Published in the January 2014 issue of Today’s Hospitalist
DOCTORS HAVE LONG ANTICIPATED the arrival of anticoagulants that don’t need burdensome laboratory monitoring. That’s certainly made the wave of new oral agents promising.
But not needing frequent monitoring could result in less oversight of patients on powerful blood thinners and potentially lead to more complications in a vulnerable population, according to Tracy Minichiello, MD, director of anticoagulation and thrombosis services at the San Francisco VA Hospital. Dr. Minichiello talked about the new oral anticoagulants at this fall’s management of the hospitalized patient conference at the University of California, San Francisco.
“Physicians need a framework to determine who is a good candidate for one of these agents and who isn’t,” she noted. Hospitalists also need to figure out how to manage these agents perioperatively and deal with patients who come in with a bleed.
And hospitalists should be more mindful of what patients need in follow-up. That’s because these patients will not necessarily be plugged into anticoagulation clinics or need routine lab monitoring, and they may not automatically have an early post-discharge follow-up visit arranged. In that sense, the advantages of these agents can present hospitalists a dilemma.
“The lack of the need for anticoagulation monitoring with these agents,” Dr. Minichiello told her audience, “poses a potential risk in transitions in care.”
Key drug differences
Three new oral agents are now on the market: the Xa inhibitors rivaroxaban and apixaban, and dabigatran, a direct thrombin inhibitor. All are approved for preventing strokes in patients with nonvalvular atrial fibrillation, while rivaroxaban has also been approved for DVT and PE treatment and prevention.
The new agents became available just as the market for anticoagulation for patients with nonvalvular Afib has grown. Guidelines published in the February 2012 issue of Chest, for example, now recommend anticoagulation over antiplatelet therapy for patients with a CHADS2 score of 1 or more. Previous guidelines had recommended warfarin or even aspirin for this group.
An important distinction among the new agents, Dr. Minichiello explained, is how they are metabolized. “Dabigatran relies most heavily on the kidneys, being 80% renally cleared,” she said. That percentage drops to between 30% and 60% for rivaroxaban and as low as 25% for apixaban. “That is one clinical feature that should help you decide who gets which agent.”
The drugs differ in other key ways. The RE-LY trial, a noninferiority trial comparing dabigatran and warfarin published in the Sept. 17, 2009, issue of the New England Journal of Medicine (NEJM), found that 150 mg of dabigatran twice daily lowered stroke risk more than warfarin and decreased the risk of intracranial hemorrhage, but increased the risk of GI bleeding.
Researchers also found a trend toward increased risk of myocardial infarction in patients taking dabigatran. “The absolute increased risk over warfarin is not high,” Dr. Minichiello noted, “but it appears to be real based on results of a recent meta-analysis.”
Post-hoc analysis of RE-LY data also revealed mortality and vascular benefits for patients in the dabigatran arm. But the degree of benefits changed depending on the time in therapeutic range (TTR) for patients taking warfarin.
“There was a marked improvement in these outcomes for patients taking dabigatran over those of patients taking warfarin if their TTR was poor,” said Dr. Minichiello.
“If the TTR was good, the benefits weren’t as impressive.” Poor TTR becomes another factor “that helps identify who may benefit from transitioning from warfarin to one of the newer agents.”
Rivaroxaban and apixaban
Next up was the ROCKET AF noninferiority trail, with researchers comparing once daily rivaroxaban to warfarin. The results, in the Sept. 8, 2011, issue of NEJM, found that like dabigatran, rivaroxaban produced fewer strokes and less intracranial bleeding, but more GI bleeds.
And the ARISTOTLE trail found that apixaban was superior to warfarin in providing a 20% stroke risk reduction “as well as a 13% major bleed reduction across the board, including GI bleeding.
While no trials have compared the three agents head-to-head, Dr. Minichiello noted that all three lower stroke risk compared to warfarin, although rivaroxaban may have “the least impressive risk reduction. It looks like dabigatran may provide the greatest risk reduction compared to warfarin, followed by apixaban and then rivaroxaban,” she said.
But among the three, dabigatran is the only agent associated with dyspepsia.
“Between 15% and 20% of patients on dabigatran will develop dyspepsia,” Dr. Minichiello noted. “Typical onset is between seven and 10 days after starting therapy and symptoms may not be relieved with a PPI.” Because this is a major cause of nonadherence, “it’s very important to counsel patients about it and check in on it early.”
Compliance, renal clearance and age
Factors to consider when choosing an oral anticoagulant include compliance, renal function, history of GI bleeding, concomitant medication, age, the need for aspirin and cost. And dosing is another important factor in terms of noncompliance: Rivaroxaban has the advantage of once-daily dosing.
“For these short acting BID-dosed drugs, you’re looking for patients who are really going to take their drugs reliably,” Dr. Minichiello pointed out. Because all these drugs have a really short half life, “patients are at risk for thromboembolism shortly after missing a dose.”
These agents are indicated for nonvalvular atrial fibrillation and contraindicated in patients with mechanical heart valves. Due to renal clearance, they should be avoided in patients with severe renal insufficiency and those on dialysis.
