Many in the medical community welcomed the recent FDA approval of dabigatran as an alternative to warfarin for nonvalvular atrial fibrillation. The new anticoagulant requires less monitoring, and research indicates a lower stroke or bleeding risk. Yet, as with any new drug, hospitalists and hospitals should develop a plan for its use that includes the kind of patients that are (and aren't) good candidates, and what to do when unintended side effects occur.
“Once this medication becomes more broadly used, there should be clear guidelines available for the hospitalist on how to manage it in certain situations,” said Tracy Minichiello, MD, associate professor at the University of California San Francisco and chief of anticoagulation and thrombosis services at the San Francisco VA Medical Center.
Facilities should develop a roadmap so that hospitalists have a standard approach to managing the drug, particularly in the periprocedural setting, and to reversing its effects in cases of severe bleeding, she said.
“You don't want to be standing there at 3:00 a.m. with a bleeding patient on this new medication wondering, ‘how does this work, how do I reverse it’,” Dr. Minichiello said.
Thinking through the inevitable “what if” scenarios is a good idea, agreed Steven B. Deitelzweig, FACP, vice president of medical affairs and system chairman of the department of hospital medicine at Ochsner Health System and Tulane University in New Orleans.
“[Dabigatran] is a wonderful improvement over the pharmaceutical selections we had a few months ago, but before we start using it, we are trying to think through a very comprehensive plan,” he said. “Anticoagulation just got more complicated.”
The clinical trial
Determining which patients can be safely treated with or transitioned to this new agent requires that hospitalists and anticoagulation experts understand the differences between the two drugs and what those differences mean for patient management, experts said.
Dabigatran, a direct thrombin inhibitor, was approved in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Unlike warfarin, dabigatran requires no weekly or monthly monitoring of international normalized ratio (INR). It becomes therapeutic in 30 minutes to two hours, has a half-life of 12 to 17 hours, and requires no special dietary or lifestyle adjustments.
FDA approval was based on results of the RE-LY trial, which included more than 18,000 patients with a creatinine clearance of 30 mL/min or greater and a mean score of 2.1 on CHADS2 (congestive heart failure, hypertension, older age, diabetes, prior stroke or transient ischemic attack), a clinical prediction rule for stroke risk in atrial fibrillation patients. The trial compared two blinded doses of dabigatran (110 mg twice daily or 150 mg twice daily) with open-label warfarin dosed to a target INR of 2 to 3. Median follow-up was two years.
The 110-mg dose was found to be noninferior, and the 150-mg dose superior, to warfarin for the outcome of stroke or systemic embolism in the original analysis, published Sept. 17, 2009 in the New England Journal of Medicine (NEJM). In updated figures in the November 2010 NEJM, the rate of stroke or systemic embolism, the primary outcome, was 1.11% per year with dabigatran vs. 1.71% with warfarin; the hemorrhagic stroke rate was 0.10% per year with dabigatran vs. 0.38% with warfarin; and the major bleeding rate was 3.32% per year with dabigatran vs. 3.57% with warfarin.
The 150-mg dose is indicated for patients with a creatinine clearance greater than 30 mL/min. A 75-mg dose, also approved by the FDA, is indicated for patients with a creatinine clearance of 15 to 30 mL/min. The efficacy of the lower dose has not been studied in a clinical trial, however. Both doses are to be taken twice daily. The 110-mg dose from the trial was not approved by the FDA, but is used in other countries.
Deciding when to use dabigatran
Several questions should be answered before deciding if a patient with newly diagnosed nonvalvular atrial fibrillation can be placed on dabigatran instead of warfarin, experts said.
First, hospitalists should determine if the patient has a renal clearance of 30 mL/min or greater. Brian F. Gage, MD, associate professor of medicine at Washington University School of Medicine in St. Louis, said that since patients with a creatinine clearance less than 30 mL/min were not included in the RE-LY trial, he would hesitate to use the 75-mg dose, even if the patient had a clearance rate in the 15 to 30 mL/min range indicated for that dose by the FDA.
Dr. Minichiello agreed. “The lower dose of 75 mg twice daily for patients with a creatinine clearance of 15 to 30 has not been evaluated clinically. I have not seen outcome studies with the 75-mg dose, so it would be a bit of a leap of faith to use it,” she said.
Second, will the patient comply with a medication that must be taken twice daily? Dabigatran's shorter half-life makes each dose critically important. Dabigatran “leaves the body fairly quickly. If the patient misses a few doses of medication, they are no longer protected,” noted Mintu Turakhia, MD, chief of cardiac electrophysiology at the Palo Alto VA Healthcare System in Palo Alto, Calif. On a related note, the hospitalist should determine who will monitor compliance when the patient leaves the hospital, he said.
“Any initiation in anticoagulation should be discussed carefully with the patient's primary care physician or cardiologist or both,” Dr. Turakhia said. “The hospitalist should ensure that there is a defined care structure for follow-up,” given that no weekly or monthly monitoring can be done to ensure compliance, as is the case with warfarin.
A third question to consider is whether the patient can afford the drug, and/or whether insurance will cover the cost. While warfarin costs only pennies a day, there are additional expenses for INR testing, travel expenses associated with the testing, and costs associated with complications. The current estimated wholesale cost of dabigatran, meanwhile, is $6.75 a day for either approved dose, according to the manufacturer.
“The hospitalist needs to make sure that a patient's insurance will cover the drug. That information needs to be known before the patient leaves the hospital,” said Amir K. Jaffer, ACP Member, division chief of hospital medicine in the University of Miami Health System.
