Published in the December 2011 issue of Today’s Hospitalist
While the new wave of oral anticoagulants has been viewed as a welcome alternative to warfarin, the therapies have both pros and cons. And as patients taking these drugs begin to present to the hospital, hospitalists will need to know how to manage the latest breed of anticoagulants.
“If you work in a hospital, you’re going to manage these medications whether you like it or not,” said Tracy Minichiello, MD, director of anticoagulation and thrombosis services at the San Francisco VA Hospital. “You’ll manage them perioperatively and you’ll probably start your own patients on them. So it’s important that you’re comfortable with them.”
Right now, there are two new oral anticoagulants on the market and one more expecting FDA approval this year. (See ” This year’s new anticoagulants“) But the best-known agent, at least in the U.S., is the direct thrombin inhibitor dabigatran (Pradaxa). The drug was approved last year for preventing stroke in patients with nonvalvular atrial fibrillation.
Dabigatran and the other new anticoagulants offer plenty of upsides. “These agents promise a much more predictable dose effect and don’t require laboratory monitoring,” said Dr. Minichiello, who spoke at this fall’s management of the hospitalized patient conference at the University of California, San Francisco (UCSF). “They also have far fewer drug interactions.”
But Dr. Minichiello noted that the new drugs have downsides as well. One is that there’s no antidote for any of these agents. “While we have vitamin K to reverse the effects of warfarin,” she explained, “there are currently no direct antidotes available for the new oral anticoagulants. ” And while these new therapies don’t require monitoring, that can be a double-edged sword. “With warfarin, we are quickly able to get an accurate measurement of the degree of anticoagulation,” Dr. Minichiello noted. “With dabigatran, we can easily get only a rough estimate of the anticoagulant effect.”
Problems in older patients
The RELY trial found dabigatran to be noninferior to warfarin for prevention of stroke in nonvalvular atrial fibrillation, although the 150 mg twice-a-day dabigatran dose did appear to be better at preventing stroke than warfarin, while producing the same bleeding risk. Subsequent analysis of the RELY trial data did find that the benefits of dabigatran were most dramatic in centers where warfarin patients had lower time in therapeutic range. Patients taking dabigatran had a decreased risk of intracranial hemorrhage compared to warfarin, but an increased risk of GI bleeding.
According to Dr. Minichiello, the data showed that bleeding risk with dabigatran was greater in patients of advanced age. “The higher risk of bleeding with dabigatran was statistically significant in patients over 80,” she said. “And not surprisingly, concomitant aspirin or Plavix increased the risk of bleeding more than two-fold.”
Also, physicians need to be wary about giving dabigatran to patients with renal dysfunction. “Post-marketing reports show that patients coming in with significant bleeding complications are often elderly and have marginal renal function,” Dr. Minichiello said. “Levels of this drug can go up markedly in patients with renal insufficiency.”
In fact, prescribing information for the drug has just been updated to recommend calculating patients’ creatinine clearance prior to initiating treatment. Recommendations also include assessing patients’ renal function annually if they are over age 75 or have a creatinine clearance of less than 50 ml/min.
Finally, dabigatran must be used carefully with certain medications.
“Inducers of P-glycoprotein like rifampin will decrease the levels of dabigatran, and concomitant use should be avoided,” Dr. Minichiello said, “while inhibitors like amiodarone, ketaconazole and dronaderone will increase it.” Although the interactions between dabigatran and all P-glycoprotein inhibitors have not yet been found to be clinically significant, she said that they’re worth noting.
And while the drug’s manufacturer initially made no recommendations about adjusting dabigatran doses if patients were also taking a P-glycoprotein inhibitor, that changed last month. The manufacturer now recommends reducing the dabigatran dose if it’s being co-administered with dronedarone or ketoconazole in patients with moderate renal dysfunction (whose creatinine clearance is between 30 and 50 ml/min) and avoiding the drug in patients with severe renal dysfunction.
