Pradaxa versus Xarelto: An e-mail exchange between a cardiologist and an ER doctor

My friend Bill is an ER doctor and a bike racer. He’s like me in that he has rediscovered the beauty of being a learner. His most recent area of inquiry is the blood clotting cascade and the use of reversal agents for the novel new blood thinners, (dabigatran, rivaroxaban and the soon to be released apixaban.)

I have been exchanging emails with Bill and two other prominent ER doctors, Robert Orman from ERCast and Dr Amal Mattu.

Here’s what Rob wrote to my friend Bill:

Hi William,

Ironically, John Mandrola is exactly the guy I would ask about this question. I am still trying to wrap my head around Pradaxa and haven’t seen any patients on Xarelto. For some of the reasons you suggest in your email, as well as the need for BID dosing, cardiologists I’ve spoken with think Pradaxa may very well be pushed aside by once daily agents like Xarelto. I’d be curious to hear what you and John have been debating about this.

I thought that I would share my response:

Hi All,

My dear friend Bill and I don’t really debate. Rather, we are struggling to best understand the role of these new blood thinners. We strive to mesh what the mega-trials tell us with what we see in the real world. That’s tough b/c our experience with warfarin is so long, and with these new agents, so short.

We both understand the benefits and risks of the drugs, but our perceptions are colored by our differing vantage points. As an ER doc and bike racer, Bill’s natural tendency is to focus on which drug can be best reversed in the event of a serious bleed. He sees bleeding a lot more than I do. I, on the other hand, am charged with protecting AF patients from stroke. I don’t see as many bleeds; I see thousands of people with AF and have to counsel them on how much risk reduction can be had, and at what cost–in dollars, convenience and bleeding risk.

Bill likes the xA inhibitors (rivaroxaban and apixaban) as they seem more easily reversed.

The problem comes when the mega-trials were analyzed more closely, the researchers found that neither rivaroxaban nor apixaban reduced ischemic (clot-related) strokes, whereas dabigatran did. Sure, each of the 3 drugs lowered OVERALL strokes, but only dabigatran did it by reducing BOTH ischemic & hemorrhagic strokes. This data point has been widely interpreted as evidence that dabigatran is the superior stroke-preventing blood thinner for AF.

Obviously, for the patient with AF, it doesn’t really matter what causes their paralysis or speech impediment; it just matters that they don’t have it in the first place. Carrying this line of reasoning further, I keep having this thought: Since in reality most patients with spontaneous brain bleeds–on any blood thinner–do poorly, isn’t it better to pick the strategy that best prevents the bleed in the first place, rather than trying to salvage marginal brain functioning after the fact with reversal agents?

For elderly trauma victims, the decision harkens back to the age-old conundrum–frailty versus stroke prevention. Surely we can all agree that if a patient is too fragile for warfarin, they are also not appropriate candidates for these drugs.

If you like learning, the new thinners are featured prominently in this advanced class: clinical-decision making 401.

JMM

References:

1.) RE-LY trial of dabigatran for AF

2.) Rocket AF trial of rivaroxaban in AF

3.) Apixaban in patients with AF;

 

Comments

  1. Verted says

    “rivaroxaban nor apixaban reduced ischemic (clot-related) strokes”

    so I’m confused – what’s the point of taking them for afib then?

    • says

      Verted,

      In AF patients at risk for stroke, blood thinners reduce the risk of stroke.

      Your confusion is my fault. My words lacked sufficient precision.

      I should have said: “Compared to warfarin…neither dabi or rivar reduced ischemic strokes.”

      The mega-trials of new blood-thinners used warfarin as a comparison, not placebo, as it would have been unethical to not thin the blood in at risk AF patients.

      Sorry about that.

      • Verted says

        Got it.

        perhaps: “the risk of ischemic stroke with rivaroxaban or apixabanis is comparable to that seen using warfarin. Dabigatran, however, showed a greater risk reduction when compared to warfarin.”

        Thank you for the clarification.

  2. Fred Ehlers says

    . When I picked up my recent prescription of pradaxa ( 3/15/12), a pamplet was enclosed with information and a web site (pradaxa.com). On the web site it stated and I quote ” After opening a bottle of Pradaxa, use within 4 months”. This is new to me and it’s coming from Boehringer Ingelheim.

  3. frank says

    started pradaxa the day my pharma. had it on the shelf. at that time the bottled was a 30 day, ” after opening” life. the blister pack was for many months, same price, so i opt. for the blister. it’s more convenient and no concern for the ” use by date ” seems like they may have extended the bottled from 30 days to 4 months. glad i’m with the blister pradaxa, so far so good. looking forward to the new ones for us that seem to have some reversal benefits. very happy that dr. john has this blog. ( thanks DR.) his first hand info. is priceless and sharing with the kindred is uplifting.

  4. Lynn Kelly says

    As a ‘retired’ from practice NP, (but not from thinking!) I love reading these blogs because they make me so delighted to see docs in reasoned discussion about how best to use their education and experience to find the absolute best and most efficacious answer. It gives me confidence in the new generation of healers to do what the ancient healers tried to do! Look at the whole patient, benefits vs. harms, and thoughtfully make a decision. The decision making has become so much more complicated with our plethora of drugs, our obesity, and our fast food revolution, and our lack of exercise, I applaud them for not just throwing up their hands and saying, “I quit!”

    As usual, Dr. John, I love you!

    Lynn

  5. says

    I’m also bike racer and afib sufferer. Had my first ablation last week and am now on Pradaxa. So far so good (with the heart rhythm & the recovery). Given issues with Pradaxa and lack of a reversible agent, I’ve decided to limit my cycling to the indoor trainer while I’m on the Pradaxa. No sense in risking a crash out there on the road. A bit nervous about the Pradaxa bleeding issues given some of the reports (www.epulseglobal.com/afib if any of you want to keep track), but I’m trusting in my doc to make the right blood thinner decisions – plus, my own read of some of the Pradaxa studies seems to support the fact that Pradaxa is at least a reasonable option for me.

  6. says

    Also: A couple days ago (3/15/2012) the UK’s health agency approved Pradaxa. This gives me a bit more confidence in the drug (see link above).

  7. says

    John,

    I am a clinical pharmacist specializing in cardiology and we too have struggled with which of the new oral anticoagulants is appropriate in the majority of our patients. As you and several others have already mentioned, I think it only underscores the complexity of clinical decision-making and the importance of making a patient-specific decision based on the anticipated risks and benefits of therapy. I do think it’s challenging to advocate the overall superiority of any one of the new agents over another, especially given the differences in study methodology and baseline characteristics among the three major trials. While dabigatran reduced ischemic strokes in RELY, neither of the three trials were powered to detect this prospectively, so we can’t entirely rule it out as an anecdotal finding. On that same point, which of the non-primary endpoints should we consider the most important? For example, since apixaban improved mortality compared to warfarin, some have argued that this is an even more important finding than the investigation’s primary endpoint. As a pharmacist, my bias is often in support of the medication that patients will continue to take, which is in some cases (unfortunately), not always the medication shown to be the most effective in clinical trials. Of the new agents, dabigatran seems to be the least tolerable and the one patients discontinue the most (surprisingly even more so than warfarin).

    Either way, whether the issue is adherence, cost, or anticipated risks versus benefits, as you indicated in your original post, the decisions are far more complex than ever before. Gone are the days where the most difficult decision was whether to discharge a patient on aspirin or warfarin. The current state of practice definitely makes things tougher for the clinician, but I think most would contend that this is actually a good thing.

    Great post!