Home Anticoagulation No antidote: reversal strategies for newer anticoagulants

No antidote: reversal strategies for newer anticoagulants

May 2013

Published in the May 2013 issue of Today’s Hospitalist

IT’S ALWAYS A CHALLENGE when an anticoagulated patient is admitted to the hospital with a serious bleed or develops one in-house. If the culprit is warfarin or heparin, doctors can rely on tried-and-true reversal strategies and antidotes: vitamin K, recombinant factor VII, and maybe fresh frozen plasma (FFP) for warfarin and aggressive protamine dosing for heparin.

But that’s far from the case if the bleeding is associated with dabigatran, the new, oral direct thrombin inhibitor, rivaroxaban or the very recently approved apixaban, both factor Xa inhibitors.

“There is no evidence-based antidote or reversal strategy for these drugs,” says Michael Streiff, MD, medical director of the Johns Hopkins anticoagulation management service in Baltimore. “That, understandably, makes doctors uncomfortable.” That’s particularly true as case reports of catastrophic bleeds make their way into the literature or crop up in institutions.

In the absence of formal guidance, hospitals are combing through those case reports, looking at the (very sparse) literature on how to try to manage bleeding in patients taking the newer agents. And multidisciplinary task forces are coming up with their own in-house protocols for reversal strategies that include the use of blood products: prothrombin complex concentrates (PCCs) like Bebulin and blood factors like recombinant factor VIIa and factor VIII inhibitor bypass activity agent (FEIBA). Some reversal protocols now add in charcoal and hemodialysis in last-ditch emergencies, at least for bleeds involving dabigatran.

“Right now, that’s the strategy,” Dr. Streiff points out. “If someone comes in bleeding, you give products that can potentially increase the amount of thrombin or factor Xa to bind up the drug and reverse the anticoagulant activity.”

But Dr. Streiff readily admits that these reversal strategies “are imperfect to a large degree, and there’s very little experience in humans. The few studies we do have were done on normal volunteers.”

Compounding that problem, physicians don’t have any good lab test to indicate if the reversal strategy is stopping the bleeding. Instead, he says, they must take a wait-and-see approach.

“The gold standard would be giving a bleeding patient a product that not only reverses the results on lab tests, but stops the bleeding,” Dr. Streiff says. “That’s what tells you that you have the right antidote, and we don’t have that kind of information yet for these medications. We’re relying on case reports.”

Not hassle-free
Although this is hardly the first time that drugs without an antidote have made their way into common use, the situation with dabigatran and rivaroxaban is catching many institutions off guard.

When these newer agents hit the market, they were touted as low-hassle, lower-risk alternatives to warfarin for patients with atrial fibrillation, offering an end to pesky INR monitoring and wide, worrisome swings in drug levels. The fact that both patients and primary care physicians heard that message loud and clear contributed to dabigatran, in particular, gaining ground in the outpatient setting. Now that rivaroxaban has also been approved for both DVT/PE prevention and treatment, the drug is increasingly being prescribed to inpatients.

But while these drugs offer some advantages over warfarin, including far fewer drug-drug interactions, hospitalists are finding that they’re anything but hassle-free. Catastrophic bleeds are occurring, often with little warning. Patients with poor kidney function “including some who never should have been prescribed the medications in the first place “are showing up at the hospital on these drugs, presenting management challenges for hospitalists because the drugs have to be cleared by the kidneys.

And given everyone’s limited experience with the newer agents, perioperative and postoperative management concerns are emerging. Hospitalists are also trying to figure out what to do with anticoagulation on discharge if they are worried about patients continuing on one of the newer agents.

In-house guidance
At Henry Ford Hospital in Detroit, a multidisciplinary team came up with what James Kalus, PharmD, calls a “one-stop shop” in terms of in-house guidelines for anticoagulation management. One year in the making, the guidelines resulted from a collaboration of many specialties and were put in place last July.

“We decided to go ahead and address all the agents, including the new ones, because when someone comes in in the middle of the night with bleeding, the experts are not always available,” Dr. Kalus says. “And finding information about reversing anticoagulation is not a quick and easy thing to do.”

While people sometimes feel paralyzed in the face of no evidence, “if you have a bleeding patient on a stretcher in front of you, you will try something,” he says. “Even though there’s no evidence-based literature on reversal, we thought it was better to have the ‘experts’ make up something.”

In cases of life-threatening bleeding, Henry Ford’s guidelines call for using PCCs in addition to either recombinant factor VIIa or FFP to overwhelm and bind the newer agents, Dr. Kalus explains.

David Paje, MD, associate division head for hospital medicine at Henry Ford, says he and his colleagues are grateful for the guidance. “In general, the rates of major bleeding with these new oral anticoagulants are not any worse than warfarin,” Dr. Paje says, “but dabigatran and rivaroxaban are more likely to cause gastrointestinal bleeding. “If hospitalists are treating patients already at risk for GI bleeding because of their history, this is something doctors “might want to keep in mind” as they choose what to prescribe.

Evaluating kidney function
Another important consideration for hospitalists, Dr. Paje maintains, is evaluating the kidney function of patients coming to the hospital already taking these agents or having them prescribed for the first time.

