Anticoagulant choice for stroke won't be easy for some time

New agents improve upon warfarin, but they are expensive and lack antidotes for urgent reversal. There is no clear winner among the current options, and more are on the way.

Anticoagulation has become “painfully more complicated” in recent years and promises to become even more so, according to Matthew W. Martinez, MD, a cardiologist at Lehigh Valley Health Network in Allentown, Pa.

“Things will get more complex as more [anticoagulants] become available,” he said during a session on managing atrial fibrillation at the Society of Hospital Medicine's annual meeting, held in National Harbor, Md., in mid-May. “For now, I'd get comfortable with at least one agent, and at least familiar with all of them.”

Nearly half of all embolic strokes are related to atrial fibrillation, accounting for about 100,000 strokes a year, he noted. Cardiologists used to tell all patients their stroke risk with untreated atrial fibrillation was roughly 5%, but the risk now can be more exactly quantified with the CHADS2-VASc score. (CHADS2 stands for the risk factors of Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack; the “VASc” adds vascular disease history and sex.)

“So what we typically say is that if you have at least two points or more on this score, it's enough to have a conversation about anticoagulation. I usually initiate a talk with a score of one point, though,” Dr. Martinez said.

While stroke risk can be reduced by between 65% and 85% with warfarin, up to 50% of patients won't or can't take warfarin because “It can be a nightmare to handle for many patients,” Dr. Martinez said. “It usually requires an anticoagulation clinic like we have, where two nurse practitioners just work on that all day—bless them.”

Many foods and drugs interact with warfarin, and the drug's pharmacokinetics are often unpredictable, he added. Plus, warfarin has a certain “reputation.”

“If you tell younger patients about warfarin, they say ‘That's the drug my grandma is on; I don't want to be part of that,’” Dr. Martinez said. “Or they say, ‘Is that the rat poison I hear about?’”

These patients may prefer one of the new anticoagulants, dabigatran, rivaroxaban or apixaban. The upsides to the newer agents include once- or twice-daily dosing; rapid onset/offset of action; minimal food and drug interactions; more predictable pharmacokinetics, thus no need for monitoring; lower bleeding risk; and a wide therapeutic window, except in patients with low creatinine clearance, Dr. Martinez said.

In terms of the new agents' downsides, “Man, they are expensive, really expensive,” he said, and the insurance coverage for them is variable and confusing. “Also, lots of pharmacies need time to get these drugs in; I've had patients call and report their pharmacy won't have [an agent] for two weeks.”

Once you've chosen a “go-to” anticoagulant, find out which of your local pharmacies carry that agent, so you can direct patients appropriately, he suggested.

Also, unlike warfarin, there is no currently available way to reverse the newer agents once they are in the system. “If you have a car accident or cut yourself with a chainsaw, which I never thought about till I managed rural populations, there is no clear antidote strategy,” Dr. Martinez said.

It can be difficult to choose which of the newer anticoagulants to use because there hasn't been a head-to-head comparison, Dr. Martinez noted. You'll need to take individual patient factors into account, such as age and liver function.

Dabigatran, a direct thrombin inhibitor, has a relatively short half-life compared to warfarin and is primarily cleared through the kidneys instead of the liver. In trials, the 150-mg twice-daily dose was found to be superior to warfarin in preventing stroke and embolism, had a lower risk of intracerebral hemorrhage, and was well tolerated, except for gastrointestinal (GI) side effects.

“About 10% of patients who take dabigatran have dyspepsia,” Dr. Martinez said. “Also, for patients older than age 75, there is a higher risk of bleeding, primarily lower GI bleeding. It's something to consider, the population for which you are prescribing. It's not a one-size-fits-all drug.”

Most patients would take the 150-mg dose twice a day, but patients with a creatinine clearance under 30 mL/min should take the 75-mg twice-daily dose, he added.

Rivaroxaban is a direct reversible Xa inhibitor with a short half-life and is primarily cleared through the liver. Its standard 20-mg daily dose also beat warfarin at preventing intracerebral hemorrhage and was noninferior to warfarin at preventing stroke embolism.

“Rivaroxaban's once-daily dose I view as a marked improvement over the other options, in terms of helping with compliance,” Dr. Martinez said. The dose should be 15 mg for those with a creatinine clearance of 15 to 50 mL/min, he added.

Apixaban is also a reversible Xa inhibitor and is taken twice a day. It, too, showed a reduction in stroke and systemic embolism when compared to warfarin. “There is less dyspepsia with this drug, making it perhaps a better option than dabigatran,” Dr. Martinez said.

Thus far, there is no clear “winner” in terms of the best anticoagulant, and there are at least three more new anticoagulants in the pipeline, Dr. Martinez said. “There are ongoing discussions and lots of editorials as to which is the best. We still need more data,” he said. “Follow the postmarketing literature; the ‘winner’ will likely emerge in this postapproval arena.”

Dabigatran is unlikely to be the front-runner, however, he opined. “If you look at all-cause outcomes, you will see that only dabigatran has a higher risk of myocardial infarction, and I think this will hurt it in the long term,” Dr. Martinez said. “Like most things we see in medicine, being first to market isn't always the best. Sometimes it's better to be third or fourth.”