An analysis published in the Jan. 4, 2011 Annals of Internal Medicine found that for patients aged 65 and older who are at increased stroke risk, dabigatran can be a cost-effective alternative to warfarin. In the cost analysis—for which Dr. Turakhia was the senior and corresponding author—the researchers determined that 150-mg twice-daily dabigatran yielded an additional 0.56 quality-adjusted life-year (QALY) compared with warfarin. The estimated cost of $45,372 per QALY gained with this dose, when compared with warfarin, was “within a range considered to be cost-effective,” the authors wrote. In addition, the cost analysis was based on a per-day cost of $9.50 for low-dose dabigatran and $13 for high-dose dabigatran, more than the current estimate for either dose.
Another factor to consider with using dabigatran is a patient's baseline stroke risk. Dr. Gage favors dabigatran for patients with new nonvalvular atrial fibrillation and a CHADS2 score of 3 or more, unless he knows INR monitoring with warfarin therapy is going to be excellent, he said. The cost-effective therapy for a CHADS2 score of 1 or 2, however, “probably depends on comorbid conditions, INR control and patient preferences,” he said.
Finally, hospitalists should consider whether the patient has existing gastrointestinal issues. Dabigatran can be a problem for patients who already have some stomach upset, because it's associated with more dyspepsia than warfarin. For patients treated with the 150-mg dose of dabigatran in the RE-LY trial, 2.1% discontinued the drug due to gastrointestinal symptoms compared to 0.6% of those treated with warfarin. For these patients, stomach upset could result in noncompliance, experts said.
Switching from warfarin
Dabigatran may be better than warfarin for a patient who has widely fluctuating INR values, is noncompliant with INR monitoring, or finds it difficult to adjust his or her warfarin dose after INR testing. It may also be better for a patient who is at elevated risk of intracranial hemorrhage, experts said.
Patients whose time in therapeutic range is below 50% with warfarin may be especially strong candidates for dabigatran, assuming the problem of low time in therapeutic range is not due to medication noncompliance, said Alan D. Brush, FACP, assistant clinical professor of population medicine at Harvard Medical School in Boston and chief of the anticoagulation management service at Harvard Vanguard Medical Associates. “It is worth asking the primary care physician whether they think this type of patient would do better on dabigatran,” he said.
However, dabigatran may not be the best choice for a patient who can't handle taking a medication twice each day. “For a patient who tends to forget their dose of dabigatran, I would rather keep them on warfarin because of its longer half-life,” Dr. Gage said. Also, if a patient develops dyspepsia or a myocardial infarction after starting dabigatran, switching back to warfarin is warranted and would be uncomplicated, he said.
Caution should also be used when considering a switch from warfarin to dabigatran for patients with coronary artery disease or a prior myocardial infarction, experts said. The rates of myocardial infarction in the RE-LY trial were 0.81% with dabigatran vs. 0.64% with warfarin, according to the 2010 NEJM study.
A focused update on managing patients with atrial fibrillation, released Feb. 15, 2011 by the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society (ACCF/AHA/HRS), said that patients already taking warfarin who had excellent INR control “may have little to gain by switching to warfarin,” due to the twice-daily dosing and greater risk of nonhemorrhagic side effects. When considering patients for dabigatran over warfarin, clinicians should ponder “clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program to sustain routine monitoring of INR, patient preferences, cost, and other factors,” it said.
Hospitalists can play a major role in developing guidelines for managing patients on dabigatran who need a procedure or who have a bleeding event, experts said. Indeed, it's vital that this is done. Unlike warfarin, which can be reversed with vitamin K or fresh frozen plasma, there is no established procedure for reversing dabigatran.
While not having to monitor INR is considered a big advantage with this medication, lack of an easily obtained, reliable way to measure anticoagulant activity can be a real challenge to the hospitalist.
“Here is a drug where you can't tell how anticoagulated someone is and for which there is no antidote and no reversal,” Dr. Minichiello said. “If the patient has really good renal function, the drug will be gone quickly, but for those who don't, that could be a problem. The hospitalist won't have an easy way to track that or have a guarantee that [dabigatran] is not still hanging around. The hospitalist is the person standing there trying to figure out these things, so it's important to have guidelines in place.”
Clinicians must appreciate that the INR is relatively insensitive to dabigatran. The activated partial thromboplastin time (aPTT) may approximate anticoagulant activity and help to estimate bleeding risk associated with the current level of drug, but it is not as good an estimate as ecarin clotting time (ECT), which is not widely available.
At the moment, hospitalists and hospitals are pretty much on their own. While the drug's prescribing information talks about stopping dabigatran prior to an intervention, and warns about bleeding risk, it has no recommendations based on clinical trial data about what to do in a bleeding event. The ACCF/AHA/HRS guidelines note that “supportive therapy for severe hemorrhage may include transfusions of fresh-frozen plasma, packed red blood cells, or surgical interventions if appropriate,” but doesn't give specifics.
Patients on dabigatran for atrial fibrillation are the ones at high risk for thromboembolic events, and at fairly high risk for bleeding events, Dr. Deitelzweig noted. Dabigatran doesn't have many known interactions, but dabigatran levels are increased in patients taking amiodarone, ketoconazole, or verapamil with cardiac medications. “Hospitalists need to respect that dabigatran is a fully loaded anticoagulant that will be additive for hemorrhagic events,” he said.