New drugs could improve anticoagulation rates

Drug options to prevent strokes have expanded, with an emerging cadre of warfarin alternatives, along with some new monitoring recommendations for those prescribed the mainstay anticoagulant.

Since late 2010, two warfarin alternatives, dabigatran etexilate (Pradaxa) and rivaroxaban (Xarelto), have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with atrial fibrillation. Patients taking the drugs don't need the regular blood checks required with warfarin, although there is a different set of tradeoffs, including the lack of an antidote to reverse bleeding, according to anticoagulation experts. Other warfarin alternatives also are in the development pipeline, including apixaban (Eliquis), which FDA officials have given a priority review designation.

These drugs provide new options for patients who are unable or unwilling to comply with the dietary requirements and repeated blood checks involved with warfarin, said Scott Kaatz, DO, MSc, FACP, medical director of the anticoagulation clinics at Henry Ford Hospital in Detroit. He pointed to one research analysis, presented at a 2010 American Heart Association meeting, which found that only 61% of suitable patients with atrial fibrillation were taking warfarin.

“My hope is that with easier therapies, that we can start to carve into that population,” Dr. Kaatz said. “And if we do that, we have the possibility of preventing lots of strokes.”

Even patients taking warfarin might not need to visit a clinic or doctor's office as frequently to check their international normalized ratio (INR) levels.

Research published in the Nov. 15, 2011 Annals of Internal Medicine found that patients achieved a similar therapeutic INR range if they were tested every 12 weeks versus every four weeks. Another study, published in the Jan. 28 Lancet, highlighted the possibility of self-testing in suitable patients. The study, which analyzed individual patient data from 11 trials, found that patient self-testing, along with adjusting warfarin doses if needed, was a safe treatment option.

Although a reduction in death wasn't identified, patients who self-tested experienced fewer thromboembolic events, including stroke, said Jack Ansell, MD, FACP, a Lancet study collaborator and professor of medicine at the New York University School of Medicine.

Too often, physicians don't give patients the opportunity to manage their warfarin regimen at home, with clinical backup if needed, said Dr. Ansell, who also chairs the department of medicine at Lenox Hill Hospital in New York City.

“All patients who are capable should be doing self-management,” he said. “It is, if anything, simpler than patients managing their insulin therapy and testing their own blood sugar.”

Limiting monitoring

For more than 20 years, warfarin has been the mainstay anticoagulant prescribed to prevent strokes in patients with atrial fibrillation. The condition, which impacts an estimated 2.66 million Americans, also causes at least 15% of all ischemic strokes, according to the Centers for Disease Control and Prevention (CDC).

The rate of diagnosis is increasing in part due to an aging population. The mean age of diagnosis is 67 years in men and nearly 75 years in women. CDC officials project that as many as 12 million Americans will be living with atrial fibrillation by 2050.

The warfarin analysis presented at the American Heart Association meeting focused on 30,202 California adults with atrial fibrillation but no contraindication to warfarin. The likelihood of taking the drug did increase with the number of stroke risk factors. But even among those classified at the greatest stroke risk based on their CHADS₂ score, no more than two-thirds were taking the drug.

Traditionally, the rigorous blood testing requirements have been one of the hurdles for patients prescribed warfarin, particularly among those living in rural areas or unable to drive, Dr. Kaatz said. “You can be eight blocks away. If you don't have a ride, you don't have a ride,” he said.

But the November 2011 Annals study, which involved 250 patients (with 226 completing the study), indicated that less rigorous monitoring might achieve similar results. The group tested every four weeks for at least six months remained in the therapeutic range 74.1% of the time compared with 71.6% for the group tested every 12 weeks.

Many more patients would have to be enrolled to measure a clinical outcome, such as major bleeding or stroke, said Sam Schulman, MD, PhD, the study's lead author and professor of medicine at Canada's Hamilton Health Sciences-Hamilton General Hospital, who also directs the thromboembolism program at McMaster University in Ontario.

But the Annals findings indicate that some patients don't require as rigorous a monitoring schedule, said Dr. Schulman, who specializes in hematology and internal medicine. The best candidates will have been stable on a particular warfarin dose for at least six months, he said. They also shouldn't have congestive heart failure, which can interfere with the metabolism of warfarin, he added.

In its prior guidelines involving vitamin K antagonist therapy, the American College of Chest Physicians had recommended testing stable patients at least every four weeks. The latest guidelines, released in the February issue of CHEST, said that doctors can wait as long as 12 weeks when treating patients with “consistently stable INRs.”

The updated guidelines, which cited the November 2011 Annals study and two others as influential, defined a stable INR as one that doesn't require any dosing adjustments for at least three months.

Testing solo

The updated guidelines also addressed another clinical dilemma: To what extent should responsible patients be allowed to participate in warfarin care? Two approaches can be potentially adopted, with one permitting patients to test their INR levels at home via a finger-stick test, then contact the doctor or clinic for any adjustments. Alternatively, but more rarely, patients can be educated to make those dose adjustments themselves, with clinical backup if required.

