Article Archive
November/December 2013

Warfarin Replacement?

By Mike Bassett
Today’s Geriatric Medicine
Vol. 6 No. 6 P. 16

New atrial fibrillation drugs possess significant advantages over warfarin for reducing the risk of embolic events such as a stroke or peripheral embolism.

Atrial fibrillation (AFib) is a major risk factor for stroke and represents a significant health problem that’s pervasive among older adults because of their age. According to a 2012 report by the American Heart Association Statistics Committee and Stroke Statistics Subcommittee, AFib increases the risk of stroke by fivefold and accounts for 15% to 20% of ischemic strokes. The most serious complication of AFib is thromboembolic stroke, according to the National Center for Biotechnology Information.

During AFib, the heart’s atria quiver rather than beat, allowing blood to remain in the chamber and potentially cause a clot. If the clot travels from the heart and reaches the brain, a stroke becomes imminent. “Patients with atrial fibrillation are at a greater risk for stroke than the general population,” says Rod Passman, MD, medical director for the Program for Atrial Fibrillation at the Bluhm Cardiovascular Institute of Northwestern Memorial Hospital and an associate professor of cardiology at Northwestern University’s Feinberg School of Medicine in Chicago.

Khalid H. Sheikh, MD, MBA, FACC, who practices with Health First Cardiovascular Specialists in Brevard County, Florida, and is the director of general cardiology services and medical director of cardiovascular echo and vascular services at Cape Canaveral Hospital in Merritt Island, estimates that 3 to 5 million people in the United States have AFib and suggests that number will grow to 15 to 20 million people by 2050.

Because he practices in a state with a large elderly population, Sheikh sees his share of AFib patients on a daily basis. “On any given day we see about 30 to 40 atrial fibrillation patients in the office and about 20 to 30 in the hospital,” he says. “So we are seeing them both in an acute setting as well as well as the stable chronic setting.”

Patients with AFib have an especially high risk of blood clots that can lead to stroke. Warfarin (Coumadin) has been the gold standard for stroke prevention in patients with AFib for the past 50 years. But to be effective, warfarin requires careful monitoring. Patients must take doses as prescribed, must have blood drawn or blood tests at regular intervals to assess their international normalized ratio (INR), and must revise their doses under the supervision of a physician in response to their INR levels.

Within the last several years, the FDA has approved several new anticoagulants as alternatives to warfarin: dabigatran (Pradaxa), a direct thrombin inhibitor; rivaroxaban (Xarelto), a factor Xa inhibitor; and apixaban (Eliquis), also a factor Xa inhibitor.

“The availability of these new drugs is really changing the landscape,” says Larry B. Goldstein, MD, FAAN, FANA, FAHA, a professor of medicine (neurology) and the director of the Duke Stroke Center at Duke University Medical Center in Durham, North Carolina. “Having options is always a good thing for patients, but it also adds a great deal of complexity because what used to be a very straightforward decision [on how to treat AFib patients] now has many more layers added to it.”

Each of these new drugs has benefits, Goldstein says, but also has aspects that will make treating AFib more challenging. “One of the problems is that these drugs haven’t been directly compared to one another in the same patient populations,” he explains. “What that means is that choosing between them is based on extrapolation and not much hard data, and we’ve learned many times that making decisions based on indirect comparisons is always hazardous and can lead you down the wrong pathway.”

Safe and Effective
In testing these drugs’ efficacy against warfarin’s performance, the newer drugs showed some significant advantages. All were studied in large clinical trials of between 14,000 and 19,000 subjects—some of the largest clinical trials ever done in cardiology, Sheikh says—and all showed that these drugs were equal to warfarin or superior in reducing the risk of embolic events such as a stroke or peripheral embolism.

“By a significant percentage—30% to 40%—there was a reduction in stroke or systemic embolism,” Sheikh says. “And all of these drugs did it with at least equivalent safety or, in some cases, even greater safety.” He notes that bleeding presents the biggest risk with any of these drugs, including warfarin, and with each of the new anticoagulants, the bleeding risks appear to be equal to warfarin or lower.