“The creatinine clearance cutoffs vary for each agent, but we avoid them in anyone whose creatinine clearance is less than 30,” said Dr. Minichiello. “We also avoid them in patients with moderate renal disease who have spurious declines in renal function, like those with heart failure, or who are prone to prerenal azotemia.”
Dr. Minichiello also urged hospitalists to consider GI-bleeding history and age.
“We tend to avoid dabigatran or rivaroxaban in patients with a history of GI bleeding of unclear etiology, given higher rates of this type of bleeding with these agents vs. warfarin,” she said. Similarly, bleeding was more common in patients older than 75 treated with dabigatran or rivaroxaban when compared to warfarin.
“Bleeding rates were lower with apixaban vs. warfarin for patients at any age,” she noted. “So we consider age as well when choosing therapy.”
Another red flag: Patients taking concomitant drugs that affect P-glycoprotein or CYP3A4. Drugs that strongly induce these systems “will decrease levels of these agents, so we’re advised to avoid them,” said Dr. Minichiello. Those drugs include rifampin, dilantin, St. John’s wort and tegretol.
As for drugs that are inhibitors, which could increase drug levels and lead to more bleeding complications if used concomitantly, “it’s a little less clear,” she said. Prescribing information indicates that physicians should adjust dosing or avoid concomitant use with ketoconazole, azoles and a lot of HIV medications.
But Dr. Minichiello noted that European prescribing information for these medications seems to be “more conservative than ours, and this gives me pause.” Information on safe concomitant use of inducers and inhibitors of CYP3A4 and P-glycoprotein transport systems “is evolving,” she pointed out. Current prescribing information for the new oral anticoagulants does not provide a comprehensive list of all medications that could potentially interact with them.
“So you need to know,” said Dr. Minichiello, “how concomitant drugs are metabolized.”
She also steers clear of prescribing one of the new agents for patients who have an indication for aspirin but who wouldn’t need to take aspirin if they were prescribed warfarin. An example may be patients with a remote history of CAD without CABG, stents or unstable angina, for whom warfarin may be deemed sufficient for secondary CAD prophylaxis.
Providers know that concomitant use of antiplatelet therapy and anticoagulation can be “a dangerous combination that increases bleeding risk by about two-fold,” she explained. At this point, “we do not know how effective these newer agents are at primary or remote secondary CAD prophylaxis.”
For instance, patients with a remote MI would likely need to continue aspirin in addition to a new oral anticoagulant while they may not need it if on warfarin, she pointed out. “I’d choose warfarin for such patients instead.”
Physicians also need to consider cost. “Warfarin comes in at less than 20 cents a day, and that’s hard to compete with,” said Dr. Minichiello. The new anticoagulants can cost as much as $8 a day, depending on patients’ insurance.
If you think a patient is a good candidate for a new agent, “just like when you start any other anticoagulant, you’re going to want some baseline labs,” Dr. Minichiello said. “You’ll need a CBC, platelets, baseline COAGs “PTT and PT “and liver function tests.” All these agents are metabolized in part by the liver, especially rivaroxaban and apixaban.
Patient education is also just as important with these new anticoagulants as it is with warfarin. While many patients started on warfarin will get longitudinal education through an anticoagulation clinic, those started on one of the new agents may not receive any systematic oversight or education. If your hospital hasn’t created patient education material, the prescribing information can serve as one tool.
And physicians can’t skimp on follow-up. “If you’re going to discharge a patient on one of these medications, make sure there is a good handoff and follow-up,” Dr. Minichiello said. Her own patients who are started on a new agent are followed up within a week, as well as at two weeks, one month and three months. Ongoing follow-up occurs every six to eight weeks.
“For longitudinal follow-up of patients on a new agent, we check in with them by phone at least,” she said. “The advantage of anticoagulation clinics is that people have the opportunity to report concerns before they become bigger problems.” But most of these patients aren’t plugged into anticoagulation clinics due to lack of reimbursement. “So patients on these agents may end up being at greater risk.”
What to do with bleeds
Then there’s this bad news: These agents as yet have no antidote. If patients are bleeding, discontinue the drug and make all efforts to maintain renal clearance.
To see if the bleeding is related to anticoagulation, check PTT or thrombin time if the patient is on dabigatran or thrombin time or a PT if the patient is on rivaroxaban. A normal PTT or thrombin time would argue against the bleed being related to dabigatran. A PT may be elevated in patients on rivaroxaban or apixaban, but this is less reliable. For life-threatening bleeding in patients on dabigatran, “dialysis can remove up to 60% of the drug within a few hours, although no clinical outcome data are available to support this approach,” said Dr. Minichiello. “This of course would require the nephrologist to agree to put in a large port access line in the setting of unknown degree of anticoagulation.”
FFP is not expected to be of benefit for major bleeding in patients on these new agents, as “these patients are not factor-deficient.” There are case reports of four-component PCC being effective in reversing the in vitro anticoagulant effect of rivaroxaban, but not dabigatran. Dr. Minichiello and her colleagues now provide supportive care, forced diuresis and charcoal if patients have recently ingested one of these agents.
