hours at CrCl between
    30 mL/min and 50 mL/min necessitating longer time periods
    between last dose and normal coagulation.”

    • says

      Appreciate the conversation. This is why I like blogs and social media. I’ve attended many sessions on the novel anticoagulants. They have all been at cardiology or EP meetings. You don’t hear about the issues that the Skeptical Scalpel raises.

      I’ve talked about parallax before. It’s when one object looks differently based on the position of the observer. Obviously, trauma folks see anticoagulants from a unique and much different perspective than a heart doctor treating AF.

      At this point in the conversation a nugget just proofed into my head. Why does my simple mind revert to prevention? Wouldn’t it be best not to have AF? Then there would be no reason to use anticoagulants. Prevent AF, you ask?

      Yeah, what if patients avoided high blood pressure by exercising and eating well? What if patients with OSA used their CPAP? What if we settled for normal productivity and stopped overachieving so much? And what if patients ingested less cardiac irritants, like alcohol?

      I know; sorry, that last paragraph was stupid.

  5. Pete Capozzoli says

    Thanks Skeptical Scalpel. I noticed there are some protocols on the web (University of Utah and Hennepin County Dabigatran Protocol)… okay, so they talk about what doesn’t work and what you could “try”, and they include everything they could think of to fill up the page… except “prayer”, but I guess they technically qualify as protocols.

    http://healthcare.utah.edu/thrombosis/dabigatran.html

    http://emcrit.org/misc/bleeding-patients-on-dabigatran/