Dr John Mandrola practices cardiac electrophysiology in Louisville, KY. He finished training at Indiana University in 1996. His practice encompasses catheter ablation, including an eight-year experience with AF ablation, device implantation, and consultative EP. Outside of the EP lab, Dr Mandrola's two hobbies include competitive cycling and writing. He has maintained a medical, fitness, and cycling blog, Dr John M, for the past two years.
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Dabigatran, rivaroxaban, apixaban vs warfarin: The parallax of the novel blood thinnersMar 12, 2012 09:50 EDT
A 45-year-old man presents because atrial fibrillation (AF) was found during a life-insurance exam. His case is rare, because unlike most AF patients, he reports no symptoms. He works a demanding job, exercises regularly, and isn't fatigued. He smiles and exudes a well-adjusted un-AF-like happy vibe. His ventricular rate is well controlled; his CHADS-VASc is zero; and multiple trials of AF drugs and two cardioversions have failed to maintain sinus rhythm. He has declined AF ablation.
I presented this unusual case to a series of middle-aged cardiologists. I was interested in what they would say about using an anticoagulant in a young patient with a CHADS-VASc score of zero. The guidelines recommend no blood-thinner; but what would they do if it were their atria fibrillating? Would a heart doc with AF take a blood thinner?
The results were unanimous and surprising. I'll tell you at the end.
First, let me tell you a story . . .
An astute and seasoned colleague recently expressed concern to me about the safety of the new blood thinners dabigatran and rivaroxaban. This doctor, not known as fearful of new things, bemoaned the rapid acceptance and willy-nilly use of these drugs. I'm paraphrasing:
"Docs are putting patients on them without thinking about kidney function and patient education. Unlike those taking warfarin, patients on the new blood thinners don't come back for blood checks. . . . I've seen dabigatran used once daily, in patients with mechanical heart valves, and in those too frail for warfarin."
My reflex response to such admonitions had been to snarkily retort: "Well . . . all blood thinners increase bleeding risk . . . and you aren't suggesting we go back to 'liking' rat poison." But now, I'm holding back a bit, because I too have growing concerns about the safety of these new blood thinners, or at least the way they are currently being used in the non–clinical-trial world—otherwise known as the real world.
So let's take a look at the new-anticoagulant debate from opposing views.
The patient-safety advocates and ER and neurosurgical communities point to case reports like this one in Utah. Here, an 84-year-old man who was taking dabigatran fell and bumped his head. The initial bleed was minor but soon progressed to severe and sadly resulted in his death.
Cases like these have prompted the nonprofit Institute of Safe Medication Practices (ISMP) to highlight three main safety concerns with dabigatran:
- Inhibiting blood clotting in an elderly population with a heart problem remains an inherently risky business, with a major capacity to cause injury.
- The drug was launched so rapidly that it was generating hundreds of adverse-event reports within weeks of approval.
- This new anticlotting drug was immediately used off-label where its risks and benefits were less known.
This most recent ISMP report of 505 cases of dabigatran bleeding (from the first quarter of 2011) adds to similar warnings from Europe and this most recent report of 78 cases from New Zealand—which was published in letter form in the New England Journal of Medicine (NEJM) last month and covered here on theheart.org.
The New Zealand report is emblematic of the problem with dabigatran: Of the 78 cases of bleeding, two-thirds occurred in elderly patients, 58% had kidney impairment, and half weighed less than 130 lbs. The author of the letter, Dr Paul Harper, echoed the concerns of my colleague: that New Zealand doctors too quickly embraced the new blood thinner. He pointed to three major issues: prescriber errors, dubious patient selection, and the lack of reversal agents. Spreading the blame around, Dr Harper implicated the New Zealand government's surprising curtailment of usually tight controls on new drugs, a decision, he says, that aided the rapid acceptance of dabigatran.
As for the lack of reversal agents, the trauma community's reticence about these drugs is captured in this recent letter to the NEJM. The Houston trauma doctors point out the pitfalls of caring for acutely injured patients on dabigatran. They contrast the care of patients on warfarin vs dabigatran:
"There is no readily available means for assessing the degree of anticoagulation with dabigatran, there is no readily available reversal strategy, and life-threatening bleeding complications can occur after an injury in patients taking this drug.
The stroke-preventer-side of the argument sees the problem differently. AF doctors counter with three major arguments:
First, we argue that reports of bleeding as a consequence of using anticoagulants should not be surprising. These drugs thin the blood after all. The recent safety alerts on bleeding episodes with dabigatran are difficult to interpret because no one knows how many patients were taking the drug.
Second, adverse events are always reported more often with new drugs than with 57-year-old ones like warfarin. Despite the fact that warfarin adverse events are the leading cause of drug-related mishaps, or maybe because they are, medical people hardly find these cases reportable.
Third, the data on dabigatran, rivaroxaban and apixaban show that these drugs compare very favorably to warfarin. More than 50 000 patients with AF were studied in the three randomized controlled trials, RE-LY (dabigatran), ROCKET-AF (rivaroxaban), and ARISTOTLE (apixaban). Taken together, these studies consistently revealed that AF patients who took the nonwarfarin blood thinners suffered fewer strokes, intracranial bleeds, and serious bleeds than those who took warfarin. That's a lot of evidence. But perhaps the strongest counter to safety hawks is the strong trend for lower mortality in those treated with the new anticoagulants. Unlike isolated reports of bleeding without denominators, hard end points like stroke, bleeds, and death are much easier to interpret.
Of course it's better not to have AF. Preventing a disease always bests treating it. Unfortunately, the facts are that AF is on the rise.
All caregivers should be able to agree that the worst thing that can happen to a patient with AF is a stroke. Unlike the reversible complications of AF, like tachycardia-mediated LV dysfunction, medicine side effects, and yes, most bleeding episodes, stroke often causes permanent disability. Stroke patients rarely get Mulligans. And at this moment, the only means doctors have to prevent stroke in patients with AF is to use blood-thinners. And no, aspirin does not work!
I also realize that the value of blood-thinning drugs depends on one's vantage point. The ER and trauma doctors muse, "What are the cardiologists thinking? . . . How can they be so dumb? Don't they know old people fall down and crash their cars?"
But of course, these docs don't see the AF patient whose stroke was prevented. Only we see them, at yearly visits, year in and year out. Surgeons don't hear AF patients describe how their parents died prematurely from stroke. Any guess that these strokes were AF-related?
Taking care of chronic conditions means balancing the risks of the disease and treatment against the benefits of the treatment. In AF, it means risking bleeding for stroke prevention. It's not easy treating the frail and the elderly, as they have both the most to lose and the most to gain from taking a blood thinner. Successful treatment of AF is the same as any other disease: it requires skillful use of therapy in an informed and engaged patient.
Back to those docs whom I asked what they would do with their AF: they all said they'd take dabigatran. They were most afraid of stroke.