Atrial fibrillation Dabigatran/Rivaroxaban/Apixaban

Update on anticoagulation for atrial fibrillation: Encouraging news for rivaroxaban (Xarelto)

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.

Dabigatran (Pradaxa):

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.

Rivaroxaban (Xarelto):

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

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.

Apixaban (Eliquis):

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.


11 replies on “Update on anticoagulation for atrial fibrillation: Encouraging news for rivaroxaban (Xarelto)”

Dr. John: I get much good information and perspectives on afib on this website. That is a good thing for someone like me with afib. Now I have a bone to pick. 🙂 I’ve noticed that many times you end with a sentence like:

“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.”

There are many “associations” with afib, but it seems like many people on the support/forum/blog websites (me included) exercise, eat well, are not overweight, sleep properly, and have no other associations like high blood pressure, cardiovascular disease, etc. In my case, my doctor says she doesn’t know. Probably age and genetics. Maybe the mild case of sleep apnea I have treated since I found out I had concurrently with the afib 2 years ago. I have to say, I was in better shape than 99% of the guys my age when I was diagnosed 2 years ago at 62. BTW, I was asleep while the sleep apnea was going on and my wife didn’t tell me she noticed anything…so…

I guess the last couple sentences bug me a little bit (not too much, don’t want any inflammation), so I thought I would mention it. Age, genetics, stuff going on while asleep… couldn’t control those. Running 10 miles everyday and lifting weights for decades until my 60s, maybe that was a mistake. But I don’t know what I could have done differently.

My point: I believe some people, many people, are just going to get afib, and you cannot “prevent” it. Maybe you can lessen the odds or even forestall afib’s onset by a few years, but the great majority of people that have all the associations/causes (like hypertension) do not get afib.
Must be something else in play. I have my own theories. They are more complex than just “eat, sleep, exercise, think well”.



My thoughts exactly in response to Dr. Mandrola’s frquent assertions that it’s better not to get AFib in the first place. I’m pretty much in the same boat as you, except I got AFib much younger (was diagnosed at 51). In my case, it seems to be genetic as my mother and several aunts had it, and a cousin got it in his 40’s (and none of these people had any of the typical associations/causes either).


Similar story here. I was diagnosed at the age of 51 following a kidney stone attack (my first, and hopefully my last). That may have kicked it off (my EP wasn’t certain and didn’t seem all that interested), but my father has had afib for many years. Up until my diagnosis I had been active in several sports and my BMI and blood pressure were in the normal range.

As to the the “better not to get afib” question, I’m fairly certain of what started my afib episodes on top of a genetic predisposition. My afib disappeared following a cardioversion, and did not come back for a year and a half – until I retriggered it with a brief encounter with the original triggers, as well as being totally inactive for a while following eye surgery.

Here’s my view on the new anticoagulants (my absolute reluctance to take them not withstanding, as my CHADS score is virtually 0 to 1).

Prior to and after my first cardioversion, I was given Pradaxa, which at the time was brand new to the market. The months I was on it were pretty bad. The dyspesia and constant upper GI and esophageal problems were awful. Ironically, one of my afib triggers has always been GERD and other related GI/stomach issues. I lived every day waiting for it the afib to re-appear with the reflux. Fortunately, I’m one of the few that Multaq seems to help in quelling episodes of afib, and I was on that nasty med at the same time. I’ll reserve my Multaq comments for the appropriate post (How about a Multaq update, Dr. J?). Once I got off both those drugs, I was afib free for a year.

Anyway, after the latest afib episode, and pre/post cardioversion, I’ve been on Xarelto, and the difference is night and day to the Pradaxa. The other nasty thing about Pradaxa was that it absolutely destroyed areas of my skin, and made me very prone to bruising and brushing. By brushing, I mean my skin was so fragile, brittle and dry, that the slightest brush up against an object would create a large tear that refused to heal. I still have some Pradaxa tattoos that probably will never go away, even after more than a year. There has been no such problem with Xarelto – just occasional spontaneous bruising.

For me, it’s no contest between the two.

I forgot one important piece. It later came out that there is an interaction between Multaq and Pradaxa where Multaq can increase the effect of the Pradaxa by as much as 1.5 to 2 times. I’m lucky more didn’t happen besides the skin problem.

With regard to giving patients stroke risk numbers, cardiologists should not quote annual risks for a particular CHADS2 score from a study of Medicare patients with a minimum age of 65 and a mean age of 80 and insist that they apply to a 50-year-old patient without correction for age. And they should not insist that someone whose high blood pressure has been beta-blocked down to 80/50 should still get a full point for hypertension – some patients are capable of looking up the Framingham data. When it’s obvious that the doctor doesn’t understand the math involved in estimation of putative risks, it creates real trust issues.

One more thing that I’d like to hear Dr. John M’s thoughts on is the lack of an effective antidote to the newer anticoagulants. The main gripe about the newer anticoagulants on the afib forum I frequent is the lack of an effective antidote, and everyone on the list who is on an anticoagulant is on Warfarin for this reason. There have been too many stories shared on that list where someone who was otherwise healthy either had a bleeding incident or an accident and bled to death where they would have survived on warfarin.

Dr. John, have you had patients on these newer anticoagulants who died for lack of of a reversal agent?

I hear you loud and clear, Jane.

My objections to anticoagulants come from both a statistical and anecdotal standpoint.

Statistically, if I add up all the all of the combined problems that anticoagulants can cause, based on many various studies (not an individual study that only looks at bleeding risk, for example) then the risk balance tips in favor of not being anticoagulated. An ischemic stroke is a scary thing, but so is a hemorrhagic stroke. a retinal vessel blowout with loss of vision, and a major bleed that cannot be stopped, especially with the lack of reversal agents with the new “novel” anticoagulants.

In real numbers, if I read the information correctly, the risk of an afb stroke is pretty small. A 5 percent risk in reality means that out of 100 people with afib, 95 will never experience a stroke. By being anticoagulated, your risk of other events might jump to 6 to 10 percent, so without significant other factors, the anticoagulated person runs greater risks. I once laid all this out on a spreadsheet, based on articles I read. I’ll see if i can find the actual numbers again.

From an antecdotal perspective, I’ve never known anyone personally with afib to experience a stroke, yet I can tell you of friends who have died, lost their vision, had a hemorrhagic stroke or lost their power of proper reasoning from being anticoagulated. I know of two people right now who have vowed they would never, ever be anticoagulated again – no matter what – based on what happened to them.

Being anticoagulated prior to, and for a time after cardioversion, makes tremendous sense to me, but long term does not, unless there are many additional risk factors.

So I’m biased, both reasonably and unreasonably so. Having said all of that, at some point I must put my trust in my cardiologist. After all, he’s been treating afib and heart disorders for about 15 times longer than I’ve been worrying with mine, He’s weighing in more factors that I may not be aware of, and has access to much more information that I don’t have access to.

That’s my 2 cents. It would have been more, but with the sequester . . . . . .

I’m going to talk to my cardio about Xarelto…although warfarin hasn’t been too bad, from a patients point of view I’m frankly sick of having my finger stuck. I’m not usually a whiner, but it hurts!

I didn’t mean to start a mutiny here, but I guess others were thinking the same thing. I have to say though, I’m impressed with my ability to start trouble. I’m going to stay away from discussing anticoagulants. I’ve been known to start heated controversies over that topic. I’ve learned there are four topics sure to cause heated discussions: politics, religion, sex, and anticoagulants. Pete

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