It’s time to do an update on the treatment of atrial fibrillation. It’s been a while, and there are worthy things to report from the real world.
Stroke prevention in AF:
Always start with basics: The most important aspect of treating atrial fibrillation is preventing stroke. Although there are some innovative devices and procedures in development, the only proven way to prevent stroke in patients with AF is to use drugs that block coagulation—anticoagulants. (I used to call them blood-thinners, but that’s not accurate; the blood is the same viscosity on or off an anticoagulant.)
In recent years, three novel oral anticoagulants (dabigatran (Pradaxa), rivaroxaban (Xarelto) and apixaban (Eliquis)) have been approved as alternatives to warfarin for patients with AF. The evidence base in support of these new agents is robust. More than 50,000 patients across the world have been enrolled in studies comparing novel anticoagulants head-to-head with warfarin. The results were clear: the new agents were either equivalent or superior in both efficacy (stroke prevention) and safety (bleeding). There was also a consistent trend towards lower mortality with the novel drugs. Other advantages of the new agents include convenience (no INR testing), lack of dietary or drug-drug interaction and rapid anticoagulation after an oral dose (rather than days for warfarin).
But there are headwinds as well. The new drugs are costly, for some, unaffordable. The drugs may be more convenient for patients, but it’s a different story for office staff toiling in the bloated US healthcare system. I know a medical assistant who spends almost every day, all day, just doing pre-authorizations for novel anticoagulants. Five to ten minutes per patient turns into a full-time job with benefits, just for sending information—in triplicate—to insurance companies. Imagine that.
Being first to the marketplace cut both ways. On the one hand, Boerhinger Ingelheim got a head start in a market that had waited nearly 50 years for a warfarin alternative. To say people were excited to have something better than a rodenticide would be a severe understatement. Once approved, dabigatran use soared.
Irrational exuberance usually ends the same way. It turns out there was a steep learning curve with dabigatran. Investigations of early bleeding reports exposed errors in prescribing and clinical judgment. To be fair though, most of the adverse events were simply bleeds that occur when one blocks coagulation, which is the tradeoff when trying to prevent stroke. This notion was born out in subsequent reports of dabigatran-related bleeding events, which failed to reveal a signal of harm. Logic aside, it did not take many adverse event reports to spark the “Bad Drug” ads in mainstream media.
Dabigatran has two other pesky issues: First, in at least 10% (probably closer to 20%), patients experience stomach and esophageal discomfort with the acidic capsule. These are real problems that I have seen range from minor nuisances up to esophageal ulcerations. This is a big issue because patients often feel bad with their AF; it’s not good when their new drugs make them feel worse. Plus, there’s a lot of education to cover with AF; getting bogged down in dealing with stomach pain from an anticoagulant distracts and creates extra work. Finally and not to be dismissed easily: dabigatran must be taken two times per day—a tough ask for many.
These problems paved the way for rivaroxaban (Xarelto). The once-daily drug is well tolerated and does not often cause stomach pain. The convenience of once-daily dosing is huge. Studies show adherence is better with medicine taken one time per day.
Yet rivaroxaban started slowly. Clinicians were worried the drug wasn’t as effective as dabigatran or warfarin. The Rocket-AF trial showed rivaroxaban to be non-inferior to warfarin, while dabigatran and apixaban could boast superiority from their trials. In fact, debate over Rocket-AF was heated, and the drug had a tough FDA hearing. Then, once approved, it entered a landscape marred by bad-drug ads. Insurance companies make (emphasis on present tense) it tough too; they aren’t paying for a new drug without adding hurdles. (Five to ten minutes of extra paperwork per patient adds up to…)
I was tentative about rivaroxaban for a different reason. As a proceduralist, I was worried that the new anticoagulant had not been tested in AF patients destined for procedures. Unlike dabigatran, which has a solid evidence base as an effective peri-procedural anticoagulant, there was simply no data with rivaroxaban. Could I use it before cardioversion or AF ablation? Would a once-daily non-inferior anticoagulant stand up to the rigors of left atrial ablation? Was it worth switching a patient doing well on rivaroxaban to warfarin before their procedure?
I am happy to report some early information on peri-procedural use of rivaroxaban.
There were 5 studies presented at the Heart Rhythm Society sessions earlier this month. The data were encouraging. For those interested in the medical details, I summed up the abstracts in a short post over at Trials and Fibrillation on theHeart.org.
The presented data mirror my experience. Over the past year, I have yet to see a major adverse event with rivaroxaban, and this experience includes cardioversion and AF ablation. I asked around and my colleagues echo the same sentiment. Although early, and I could be wrong, I don’t think this is fluky. Consider that in the Einstein-PE trial, rivaroxaban, albeit at a higher dose, proved to be an effective strategy to treat pulmonary embolus (blood clot in the lung.) This is significant because PE is a disease that requires potent anticoagulation. That rivaroxaban worked so well speaks to its anticoagulant effects.
I have not used the newly approved drug enough to render an opinion. Its clinical trial boasts the most impressive data against warfarin, and apixaban is the only one of the new agents that can claim a mortality reduction. As a twice-daily drug, adherence will be an issue. I’ll give you an update when I know more.
Drugs that block normal coagulation increase the risk of bleeding. That’s how they prevent strokes. It’s a trade-off. The cost of preventing stroke is an increased risk of bleeding. In patients with AF and risk factors for stroke (high blood pressure, diabetes, prior stroke, weak heart muscle, vascular disease, female gender and age > 65), multiple trials have shown a net clinical benefit in favor of anticoagulation. But we must be mindful of two important issues: the risk of stroke in AF is not binary (yes or no); rather it varies depending on associated diseases. (See CHADS-VASC score.) Patients at higher risk of stroke enjoy more risk reduction from anticoagulants than lower risk patients.
Second, and most important, the decision to take an anticoagulant should be a shared one between patient and doctor. The risk of stroke on and off anticoagulants should be presented. Bleeding risk should be considered as well. I never tell my patients they need to take an anticoagulant. I simply try to replace fear and ignorance with the best evidence. Then I am comfortable with what they choose, for it is always their choice.
And to ward off commentary that I am promoting dangerous anticoagulants, let me leave you with the obvious:
It is better not to get AF. If you prevent the disease, then you don’t have to face tough decisions about drugs and procedures. Good movement, good food, good sleep and good attitudes will make it more likely that you will see me on a bike ride than in the clinic.