Given the logistics involved, particularly in a typically older population, it's not always easy to find a good candidate for self-testing, said Neeraj Tayal, MD, FACP, an assistant clinical professor in the department of internal medicine at Ohio State University Medical Center in Columbus.

“It has to be somebody, either themselves or a family member, who has the dexterity and the motivation to check at home,” he said. He estimated that a handful of his patients do so. One travels overseas a lot for work. Another patient is disabled and has difficulty reaching the clinic.

The CHEST guidelines do support self-management for motivated and competent patients, relying in part on the recently published Lancet analysis. That study, which assessed data from 6,417 people involved with 11 trials, found a significant reduction in thromboembolic events among patients who self-tested or self-managed, but no reductions in major bleeding or death.

Despite limited reimbursement for self-monitoring, doctors should more frequently raise the option with their patients, Dr. Ansell said. A caregiver also could perform the testing if the patient's dexterity or cognitive ability is in doubt, he said.

“I think the excuse that patients can't do this is really not valid,” he said. Dr. Ansell pointed to data published in the Oct. 21, 2010 New England Journal of Medicine, which found that 80% of 3,643 patients who were trained could test by themselves or with the help of a caregiver.

Warfarin alternatives

With the new oral anticoagulants, dabigatran and rivaroxaban, a patient's INR levels don't have to be checked, making the drugs easier to take over a long period of time, Dr. Kaatz said. But the flip side is that the doctor can't check how well the anticoagulant is working, or even if the patient is complying with the recommended dose. “With warfarin, you can tell if the patient is taking it or not,” he said.

The FDA approved dabigatran in fall 2010 and rivaroxaban last November for stroke prevention in patients with atrial fibrillation. At this point, unlike with warfarin, there's no antidote to reverse bleeding with the newer drugs, Dr. Kaatz said, although researchers are working hard to identify one.

The new drugs also should be avoided in patients with poor kidney function, Dr. Kaatz said. But they may provide a new option for doctors nervous about prescribing warfarin, particularly in the elderly or other patients who appear vulnerable to falling and hitting their heads, he said.

Research to date shows that the two recently approved drugs, as well as apixaban, are less likely to cause bleeding in the head than warfarin, Dr. Kaatz said. “All three of these new [drug] molecules offer a statistically and clinically significant reduction in intracranial hemorrhage compared with warfarin.”

Not all the news is good, he cautioned: Studies also have found that risk of gastrointestinal bleeding is higher with dabigatran and rivaroxaban compared with warfarin. “You trade somewhat bleeds in the head with bleeds in the gut,” he said.

Last December, FDA officials announced that they were looking into post-marketing reports of serious and sometimes fatal bleeding in patients taking dabigatran. Federal officials want to determine if the rate is higher than would have been anticipated based on clinical data reviewed prior to drug approval.

The quality-of-life benefits for patients are intriguing, said Dr. Tayal.

“If I had my choice, I would probably switch a significant number of my patients over to dabigatran (Pradaxa),” he said. But at this point, he noted, the drug remains costly for many patients. Also, he said, some doctors might be taking a wait-and-see attitude toward the relatively new class of drugs.

The next phase

Given the growing panoply of options, primary care doctors should take the time to lay out the pros and cons of the newer drugs if a patient is an appropriate candidate, Dr. Kaatz said. Patients starting an anticoagulant for the first time might be particularly intrigued, once they learn they could largely avoid warfarin's dietary concerns and the logistics of blood monitoring, he said.

“I would predict that where you're going to see the biggest uptake to start with is among what we call the starters, but not the switchers,” he said.

Meanwhile, a third warfarin alternative appears to be on the verge of approval. FDA officials have projected that they'll make a decision about apixaban by late March, according to the drug's developers, Bristol-Myers Squibb and Pfizer.

A double-blind study comparing apixaban and warfarin, published in the Sept. 15, 2011 New England Journal of Medicine, found that patients with atrial fibrillation and at least one additional stroke risk factor who took apixaban experienced a 21% lower risk of stroke or systemic embolism compared with those taking warfarin. The apixaban patients also had a 31% lower risk of major bleeding and an 11% lower risk of death. The study was funded by Bristol-Myers Squibb and Pfizer.

Dr. Ansell, an author on the apixaban study, added a few other cautionary notes regarding the new warfarin alternatives. Their shorter half-life compared with warfarin doesn't make them a good choice for patients who skip doses and thus might suffer the related coagulation risk, he said. Moreover, the new drugs haven't been studied in patients with mechanical heart valves.

Even so, Dr. Ansell remains bullish as he discusses the next generation of anticoagulant therapy. “These drugs will have a major impact on the numbers of patients on warfarin,” he said. “I would anticipate that over the next four or five years, the population of patients on warfarin will decrease significantly, perhaps to as much as 50% of the current population.”