All three of the new medications are partially eliminated through the kidneys. “That’s one thing that we have to think about when using these drugs,” Dr. Paje notes. “Patients’ kidney function can change dramatically in a short period of time, particularly during acute illness. That may significantly affect the elimination of these anticoagulants.”

David Garcia, MD, who’s with the University of Washington in Seattle, is immediate past president of the Anticoagulation Forum, a national forum that maintains an up-to-date database of protocols related to all anticoagulants. He points out that the reversal guideline developed at his facility calls for activated charcoal when either dabigatran or rivaroxaban has been ingested in the past few hours. That strategy is followed by two units of FFP and PCC in a dose of 25 units per kilogram over 10 minutes for patients who do not have a recent history of a thrombotic event.

In emergency situations and when renal failure is suspected, dialysis may be ordered for patients on dabigatran. (The manufacturer of rivaroxaban says the agent is not dialyzable “because of high plasma protein binding.” Dialysis is likewise not recommended as a reversal strategy for patients on apixaban.)

“The good news is that these drugs have a short half-life,” says Dr. Garcia. “If you can support the patient with blood products, intravascular volume repletion and other treatment, it may not be necessary to reverse them in all situations.”

“Set it and forget it”
That advantage of a short half-life disappears, however, in patients with poor renal function. According to Henry Ford’s protocol, for instance, the anticoagulant effect of dabigatran in patients whose creatinine clearance is less than 50 mL/min may last as long as five days. That’s a problem because hospitalists are increasingly encountering patients who shouldn’t be on the drugs to begin with because of borderline or poor renal function.

It’s what Thomas Rivers, PharmD, clinical lead pharmacist at Swedish Medical Center in Seattle, calls the “set it and forget it” mentality. He thinks that some community physicians have the mistaken notion that because there’s no recommended monitoring schedule and no INR to review, patients don’t need to be seen regularly. It’s the patients who’ve been on the drugs for several months unmonitored who are showing up in the case reports with bleeding, whether it’s manageable or life-threatening.

“In my conversation with physicians,” Dr. Rivers says, “I tell them that I’d have patients come in for a kidney function test as a baseline, and then come in for a quick blood count every few months.” The point of that regular follow-up, he explains, is to look for changes that suggest bleeding.

“These are not the be-all, end-all wonder drugs of anticoagulation,” he adds. “Every drug carries a little bit of its own baggage. That’s what I think some prescribing physicians aren’t taking into account.”

Dr. Rivers also advises hospitalists to be quick to convert patients to warfarin or other alternatives if there’s any concern about renal function worsening. “I think it’s also appropriate to have a conversation with the outpatient physician if the patient comes in on dabigatran but really isn’t a safe candidate for it,” he says.

Knowledge gap
Allison Burnett, PharmD, the clinical lead on the inpatient anticoagulation service at the University of New Mexico Hospital in Albuquerque, sees a similar knowledge gap among prescribers.

“When dabigatran first came out, even though it’s a good drug, I think it got used too loosely,” Dr. Burnett says. “We saw some adverse events such as bleeding, and often it was because patients weren’t appropriate candidates, such as those with impaired renal function.” She notes that the important questions are these: Were patients appropriate when therapy started and then renal function declined? Or were they inappropriate to begin with? “In our experience, the latter is more often the case.”

She and several other team members have created robust systems and protocols that attempt to address all clinical use of anticoagulants in hospitalized patients and in those coming in for procedures. Topics addressed include initial prescribing, perioperative management and potential reversal.

Until recently, the hospital had no standardized processes or guidelines for uniformly managing patients on anticoagulation who needed invasive procedures. With the advent of these new agents, however, it quickly became apparent that such processes were needed, due to a lack of provider awareness that these agents are high-risk medications.

“It’s piecemeal now if the outpatient physician hasn’t or isn’t willing to set up a perioperative bridging plan,” says Dr. Burnett. “We’re especially concerned about patients managed outside our Coumadin clinic or who come in from rural communities, where providers may not be as familiar with bridging guidelines or the newer anticoagulants.” The protocol tries to funnel all of those patients, whether they are on new or old anticoagulants, to clinicians with anticoagulation expertise.

While the hospital has seen relatively few patients on the newer anticoagulants, Dr. Burnett says that use of the drugs will increase and that she and her colleagues want to proactively anticipate clinical challenges.

“In the two major bleeds associated with newer anticoagulants that we’ve seen,” Dr. Burnett says, “we used a combination of factor VII and PCCs for one and just PCC for the second patient.” The first patient, who was a GI bleed, had a poor outcome, she notes. “The other patient, an intracranial hemorrhage, did fairly well.”

The upsides
According to Baltimore’s Dr. Streiff, an antidote for dabigatran is already in early stages of development, and work is being done on reversal agents for the other new anticoagulants.

For hospitalists, the development of those antidotes can’t come soon enough. And the new indications for rivaroxaban for clot prevention and treatment means hospitalists will likely be seeing more patients on the newer agents in their facilities.

