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.