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New Kids on the Block

From: The Hospitalist, June 2011

As new anticoagulants seek to replace warfarin, hospitalists need to know all the facts before making therapy decisions

by Thomas R. Collins

New Kids on the Block

As director of the hospitalist program at University of Utah Healthcare and the medical director of the University of Utah Health Care Thrombosis Service, Robert Pendleton, MD, closely monitored the progress of the anticoagulant dabigatran as it marched toward regulatory approval in the U.S. Developed by Boehringer Ingelheim and marketed as Pradaxa, the drug is a big deal.

“We were sort of primed and poised and anticipating that dabigatran would be approved,” Dr. Pendleton says. The FDA approved dabigatran in October for stroke prevention in nonvalvular atrial fibrillation patients. It is the first new oral anticoagulant approved in 50 years and the first of three drugs expected to mount a challenge to the longtime standard of care, warfarin (Coumadin).

When Dr. Pendleton’s hospital got ready to add the drug to its formulary, though, the process had to slow down. The hospital wasn’t quite ready for dabigatran.

“The first thing we did is sent out an institution-wide survey to get some understanding of baseline knowledge of practitioners who might be prescribing dabigatran … and found an enormous educational need,” Dr. Pendleton explains, but “most people who we anticipated would have been prescribing dabigatran, such as our cardiologists, had a very poor understanding of the clinical data and the drug itself.”

So University of Utah Healthcare developed an education plan for providers, made resources available so that providers could easily get information about the drug, and developed institutional guidelines on appropriate use, how they would handle off-label uses, and managing urgent situations. The drug was added to the formulary in February, and the change has been working out well, with “an exponential increase in prescribing,” Dr. Pendleton says.

The challenges at University of Utah Healthcare are being experienced—or probably soon will be—by hospitalists around the country as new oral anticoagulants become available for use. Experts say hospitalists need to take a keen interest in the new drugs, given the large number of CVT, VTE, atrial fibrillation, and other patients who are at an increased risk of clotting.

Most hospitalists see anticoagulated patients on a daily or weekly basis, experts say. Dr. Pendleton estimates that if you include patients who are on a preventive dose (e.g. to prevent DVT), as many as 80% or more of HM patients use anticoagulants.

Robert Pendleton, MD“The first thing we did is sent out an institution-wide survey to get some understanding of baseline knowledge of practitioners who might be prescribing dabigatran … and found an enormous educational need.”

–Robert Pendleton, MD, University of Utah Health Care Thrombosis Service

“Anticoagulants are dangerous and they are often a bit tricky to use,” says Gregory Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego, where he has won awards for their DVT prevention program. “If you look at the top three or four adverse drug events that occur, usually warfarin is one of those. … It’s common, it’s a safety issue, it’s tricky to use—all of those things add up to something that hospitalists need to pay attention to.”

New Options, New Challenges, New Costs

Dabigatran, which inhibits thrombin, is part of a new anticoagulant parade, along with rivaroxaban (Xarelto) and apixaban, both of which inhibit Factor Xa. They offer patients attractive anticoagulant options that, unlike warfarin, don’t require blood draws for monitoring every few weeks. The new options also omit the lengthy list of drug and food contraindications of warfarin.

But questions about the ability to reverse bleeds while patients are on the new drugs, as well as concerns about their costs, are forcing hospitalists to evaluate carefully. So far, dabigatran is the only one approved in the U.S., and only for one indication.

The intention in development was to create “drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise,” says Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia. “When you look at the studies, actually they do reasonably well. It’s a pretty big step.” (For a list of major anticoagulant studies, see Figure 1, below.)

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Figure 1. Major Studies on Potential Anticoagulant Successors to Warfarin

Apixaban

Topic: Stroke prevention in nonvalvular atrial fibrillation
Study: AVERROES
Conclusion: Apixaban superior to aspirin, with a number needed to treat of 47, in 5,600 patients not suitable for warfarin
Publication: N Engl J Med. 2011;364(9):806-817.

Topic: Venous thromboembolism prevention after orthopedic surgery
Study: Lassen et al
Conclusion: Apixaban equivalent to enoxaparin in total knee replacement
Publication: J Thromb Haemost. 2007;5(12):2368-2375.

Study: Lassen et al
Conclusion: Apixaban failed noninferiority against enoxaparin 30 mg every 12 hours in total knee replacement
Publication: N Engl J Med. 2009;361:594-604.

Study: ADVANCE-2
Conclusion: Apixaban superior to enoxaparin 40 mg once a day after total knee replacement
Publication: Lancet. 2010;375:807-815.

