The first four months of a new era.

My iPhone vibrated with an urgent message that read:

Please call…The INR on your atrial fibrillation patient scheduled for cardioversion is too low.  He is on that new blood thinner, Pradaxa.  What do you want to do?”

I responded, sounding like an expert:  “It’s Ok.  Pradaxa thins the blood adequately, it just doesn’t change the INR.”

She astutely responded, “How do know the blood is thin?  What if the patient doesn’t take the medicine faithfully?”

“Hmm?”

In the treatment of atrial fibrillation, this exchange illustrates a sea change in thinking.

Until only four months ago, the only way to prevent stroke in patients with AF was to use a rodenticide.  No one likes warfarin (Coumadin).  Doctors don’t like it because of its variable effects, risk of under or over-treatment, and multiple drug/dietary interactions.  In the best case, in closely supervised clinical trials, warfarin-treated patients are in therapeutic range only two-thirds of the time.  Patients dislike warfarin because of the hassle of frequent INR measurements, and because they are scared to take a drug which can cause excess bleeding.  Who wants to take a rat poison?

Heart rhythm doctors-in-training will start their practice hardly knowing the enormity of this change in blood-thinning practice.  Us seasoned doctors have toiled with warfarin for the entirety of our career.   It’s hard to put into words the anticipation (and surprise) that dabigatran brings.

Here are a few of the many upsides of dabigatran:

• It replaces warfarin, a drug whose downsides are legion.
• The science supporting dabigatran is stellar.  The 18,000 patient-strong RE-LY trial clearly showed that—for AF patients—dabigatran is a better blood-thinner than warfarin. Dabigatran-treated patients had fewer strokes and less intracranial bleeding than those who took warfarin.
• The novel way in which Dabigatran thins the blood means that INR testing is not needed.
• The metabolism of Dabigatran offers patients many useful advantages.  Unlike warfarin, there are no significant drug or dietary interactions.  Patients can drink cranberry juice and eat salad to their heart’s content.
• The rapid onset of dabigatran’s blood-thinning effect allows for shorter hospital stays.  In the past, rightly or wrongly, common practice held that patients stayed hospitalized on IV (or subcutaneous) blood-thinners for the three-five days that it took warfarin to adequately thin the blood.  Dabigatran shortens this multi-day kabuki dance to hours.
• Dabigatran is cost-effective.  This Annals of Internal Medicine trial suggested that although the drug costs more upfront, its convenience (no INRs), superiority and better safety profile pay off in the long run.

That’s a lot to like.  But of course, dabigatran has some downsides.  These include:

• For most patients, it costs much more than warfarin.  Patients need to ante-up more of their money.  How much they are willing to pay for the convenience and superiority of dabigatran remains to be seen.
• It’s a twice-a-day drug.  Many experts are rightly worried that the compliance of real-world patients may be less than the RE-LY cohort.
• One in ten patients who take dabigatran get heartburn.  Warfarin doesn’t have any of these nuisance side-effects.
• Dabigatran is cleared by the kidneys.  Patients who have (or develop) kidney disease require dosing adjustments.
• The un-measurability of dabigatran makes doctors nervous. We are still getting used to the foreign notion of not knowing whether the blood is thin.  With warfarin, the standardized INR measurement provides assurance that the blood is thin.  With dabigatran, on the other hand, whether the blood is thin depends simply on whether the patient actually takes the medicine.  This issue isn’t a small point.  Consider the above vignette on cardioversion.  To protect patients from a dislodged blood clot, the current protocol before cardioversion mandates three weeks of adequate blood-thinning with warfarin, the adequacy of which is confirmed with serial INRs.  With dabigatran, there exists no such measurement.

So, what am I doing (or seeing) with dabigatran?

I guess you could call me a cautious early-adapter.

I started using dabigatran slowly.  It’s not just another new medicine; it’s a paradigm shift—a sea change.  The water is cold and the waves strong; I am dipping my toes before plunging in.  Remember, the last non-generic medicine heart rhythm doctors saw was Multaq.

My approach to Dabigatran is to discuss its risks, benefits, alternatives and expectations.  This includes the drug’s newness.  Then, each patient decides whether to take the drug on their own; that’s called patient-centered care.

Thus far, most patients look favorably on dabigatran’s obvious positives, but whether they switch depends mostly on how much of their own money they have to part with at the pharmacy.

I also emphasize the fact that dabigatran may be especially helpful to AF patients with multiple risk factors for stroke (diabetes, heart failure, previous stroke, high blood pressure or age greater than 75), or in those with difficult to control INR levels.

Discussing all of AF treatment in a single office visit is a challenge.  Dabigatran makes this task harder.  The novelty of how it works, the newness of the concept of a non-warfarin blood-thinner and the complexity of discussing clinical trials has added even more complexity to the already complex typical office visit for AF.

I recommend dabigatran only for patients with non-valvular AF.  Though it will likely prove effective for many other diseases that warfarin is currently used, it’s clearly too early to venture off-label.

In the first four months, I have yet to see a major bleed with dabigatran.  A couple patients stopped the drug because of heartburn.  Many more declined because of cost.

In summary, my very early real-world experience with dabigatran looks encouraging.  No doubt, there remains much to learn.  It’s a great time to be an AF-doctor.

Stay tuned.

JMM

Disclosure:  I am not a paid thought-leader. I have no relationship with the makers of dabigatran, Boehringer-Ingelheim, or any other pharmaceutical or medical device company.