The most catastrophic form of bleeding that can occur is intracranial hemorrhage, “which is fatal in almost all cases,” Sheikh says. “But one of the great advantages in almost all of these drugs is that they substantially reduce the risk of intracranial hemorrhage, so that one horrific scenario we often see with warfarin patients is significantly reduced.”

One of the biggest advantages of the new anticoagulants is that they don’t require the same intensive INR monitoring (a measure of bleeding time). “They have such predictable pharmacokinetics that you can take them like any other drug, which doesn’t require monitoring of drug levels,” Sheikh says.

Pros and Cons
According to Mark D. Coggins, PharmD, CGP, FASCP, director of pharmacy services for Golden Living Centers, practitioners who prescribe warfarin use the INR to measure how well warfarin is thinning the blood and preventing the possibility of blood clots.

The need for routine lab monitoring is disruptive to patients and requires health care professionals to invest time and effort in drawing blood, transferring the blood to a lab, interpreting the values, and then implementing dosage changes that could result in a physician writing a new prescription and requiring a patient to go to the pharmacy to have the new prescription filled. “But with the new anticoagulants such as Pradaxa and Xarelto, there is no need for this lab monitoring, which is a significant advantage,” Coggins says.

When it comes to the issue of drug interactions, warfarin “has a whole slew of potential interactions that can increase its anticoagulation effect,” Goldstein says. “But it’s important to know that these new drugs have potential drug interactions.” For example, he points out that dabigatran can interact with P-glycoprotein inhibitors such as amiodarone, ketoconazole, quinidine, and verapamil.

Additionally, there are dietary restrictions associated with warfarin that aren’t necessary with the new anticoagulants. Warfarin works against vitamin K, which the liver uses to make blood-clotting proteins, reducing the liver’s ability to use vitamin K to produce these proteins. So if a patient on warfarin eats too many foods with high levels of vitamin K, such as leafy greens or liver, it can affect warfarin’s metabolism. “It could either get very high or very low and increase the risk of bleeding or stroke,” Sheikh says. “But with these new drugs you don’t have to worry about these types of food interactions. People can eat what they want.”

While these new anticoagulants offer several advantages compared with warfarin, this drug does have something going for it that the new ones don’t: an antidote. “When someone [on warfarin] comes in with bleeding or toxicity, we can reverse it with vitamin K,” Sheikh says. “But there is no current antidote for any of these [new] drugs. So if someone comes in with an episode and needs to have a reversal, the only way to do it is to basically just let the drug wear off.”

The lack of specific proven antidotes for these new agents “makes bleeding episodes potentially much more dangerous because the steps to reverse anticoagulation are much more difficult,” Coggins says.

Vigilance Required
Sheikh says that even though clinical trials demonstrate the new anticoagulants generally are safer, physicians should keep in mind that patients still are taking blood thinners. As previously noted, physicians should remember that the risk of bleeding is significant for both warfarin and the new anticoagulants. “There are questions being brought up around whether the newer agents—more specifically Pradaxa—causes increased bleeding,” Coggins says. “But it’s not clear if the number of bleeds reported for the newer agents is higher because they are newer medications, and if the number of bleeds reported for warfarin is lower because serious bleeding is a well-known and recognized side effect which can occur when warfarin is used.”

After having approved Pradaxa in 2010, the FDA reexamined the drug following receipt of a large number of reports of bleeding among Pradaxa users. As a result, the FDA compared the actual rates of gastrointestinal bleeding and intracranial hemorrhage for new users of Pradaxa with those of new users of warfarin. The FDA found that bleeding rates associated with the new use of Pradaxa appear to be no higher than those associated with the new use of warfarin, which was consistent with the findings of the clinical trial on which the FDA based its approval of the drug.

But there are increased concerns about warfarin as well. A five-year study of 125,195 older adults with AFib, published in February 2013 in the Canadian Medical Association Journal, found that the rates of serious bleeding among patients taking warfarin are much higher than those found in the drug’s clinical trials.