Rivaroxaban

Topic: Venous thromboembolism prevention after orthopedic surgery
Study: RECORD trials
Conclusion: Compared with enoxaparin in total hip and knee replacement patients, rivaroxaban was superior in all cases, even at an enoxaparin dose of 30 mg every 12 hours. The total VTE rate was 2% in the rivaroxaban group and 9.3% in the enoxaparin group; number needed to treat was 13.7.
Publication: Lancet. 2008;372(9632):31-39.

Dabigatran

Topic: Stroke prevention in nonvalvular atrial fibrillation
Study: RELY
Conclusion: When comparing dabigatran to warfarin in nonvalvular atrial fibrillation patients: 1.69% of patients had a stroke or systemic embolism in the warfarin group, compared with 1.53% for the 110-mg dabigatran group and 1.11% in the 150-mg dabigatran group. The major bleeding rates were 3.36% for warfarin, 2.71% for 110-mg dabigatran, and 3.11% for 150-mg dabigatran. The number needed to treat was 172.
Publication: N Engl J Med. 2009;361:1139-1151.

Topic: Venous thromboembolism prevention after orthopedic surgery
Study: BISTRO II
Conclusion: Various doses of dabigatran reduced VTE compared with enoxaparin 40 mg in total hip and total knee replacement patients
Publication: J Thromb Haemost. 2005;3(1):103-111.

Study: RE-NOVATE
Conclusion: 220 mg or 150 mg of dabigatran compared to enoxaparin for total hip replacement. Both doses were noninferior.
Publication: Lancet. 2007;370:949-956.

Study: RE-MODEL
Conclusion: 220 mg and 150 mg of dabigatran both noninferior in total knee replacement
Publication: J Thromb Haemost. 2007;5(11):2178-2185.

Study: RE-MOBILIZE
Conclusion: Dabigatran failed noninferiority to 30 mg of enoxaparin every 12 hours 30 q12, but dabigatran was started later
Publication: J Arthroplasty. 2009;24(1):1-9.

Topic: Acute venous thromboembolism
Study: RE-COVER
Conclusion: Dabigatran, 150 mg twice a day, was compared to warfarin after an average of a nine-day run-in with heparin in patents with acute venous thromboembolism. 60% of the time was spent with a therapeutic INR in the warfarin arm. VTE was recurrent in 2.4% of patients in the dabigatran arm and in 2.1% in the warfarin arm. Major bleeds were less common in the dabigatran arm, at 1.6% compared to 1.9%.
Publication: N Engl J Med. 2009;361:2342-2345.

Rivaroxaban, being developed jointly by Bayer Healthcare and Johnson & Johnson, has been submitted to the FDA for approval for stroke prevention in nonvalvular atrial fibrillation patients, which would put it in direct competition with dabigatran. And apixaban, being co-developed by the global alliance of Bristol-Myers Squibb and Pfizer, expects to submit for the same indication approval this year, Bristol-Myers Squibb spokeswoman Christina Trank says. (updated June 16)

All three are under study for other indications, including VTE prevention after hip and knee replacement surgeries, and clot prevention in the acutely ill.

The stakes are high for the companies: Manufacturers and analysts estimate that the market for anticoagulants will top $10 billion by 2015, with some estimates even higher. Dabigatran has been in development by Boehringer for about 15 years and studied in more than 19,000 patients, spokeswoman Anna Moses says.

Bayer Healthcare says rivaroxaban’s development costs amount to more than $1.5 billion.

“I think all of them are promising,” says Shaun Mickus, a Johnson & Johnson spokesman. “We’re looking at meeting unmet medical needs. We have patients who, for one reason or another, are having blood clots in these indicated areas, and some of them are doing fine and getting the help they need, and others may not be.”

Boehringer spokeswoman Anna Moses said dabigatran is on formulary with 70% of the top 1,600 hospitals in the U.S.

“Our current focus is on efforts to educate physicians and payors about the product, including its efficacy, safety, and appropriate use,” Moses said in an email.

Geno Merli, MD, FHM“[These are] drugs that don’t require monitoring, drugs that have very little drug-drug interaction, and drugs that have no food interaction; a drug where you give a fixed dose and the patients get the same effect anticoagulation-wise.”

–Geno Merli, MD, FHM, director of the Jefferson Center for Vascular Disease and CMO at Thomas Jefferson University Hospital in Philadelphia

Warfarin’s Way Out?