As a result, Dr. Minichiello urged physicians to be selective when choosing patients for dabigatran.
Who is an ideal candidate? According to Dr. Minichiello, the obvious choice is a patient with nonvalvular afib and normal renal function on warfarin whose INR isn’t well-controlled. But, she added, before prescribing dabigatran, physicians need to first ask some questions.
“Why isn’t the INR well-controlled?” she asked. “If the patient isn’t taking the medicine, the therapy is not going to work no matter what medication you give.”
Compliance is particularly important with dabigatran, she pointed out, precisely because it has a shorter half life. “If you miss a dose of dabigatran, you are at higher risk for a stroke than if you miss one dose of warfarin,” she said.
Because dabigatran offers a lower risk of intracranial hemorrhage, the drug may be a better option for patients at risk for that type of bleeding. And freedom from frequent coagulation monitoring makes dabigatran a good option, Dr. Minichiello said, for patients who cannot adhere to lab-draw testing because of work or life demands, travel issues, or problems with venous access.
But because data from the RELY trial pointed to problems with patients 80 and older, Dr. Minichiello stressed that physicians should be very careful when considering it for older patients, particularly those with some degree of renal insufficiency.
“We are hesitant to give dabigatran to patients over 80 because of the increased risk of bleeding when compared to warfarin,” she said. “In addition, we avoid giving it to patients with decreased renal function and patients receiving P-glycoprotein inhibitors.”
While you don’t have to monitor blood tests of patients taking dabigatran, Dr. Minichiello said this does not mean that the patient does not need oversight. “While the INR does not need to be monitored,” she pointed out, “the patient does.”
“All anticoagulants are high-risk medications,” Dr. Minichiello explained. “There’s a decreased risk of intracranial hemorrhage with these agents, but the risk hasn’t gone away entirely. My concern is that with the clinician and patient free of routine lab monitoring, we may actually see more bleeding with these drugs because we’re not going to be watching patients as carefully.”
Physicians should start by ordering baseline labs, just as they do when starting any anticoagulant. “You need a CBC,” she noted. “You want to know patients’ creatinine clearance. A baseline PTT will be helpful.”
But the most important thing in the first two weeks after starting dabigatran is adherence. Dyspepsia is a common side effect that can lead patients to discontinue the medication. Physicians have to rely on patients being forthcoming about nonadherence because, otherwise, doctors have no way of knowing if patients are actually taking the drug. “You would know if patients stopped taking warfarin by their low INR,” said Dr. Minichiello.
“We strongly recommend following up within a week or two after initiating this drug to check in and make sure that patients are actually taking it,” she said. “The other reason you do this is that the highest risk for developing a bleeding complication from anticoagulation is right after you start it.”
At her institution, these patients are followed within the anticoagulation clinic, and practitioners check in with patients at two weeks, one month and three months.
“We decide after the first three months of therapy how often patients should be monitored,” Dr. Minichiello said, “but it’s probably no less than a couple of times a year. These patients are taking a powerful anticoagulant.”
Is there any point in ordering an INR on patients taking dabigatran to assess their level of anticoagulation?
“The INR is not going to help you at all in assessing the anticoagulant effect of dabigatran,” she explained. “It may go up, it may not, but it’s not predictable. The PTT is the poor man’s assessment. You should see about a two-fold increase in somebody who’s at peak effect and 1.5-fold at the trough.”
While the PTT is helpful in establishing that a patient is anticoagulated, it doesn’t provide details about the level. “At higher doses, it’s nonlinear, so it’s not really going to tell you the dabigatran level,” Dr. Minichiello said. While the ECT (ecarin clotting time) is the best test to assess the dabigatran level, she added, it is not widely available.
“The thrombin time is a test most clinicians can obtain and it will tell you qualitatively if the drug is there or not, so this is more useful perioperatively. What a surgeon wants to know is: Is there any drug left?”
You know how to reverse the anticoagulation effects of warfarin “think vitamin K “when patients need urgent surgery. What do you do for patients taking dabigatran?