“And remember to provide platelet transfusion if patients are on an antiplatelet,” Dr. Minichiello said. “Even though their platelets are normal, the platelets aren’t functional in severe bleeding.”
In terms of VTE treatment and prophylaxis, researchers in the EINSTEIN trail, published in the Dec. 23, 2010, NEJM, found that rivaroxaban “as monotherapy “was not inferior to low molecular weight heparin bridging to warfarin in terms of recurrent DVT and PE or bleeding rates.
Dabigatran has also been evaluated for treating PE, but patients in that trial “got at least five days of low molecular weight heparin,” Dr. Minichiello noted. “If it is approved, most likely the prescribing information would advise a course of parenteral therapy first, then dabigatran BID through the course of therapy.” Rivaroxaban, on the other hand, “will not require use of a parenteral agent and is BID for the first three weeks only, then daily” “a dosing change that doctors need to alert patients to.
“It would be very easy for patients to stay on BID dosing of rivaroxaban inadvertently without proper follow-up and education,” she pointed out.
Dr. Minichiello admitted that the new oral agents make for a lot of complicated decisions. But an antidote for all three is in phase III development, she said. A number of Web-based clinical decision-support aids are also being devised to help doctors decide which agent may be best for a particular patient with atrial fibrillation.
As for now, “perhaps these patients should continue to be managed in anticoagulation clinics,” said Dr. Minichiello. “That would probably improve safety.”
Phyllis Maguire is Executive Editor of Today’s Hospitalist.
What’s in a name?
HERE’S A NEW ACRONYM FOR YOU: TSOACs (pronounced SO-acks), which stands for target specific oral anticoagulants. The newly-minted acronym is used to refer collectively to dabigatran, rivaroxaban and apixaban, three oral anticoagulants approved in the last couple of years.
“It does not roll off the tongue,” said Tracy Minichiello, MD, who mentioned the new moniker at the management of the hospitalized patient conference in San Francisco this fall. But it is replacing the former acronym “NOACs (for new oral anticoagulants) “that was first used.
Why the name change? “They’re not going to be new forever,” Dr. Minichiello pointed out, “so this is how they’ll be referred to increasingly in the literature.”
New anticoagulants: perioperative management
WHEN IT COMES TO THE NEW ORAL ANTICOAGULANTS, hospitalists are being called on to manage them perioperatively. When should patients stop taking these medications before an elective procedure?
“To answer that question, you need to know two things: the patient’s current renal function and the bleeding risk of the procedure,” said Tracy Minichiello, MD, speaking at the management of the hospitalized patient conference in San Francisco this fall. “These factors determine when the last dose should be so the patient can safely be taken to the OR.”
Dr. Minichiello recommended that hospitals have perioperative guidelines available for managing all anticoagulants around surgery. She also urged hospitalists to “make sure they have an up-to-date assessment of renal function before providing any advice.”
Then there’s this problem: A surgeon calls to say a patient is already in preop and can’t remember if he took his dose of dabigatran yesterday. He asks “should we get an INR to make sure the drug is cleared?”
There are many scenarios in which clinicians would like to know how anticoagulated a patient is on one of the new anticoagulants: prior to urgent surgery, when patients come in bleeding or when doctors are trying to gauge how concomitant drugs may be affecting anticoagulation levels. Unfortunately, while a number of assays are being developed, “right now, there is no accurate way to do that “which is one of the big disadvantages of these agents currently.”
A PTT should be two times baseline at the peak and one-and-a-half times at trough. But for dabigatran, the PTT is an imperfect estimate, Dr. Minichiello noted.
“The PTT isn’t sensitive enough to the presence of dabigatran for you to say to the surgeon, ‘Sure, it’s gone,’ if the PTT is normal,” she said. “But the thrombin time is exquisitely sensitive to dabigatran. You can order a stat thrombin time and, if it is normal, you can say the dabigatran has cleared.”
While the thrombin time cannot be used to assess the presence of apixaban and rivaroxaban, rivaroxaban does influence the PT. “It can kind of tell you if the drug is there,” said Dr. Minichiello, “but again, it is not precise.”
Rivaroxaban: different doses
AMONG THE THREE NEW ORAL ANTICOAGULANTS approved in the last two years for stroke prevention in nonvalvular atrial fibrillation, only rivaroxaban has received FDA approval for DVT and PE prophylaxis and treatment.
With rivaroxaban, “remember there’s different dosing for each indication, and the drug should be taken with food unless used at prophylactic dosing, which is 10 mg,” said Tracy Minichiello, MD, director of anticoagulation and thrombosis services at the San Francisco VA Hospital who discussed the new agents at a conference this fall.
For VTE treatment, Dr. Minichiello recommended choosing warfarin instead if patients are on a contraindicated drug, if they have renal insufficiency, if cost is an issue or if you want to track INR for adherence. “Rivaroxaban may be a better choice,” she said, “if monitoring is considered a really big burden or if the patient refuses parenteral therapy.”