While clinical trials for warfarin found that its use resulted in serious hemorrhage rates of 1% to 3% per year, the study found that the overall rate of hemorrhage was 3.8% per person per year. And according to Tara Gomes, a scientist at the Toronto-based Institute for Clinical Evaluative Sciences, about 11,000 people in the study had a serious bleed.

Renal Function Concerns
In addition to concerns about bleeding, physicians also should be aware of issues regarding renal function. “It is critically important for patients to have their renal function checked and for lower doses to be prescribed in any patient with reduced renal function, especially in the frail elderly patient,” Coggins says. For example, he says, patients with a creatinine clearance rate (which compares the level of creatinine in urine with the creatinine level in the blood) greater than 30 would receive Pradaxa dosed at 150 mg twice daily. Those with a creatinine clearance between 15 and 30 would receive Pradaxa dosed at 75 mg twice daily, while patients with levels below 15 would probably not be appropriate candidates for these new drugs.

“It is also important to recognize that the effects of these medications can last for several days, and this increases with reduced renal functioning,” Coggins says. “This is important to keep in mind if the anticoagulant effect is not desired during surgery. Many more steps are necessary to reverse the effects of these new medications, and surgery may need to be delayed.”

When patients stop taking anticoagulant drugs to undergo minor surgery or dental procedures, their risk of experiencing a stroke or system embolism is higher, which means they must be carefully monitored during this time, according to Sheikh.

Physicians also should take into account whether patients have compliance issues before physicians consider ceasing a warfarin regimen and prescribing a newer anticoagulant. Warfarin has a relatively long half-life, Goldstein points out, so if a patient skips a dose, there usually are no major consequences.

On the other hand, the new anticoagulants have relatively short half-lives, “so if you miss a dose, you’re not protected,” Goldstein says. “We’ve had several patients with atrial fibrillation who’ve been on these drugs, have missed one or two doses, and come in with a stroke associated with having—at least with dabigatran—no detectable drug levels. So with patients who are noncompliant with warfarin, there may be real concerns about having them on one of these drugs.”

Advise Patients
Goldstein explains that eliminating the need for monitoring a patient’s INR can be a double-edged sword. While it may be inconvenient, having patients undergo frequent monitoring means they are maintaining some kind of regular contact with the health system, which can result in health-related dividends, even if it’s simply taking a patient’s blood pressure. “But if there’s no blood check, that’s not happening,” he says. “And compliance reinforcement isn’t happening either.”

Because of the increased risk of stroke, physicians should counsel patients prior to any decision to stop taking one of the new anticoagulants. Additionally, Coggins says, whether patients are taking warfarin or any of the new agents, physicians should explain that patients may bruise more easily and that it may take longer for any bleeding to stop.

Coggins says patients should be advised to contact their physicians and seek immediate care if they note unusual bleeding from the gums or nose, cough up or vomit blood, experience heavier than normal menstrual bleeding or vaginal bleeding between periods, notice pink or brown urine, pass red or black stools that may have a tarlike appearance, or experience bruises that occur or increase in size without a known cause.

While the use of these new anticoagulants is becoming more widespread, warfarin “remains much more widely used,” Coggins says. “This should change over time as we continue to understand the bleeding risk associated with the newer agents.”

Sheikh notes that the newer drugs are expensive, which could prove to be a barrier to broader use, although he expects them eventually to be used on a wider scale, particularly with the United States’ burgeoning aging demographic.

“I think these new drugs are being embraced,” Goldstein says. “Physicians feel they are much easier to administer; they don’t need to follow them [patients]; they don’t worry about food interactions. Patients like that, and they like the fact that they don’t have to get their blood checked.”

However, Goldstein points out that there is no comparative data between the drugs, so “the choice of which agent to use on which patient requires a good deal of discussion and thought. There are roles for all of these drugs. But I think that the decisions are not going to be easy or straightforward, and that we still have to get more experience with them as time goes on.”

— Mike Bassett is a freelance writer based in Holliston, Massachusetts.