Newly-Approved Anticoagulants Offer More Options, Different Risks

by U.S. Medicine

June 12, 2013

Annette M. Boyle

Dr. Alan Jacobson, MD, Director of the anti-coagulation services at the Loma Linda, CA, Veterans Administration Medical Center

BOSTON – While newer anticoagulants provide options for many patients with atrial fibrillation (AF) who are at risk for stroke and not currently on blood thinners, real-world challenges accompany their strong clinical results.

“About half of patients with atrial fibrillation who should be on anticoagulants to prevent strokes are not. There’s a great opportunity now to treat those who are ineligible to take warfarin, or prefer not to be on it, with the new drugs,” Kenneth Bauer, MD, head of hematology at the Boston VAMC, told US Medicine.

The rate of stroke among adults with AF ranges from 1% to 20%, depending on patient-specific variables, according to the American Heart Association and American Stroke Association (AHA/ASA). Warfarin poses a bleeding risk of 1% to 12%, so it typically is reserved for patients at greatest thromboembolic risk.

The novel oral anticoagulants (NOACs) — dabigatran, rivaroxaban and apixaban — performed as well or better than warfarin in clinical trials.

“Overall, the new anticoagulants are clearly superior to warfarin. They are more efficacious and have fewer safety concerns, particularly in terms of intracranial hemorrhage,” said Bauer. Consequently, they may offer a reasonable treatment option for a broader band of AF patients.

The intensive management needed for warfarin also contributes to a high drop-off rate among those who do start anticoagulation treatment.

“Patients with atrial fibrillation have an increased risk of stroke for 10 to 20 years but typically stay on blood thinners for just two or three years,” noted Alan Jacobson, MD, director of the anti-coagulation services at the Loma Linda, CA, Veterans Administration Medical Center. “Our ability to control their risk goes out the window if they won’t stay on the medication.”

The newer drugs generally require less monitoring and have predictable effects with fixed dosages, unlike warfarin, making them more appealing to many patients.

Treatment Issues

The newer drugs have their own issues, ranging from the need for clear expectations to irreversible bleeding in an emergency.

“In the clinical trial setting, you have selected, well- supervised patients, all seen once a month. If I have a 30 second conversation with you and see you in six months, you won’t see the same safety or effectiveness seen in the trials,” Jacobson cautioned.

Within the VHA system, however, the outcomes on NOACs may be better than average. “If you go on one of the new drugs, you will be followed with warfarin patients and seen once every three months. Patients will be monitored for kidney function. They’ll be seen in a visit that focuses on blood thinners, with a clinician looking for signs of bleeding and monitoring for drug-drug interactions,” Bauer pointed out.

Unlike warfarin, which is metabolized in the liver, the NOACs are cleared by the kidneys. Consequently, patients with impaired renal function might not be good candidates for the newer drugs, particularly dabigatran, Bauer noted.

Because the kidneys excrete as much as 80% of dabigatran, impaired functioning increases the risk of serious hemorrhage. The Food and Drug Administration (FDA) advises physicians to assess renal function prior to prescribing the drug and periodically thereafter.

Drug interactions also can pose problems.

“Dabigatran has one pathway and three drugs to monitor for interaction. For the others, there are eight major drugs and multiple pathways to monitor,” Bauer observed. “There are a lot of moving parts in the equation when deciding which anticoagulant to recommend.”

Patient education with the new drugs is also very important.

“While the risk of bleeding is the same or less than warfarin, you have to keep in mind that warfarin is the No. 1 drug that causes older patients to go to the ER,” Jacobson said. “The new drugs reduce the risk by about 30%, but it would take a 60% drop for anticoagulants to drop below the No. 2 cause — insulin. We have to educate patients that, if they fall and hit their heads, they risk a hemorrhage and need to go to the ER.”

Warfarin causes 33% of emergency hospitalizations as a result of drug reactions among the general population over the age of 65.1

Bleeding Reversal

For many physicians, choosing between warfarin and the NOACs is all about the bleeding. While newer drugs have a lower incidence of bleeding in clinical trials, concerns have been raised because of widely reported issues with hemorrhaging and the lack of a specific agent to reverse the drug’s effects in an emergency.

In a recent Perspective article in The New England Journal of Medicine, FDA researchers presented results of a Mini-Sentinel analysis of bleeding associated with dabigatran, the first approved and most widely used of the NOACs.

Coagulation clinics, such as this one conducted by the Asheville, NC, VAMC, may become less common with wider adoption of alternatives to warfarin.

Post-marketing “reports of bleeding were anticipated, but the rate of reported incidents was unusually high and was greater than the concurrent rate of reported bleeding incidents with warfarin,” wrote the authors. They concluded, however, that the “large number of reported cases of bleeding associated with dabigatran provides a salient example of stimulated reporting,” and that the bleeding rate associated with dabigatran was not greater than that of warfarin.2

None of the newer anticoagulants has a clear reversal agent.

“Let’s be clear. There is no real effectiveness data for a bypassing agent,” said Bauer. “If one really needs to deal with a life-threatening bleed, it’s dealer’s choice which to use. The important thing is to get something into the patient quickly. You can use factor VIIA, drugs approved for hemophilia or other inhibitors and bypass agents. Usually, hospitals that treat hemophiliacs carry these medications, as would very large hospitals. We don’t usually carry these at our VA but can access them quickly.”

“It’s important to keep in mind that patients on these drugs aren’t bleeding in the streets or wandering in every night,” noted Jacobson. “If a physicians says, ‘I want to use warfarin because it’s reversible,’ I’d argue the point. For every patient on one of the new anticoagulants that comes in with a bleed in the brain that I can’t reverse, two don’t come in because they do not develop a bleed.”

Further, “most hospitals in the U.S. cannot reverse warfarin fast enough to make a difference in an emergency. If you have an emergent-surgery situation, you can’t wait for the drugs to wear off. You’re going in, regardless. In those situations, warfarin has no fewer postsurgical bleeds than the others,” noted Jacobson.

1 Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. NEJM. 2011;365:2002-2012.

2 Southworth MR, Reichman ME, Unger EF. Dabigatran and post-marketing reports of bleeding. NEJM. 2013;368:1272-1274.

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