“If a patient takes a dose of dabigatran in the morning,” said Dr. Minichiello, “12 hours later they have about 50% of the anticoagulant effect. If you hold it for 24 hours, you’re down to about 25%. After 48 hours, they’re down to 3% to 5%.”
How does that factor into a calculation of bleeding risk? “With some procedures, you can have a small degree of anticoagulation on board,” she explained, “and some you cannot. Any surgery that involves a major organ, neurosurgery, epidural or cardiovascular surgery, the anticoagulant effect must be gone.” In such cases, the medication may need to be held between two and four days, depending on patients’ renal function.
How do you return the patient to dabigatran after surgery? Dr. Minichiello said that it’s important to remember that unlike warfarin, dabigatran’s effects are nearly immediate.
“Once you start this drug,” she pointed out, “the patient is fully anticoagulated.” Full-dose anticoagulation within 72 hours of major surgery is associated with a high risk of bleeding, she noted, a factor that doctors should consider when restarting this or any other immediately effective anticoagulant.
Then there’s this question: What do you do with a patient who took his dabigatran this morning and then presents a few hours later with a major bleed? How do you manage his anticoagulation?
“This is a powerful medication with no reversal agent,” Dr. Minichiello said. “As with all bleeding complications related to anticoagulant therapy, you start by discontinuing the drug.”
Physicians should also remember that dabigatran is dialyzable. “About 60% of the drug can be removed within a couple of hours,” she pointed out. “We don’t have clinical data to say that this turns things around in a bleeding situation, but it would make sense that this should help. And in an overdose situation, you could use charcoal.”
Dr. Minichiello also noted that there are case reports of activated prothrombin complex concentrate being effective in reversing the effects of dabigatran “but this is, of course, an off-label use. Platelets should be transfused if the patient is also on antiplatelet therapy, even if the patient’s platelet count is normal.
And according to Dr. Minichiello, it’s critical that hospitals create a reversal protocol before patients present with problems from taking dabigatran.
“It’s going to happen, so you need to be prepared,” she said. “You don’t want to be the person at 3 a.m. in the ER trying to figure out what to do. You want it to be algorithmic.”
Edward Doyle is Editor of Today’s Hospitalist. Today’s Hospitalist
WHEN IT COMES TO NEW ANTICOAGULANTS to prevent stroke in nonvalvular atrial fibrillation, dabigatran has been the only choice since it was approved late last year. But the FDA just approved another drug for that indication, and the agency is expected to approve a third by the end of the year.
Over the summer, the FDA approved rivaroxaban (Xarelto) for DVT prophylaxis in patients with knee or hip replacement surgery. Last month, the drug received approval for stroke prevention in nonvalvular afib patients as well.
One advantage of rivaroxaban, which is a factor Xa inhibitor, is its once-a-day dosing. Dabigatran, by comparison, must be taken twice a day. Clinical studies found that rivaroxaban was noninferior to warfarin for stroke prevention and that major bleeding risks were about the same. But there was a decreased risk of fatal bleeding and intracranial hemorrhage.
But like dabigatran, rivaroxaban is not a good option for patients with significant renal insufficiency. Manufacturers warn that rivaroxaban is to be avoided in patients taking the therapy for DVT prevention if their creatinine clearance is less than 30 ml/min “and avoided in those with a creatinine clearance of less than 15 ml/min for stroke prevention. Patients whose creatinine clearance is below 50 ml/min should be monitored closely for bleeding, said Tracy Minichiello, MD, director of anticoagulation and thrombosis services at the San Francisco VA Hospital.
“It’s probably best to use this drug,” she said, “in patients who have robust renal function.”
The oral anticoagulant apixaban (Eliquis) is still awaiting FDA approval, but study data released this fall have generated a lot of excitement.
“The big news was that apixaban was superior to warfarin,” Dr. Minichiello said. “The study found a 20% stroke risk reduction, a decreased risk of major bleeding and a statistically significant decrease in death.”