Data on Pradaxa for stroke prevention in nonvalvular atrial fibrillation might be encouraging, but to some experts, it’s not automatically going to prove to be a superior alternative to warfarin, says Ian Jenkins, MD, assistant professor in the Division of Hospital Medicine and part of the VTE prevention team at UC San Diego.

“It is, statistically, significantly better than warfarin for nonvalvular atrial fibrillation when you look at the stroke rate, but the number needed to treat is not small—it’s 172 patients a year,” Dr. Jenkins says. “So, as far as looking at an individual patient and saying, ‘Am I going to prevent a stroke in this person by switching them to dabigatran?’ it’s actually unlikely that you would. And depending on the type of institution you’re at and how good they are at managing warfarin, you might be able to get a similar improvement in their stroke risk by, say, improving the quality practices for warfarin use at your hospital.”

“I think a lot of people are reluctant to start it on people who are doing well on warfarin,” Dr. Maynard adds. “There’s a lot of people who have been fine for many years on warfarin, even though it’s a tricky drug.”

At Thomas Jefferson, Pradaxa’s use is restricted to cardiologists, hematologists, and the hospital’s vascular anticoagulation service, and a doctor outside those categories has to get a consult first, Dr. Merli says. At University of Utah Healthcare, off-label uses have to be funneled through the thrombosis service, Dr. Pendleton says.

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Warfarin’s Many Medical Contributions Have Strange Origins

Warfarin’s Many Medical Contributions Have Strange Origins

The standard in anticoagulation therapy for 50 years, warfarin might not have been discovered if a farmer hadn’t sought help for his dying cattle.

In February 1933, farmer Ed Carlson drove through a blizzard to Madison, Wis., stopped biochemist Karl Paul Link on the campus of the University of Wisconsin, and told him that sweet clover hay disease was causing his cattle to bleed to death. Link’s advice was perfunctory: have the cattle avoid eating spoiled hay.

But after the farmer’s visit, Link’s “senior student” persuaded him to try to find the agent within spoiled sweet clover hay that was causing the hemorrhaging effects. Link’s work eventually led to warfarin, a derivative of Coumadin, the substance that gives sweet clover its sweet smell. The name is a combination of WARF, which stands for Wisconsin Alumni Research Foundation, and coumarin. It was first used as a rodenticide.

Faith grew that the compound would not be fatal to people when, in 1951, an army inductee tried to commit suicide using the rat-killing compound. But he was unsuccessful, and his bleeding was reversed with doses of vitamin K.

By then, Link had perfected warfarin sodium and it was first made available for widespread clinical use under the trade name Coumadin sodium.

Howard Bremer, a retired patent attorney for WARF who still does consulting work for the foundation, says warfarin made $4 million for the foundation during the patent period from 1952 to 1972 (about $20 million in today’s dollars).

Money isn’t the main point, though, he says. “All the inventors are dead, the royalties long since ceased to flow to WARF with the expiration of the patents that were licensed,” Bremer says. “And here it still is the number-one anticoagulant utilized in cardiovascular programs worldwide.”

Thrombosis experts say that warfarin will still play a big role in anticoagulation treatment even as new drugs hit the market, in part because of familiarity and because some indications will not be studied right away.

“For all of its limitations and complexities, it has absolutely and markedly improved healthcare for patients with those disorders,” Dr. Pendleton says. “It took a long period of time to understand how to use warfarin appropriately and in what patients and at what dose. I think there will be—although different—similar challenges with the new drugs.”—TC

“Our concern was that our clinicians may use the drug for off-label indications and not for atrial fibrillation, as approved by the FDA,” says Dr. Merli, whose job as chief medical officer includes overseeing patient safety. “We felt that Pradaxa’s a good drug, has a good track record, but our fear was, how do we control the doctors who may want to use Pradaxa for other indications that have never been studied?”

Pradaxa also is considered for use in especially complicated cases that might be unsuitable for warfarin, he says.

A major consideration for the new drugs is that, unlike warfarin, they have no proven antidote should a patient have a bleeding episode while taking them. Warfarin patients are given vitamin K to ease the bleeding, but it’s not so simple with the new medications.

Dr. Merli expects those concerns will have a “big impact on physician utilization of these new agents.”

Experts say the main option in the event of a bleed on the new agents, at least for now, is to simply wait it out while giving the patient fresh frozen plasma.

“What if you fall down and hit your head and you bleed into your brain?” Dr. Merli asks. “I’m waiting for our first patient to come in, you know, with a massive brain bleed on Pradaxa.” The hospital, he notes, probably would treat with fresh frozen plasma, but then resort to Factor VII, which costs $10,000 to $12,000 per treatment.