The University of New Mexico, for example, recently added rivaroxaban to its formulary for orthopedic post-procedure DVT/PE prophylaxis, and doctors there are mostly pleased with the results. Physicians report some additional bruising and mucosal bleeding with the drug, Dr. Burnett explains, but nothing like major bleeds into critical areas or anything that required a return to the operating room. The drug is turning out to be a good alternative to subcutaneous enoxaparin, she adds, because of the ease of use and patient and provider satisfaction.

“Our hospitalists are chomping at the bit for us to expand our approved inpatient formulary for these newer anticoagulants, rivaroxaban in particular, for VTE treatment,” she points out. “It’s an easier regimen and there are fewer drug interactions than with warfarin.”

That doesn’t mean that drug-drug interactions aren’t an issue. The short list of interactions with the new agents includes antiarrhythmic agents such as dronedarone and amiodarone, quinidine, and antifungals, as well as some antiretrovirals like ritonavir.

“The list of drugs that these new agents interact with isn’t huge, but checking for these is still an important issue,” Dr. Streiff says. “It’s one that hospitalists especially should keep in mind because they often add new drugs in the hospital.”

Bonnie Darves is a freelance health care writer based in Seattle.

Talking through the decision to reverse

DETROIT’S HENRY FORD HOSPITAL is one of many facilities around the country that has crafted reversal strategies for all anticoagulants, including dabigatran and rivaroxaban. The big advantage of having guidance in-house, after all, is making sure that frontline physicians facing an anticoagulated patient having a bleed don’t have to try to cobble together a reversal strategy on their own at 3 in the morning.

But unlike some hospitals, Henry Ford has imposed an important restriction: Doctors who want to prescribe factor VIIa and prothrombin complex concentrate (PCC)-agents recommended to try to reverse the anticoagulating effects of dabigatran and rivaroxaban-must first have those orders approved by a physician member of the hospital’s anticoagulation subcommittee.

“We opted to have an ‘approver’ because we wanted someone who was familiar with the risks and benefits of reversal involved at the point where the decision was made to reverse,” says James S. Kalus, PharmD, senior manager of patient care services.

When clinicians know a reversal option is available, Dr. Kalus adds, their “knee-jerk response is to attempt to reverse, even if they aren’t as familiar with the potential risks of reversal. We wanted experts from the committee to have an opportunity to say, ‘Maybe this isn’t the best person to reverse’ after hearing the clinical scenario.”

Hospitalist David Paje, MD-one of the designated people on the list-agrees.

Many clinicians, he explains, aren’t familiar with using factor VIIa or PCC as potential reversal agents, particularly with the new anticoagulants. “The potential risk of thrombosis with these blood factors and the absence of data to support an overwhelming benefit led us to require a thoughtful discussion of case-specific clinical and patient values prior to administering these agents,” he says.

But do doctors feel the requirement is micromanaging their clinical decisions? “Overall,” says Dr. Kalus, “I think the frequently contacted approvers are viewed as a resource.”

Tips for prescribing

WHILE BLEEDS IN PATIENTS taking either dabigatran, rivaroxaban and apixaban are making headlines, hospitalists also have to make good clinical calls whether they’re prescribing one of the new agents to a patient for the first time or resuming the therapy after a surgery or procedure.

In terms of initial prescribing, David Garcia, MD, says that there is a push to try one of these new agents in patients who might be poor candidates for warfarin. But Dr. Garcia advises a go-slow approach, whether prescribing an agent for a new diagnosis of atrial fibrillation or as postop prophylaxis.

“When selecting appropriate candidates for these drugs, the key is to check the renal function,” notes Dr. Garcia, who’s at the University of Washington in Seattle and is immediate past president of the Anticoagulation Forum, a national forum of anticoagulation professionals. “The drugs are cleared by the kidneys to varying degrees, but all depend to some extent on renal clearance.”

“If a patient’s creatinine clearance is less than 30 ccs per minute, I wouldn’t touch either dabigatran or rivaroxaban,” cautions Michael Streiff, MD, medical director of the Johns Hopkins anticoagulation management service in Baltimore. And hospitalists should remember that for rivaroxaban, liver function is also a concern. Patients were excluded from studies on the drug if their liver function ALT was twice the upper limit of normal.

“I use that even though it’s conservative and strict,” Dr. Streiff says, “because these drugs are so hard to reverse.”

Hospitals forming teams to come up with in-house guidelines also need to address perioperative management. When restarting anticoagulation after surgery, for instance, remember that both dabigatran and rivaroxaban have a relatively rapid onset of action, notes David Paje, MD, associate division head for hospital medicine at Henry Ford Hospital in Detroit.

“These drugs can be very effective as early as two hours after administration,” he says, “so make sure the risk for bleeding is significantly reduced before restarting the drug and collaborate closely with the surgeon.” This is also important, Dr. Paje adds, even when the lower dose of rivaroxaban is being used for DVT/PE prophylaxis.

Want more info?

Go online to the Clinical Protocols page at Today’s Hospitalist to see protocols developed by the University of Washington in Seattle and the University of New Mexico Hospital in Albuquerque for anticoagulation management and potential reversal.