Dr. Merli also says that the test recommended by Boehringer for assessing the degree of anticoagulation (the ecarin test) is not widely available. “That test is not available even at our hospital in Philadelphia,” he says. “The companies that make them tell us that in the case of Pradaxa, you can use the [activated] partial thromboplastin time as a measure of the degree of anticoagulation, but in the studies, there was no correlation.”

Gregory Maynard, MD, MSc, SFHM“If you look at the top three or four adverse drug events that occur, usually warfarin is one of those. … It’s common, it’s a safety issue, it’s tricky to use—all of those things add up to something that hospitalists need to pay attention to.”

–Gregory Maynard, MD, MSc, SFHM, chief of the Division of Hospital Medicine at the University of California at San Diego

Then there is the cost hurdle. Warfarin, even with one or two blood tests a month to monitor international normalized ratio (INR) and assess its effectiveness, costs patients a total of $15 to $50 a month out of pocket. Paying cash for dabigatran is about $200 a month.

“Some sites haven’t added it to their formulary because they were concerned that it could get started in the hospital and then the patient might not be able to obtain it outside of the hospital, and then they would end up on no anticoagulation for a period of time,” Dr. Jenkins says.

On the flipside, dabigatran use could shorten hospital stays, saving costs. Patients on warfarin typically have to be weaned off faster-acting IV heparin first, then weaned onto warfarin. It also can take time to make sure anticoagulation is at the proper level, also extending the stay.

Boehringer Ingelheim spokeswoman Moses notes that the company is taking steps to address the cost. “Pradaxa is now included at the lowest branded copay level on formularies that insure about 35 percent of NVAF patients [Irregular heartbeat in a patient without a diseased, repaired, or replaced mitral heart valve] in the U.S.,” she wrote in an email. “For those patients who may not otherwise be able to afford treatment, BIPI [Boehring Ingelheim] offers patients assistance programs to help provide coverage for the cost of their medications.”

Dr. Merli expects the majority of physicians will take a wait-and-see approach to the new anticoagulants.

“I think 20 percent will adopt the drug early,” he says. “Then there’s that big group in the middle, 60 percent, that will wait and see and they’ll start using it. And then there’s that end group of 20 percent that will never use the drug.” TH

Thomas R. Collins is a freelance writer based in Florida.

Hospitals Collect Valuable Experiences with New Anticoagulant

In February, a patient was sent to Thomas Jefferson University Hospital in Philadelphia and was about to get a spinal injection for pain management. The patient had been assessed and it was noted that he was on a drug called Pradaxa, but no one thought much of it at the time—that is, until the anesthesiologist saw the newly approved anticoagulant on the patient’s list of medications.

“The anesthesiologist said, ‘This is sort of a funny drug,’ looked it up and said, ‘Oh, this is Pradaxa, this is an anticoagulant,’ so they stopped the procedure,” recalls Dr. Merli, Jefferson’s chief medical officer, who oversees patient drug safety. “If you look at the package insert for Pradaxa, it tells you that if you’re going to do spinal anesthesia or access the spine, you need to be off the drug at least 72 hours.”

Pradaxa, the brand name for dabigatran, was approved nine months ago and has been in use at hospitals across America for only a few months. But there already are potentially valuable experiences—some cautionary—to be shared by those who have added it to their formularies.

The bottom line, experts say, is that hospitalists have to educate themselves about the new drugs so that they are armed with the information needed to decide which patients to treat with which drugs. There also might be a certain amount of “unlearning” that will have to take place, because what applies to warfarin might not apply to the new drugs.

“Providers are just absolutely in tune with an obtaining INR [international normalized ratio] value and knowing that what that means in terms of anticoagulation [on warfarin]. Unfortunately, providers try to extrapolate that same interpretation to dabigatran. [But] the INR is not at all sensitive to the effects,” Dr. Pendleton says.

When one patient was about to be transferred to the University of Utah Medical Center with life-threatening bleeding complications, an outside hospital “just mentioned in passing that the patient was on dabigatran, but were falsely reassured that the INR value was not super-therapeutic.” So hospitals, he notes, need to have ideal laboratory tests in place to assess patients’ anticoagulation levels.

As dabigatran, and other new anticoagulants, come into wider use, it will be important for hospitals to share their experiences so that, collectively, patients will benefit, Dr. Pendleton says. His university’s thrombosis service Web page (www.healthcare.utah.edu/thrombosis) has links to information about the new drugs.

“I think that if hospitals pool together, people aren’t having to reinvent the wheel at the local level,” he says, “but there are resources available to help.”—TC

 


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