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With four new oral anticoagulants (NOACs) to chose from, even the most experienced clinicians face a quandary: which NOAC is the best choice for the patient?

"In the absence of head-to-head data on these agents, even for physicians who are well-versed with the nuances of these trials, picking one agent over another is very challenging," , an interventional cardiologist at Columbia University Medical Center/New York-Presbyterian Hospital in New York City, told MedPage Today.

In 2010, dabigatran (Pradaxa) became the first new anticoagulant on the market in 50 years, with an indication initially for stroke prevention in nonvalvular atrial fibrillation.

Rivaroxaban (Xarelto) and apixaban (Eliquis) followed, and edoxaban (Savaysa) became the latest addition to armamentarium early in January.

All four are approved for treatment of VTE, but only rivaroxaban and apixaban are approved in VTE prevention.

"The NOACs have opened up all kinds of new opportunities and also opened up Pandora's box," said , a cardiologist at Northwestern Memorial Hospital in Chicago and past president of the American Heart Association.

Cost, renal function, and bleeding risk are at the heart of the strategies experts described to MedPage Today in navigating the decision.

Navigating the NOACs

Comparing hazard ratios between pivotal trials is not the way to go, cautioned , an interventional cardiologist at University Hospitals Case Medical Center in Cleveland.

"Any statements that are made about comparative efficacy between the NOACs are probably misplaced," he told MedPage Today. "There isn't any data really to support that one is better than the other. All you can do is compare its efficacy to warfarin."

Parikh explained his algorithm: "First are they a candidate for a NOAC, secondly do they have comorbid illnesses that would preclude the use of a NOAC, and thirdly what is their compliance and ability to afford the medication before we select the specific drug."

In terms of the specific agent, the choice will likely be among apixaban, dabigatran, and rivaroxaban, because edoxaban hasn't been on the market long enough for clinicians to get comfortable using it, Parikh suggested.

And even among the three, most clinicians will narrow their options based on familiarity, he added.

Rivaroxaban and edoxaban's once-a-day dosing also is a factor compared with twice-daily apixaban and dabigatran, , director of the cardiac ICU at Massachusetts General Hospital in Boston, added.

While the newer generation agents are likely to eventually become the gold standard in nonvalvular afib and VTE, "it's necessary to emphasize that warfarin, with all its drawbacks -- drug-drug interactions, dietary issues, need for monitoring -- is still a reasonable choice," he argued.

In terms of medication adherence, for example, short half-lives mean the NOACs aren't a good choice for patients likely to miss several doses in a row, Parikh pointed out. The lack of monitoring is actually a disadvantage for such patients, whereas regular visits to a warfarin clinic can catch problems help keep patients in the therapeutic range, he said.

While Bonow called NOACs already his first choice for nonvalvular atrial fibrillation patients and even for those with forms of valvular heart disease where he believes the afib is not related, cost keeps warfarin a go-to drug, he said.

The Cost Equation

Whereas warfarin is by far the cheapest option for patients, the three NOACs already available clinically haven't differed much in price, noted , of Brigham and Women's Hospital in Boston.

Retail cash prices cited on for a 30-day supply as indicated in stroke prevention for nonvalvular afib at the same pharmacy were:

• $16 for generic warfarin 2 or 5 mg once daily
• $383 for rivaroxaban 20 mg once daily
• $400 for apixaban 5 mg twice daily
• $373 for dabigatran 150 mg twice daily
• Not yet available for edoxaban 30 mg or 60 mg once daily

"However, if there were an appreciable difference in costs of a NOAC (e.g., 10% or more), then that could be a factor," Giugliano told MedPage Today.

With four agents on the pharmacy shelves, perhaps that will happen, Bonow suggested.

"I'm hoping that with more of these drugs getting on the market there will be some market forces that begin to make them less expensive, because cost has become a real issue," he said.

Meanwhile, insurance often is the ultimate deciding factor among NOACs, Kirtane noted.

"We are in fact in many ways forced to use one agent or another by patient's ability to afford the drug and their coverage from insurance," Parikh agreed. "Typically after a little research we are able to figure out which drug is the most appropriate for the patient, and by appropriate I mean which is the most affordable."

Renal Function

All four NOACs are predominantly cleared by the kidneys, which raises concerns as most elderly patients have some element of renal dysfunction, Kirtane pointed out. But the degree of effect on dosing in use for afib varies:

• Rivaroxaban was approved with dose adjustment down to 15 mg taken with the evening meal in moderate-to-severe dysfunction of 15 to 50 mL/min and a contraindication below 15 mL/min.
• Dabigatran has to be lowered to 75 mg twice daily for those with severe renal impairment (creatinine clearance 15 to 30 mL/min).
• Apixaban only has to be dose reduced for patients with end-stage renal disease on hemodialysis who are either at least 80 years old or who weigh 60 kg (132 lb) or less.

Efficacy isn't the problem for low kidney function with those agents, "but the risk for bleeding rises as renal function worsens," Januzzi noted.

Edoxaban, on the other hand, is actually only approved for use in patients with renal impairment for prophylaxis in nonvalvular afib.

The black box warning of reduced efficacy of edoxaban in afib when creatinine clearance is in the normal range of greater than 95 mL/min will likely seriously curtail its use in the absence of head-to-head data showing some endpoint advantage against other NOACs, Kirtane noted.

The label also mandates creatinine clearance assessment before edoxaban use and dose adjustment down to 30 mg for moderate to severe renal impairment, weight of 60 kg or less, or use of P-glycoprotein inhibitors except amiodarone (Cordarone).

Such "clinically cumbersome" aspects make a NOAC less attractive, , medical director of the education program of the University of North Carolina at Chapel Hill, told MedPage Today at the time of edoxaban's approval.

"In our group because of the concern about renal function and renal dysfunction, frequently the agents that don't require adjustment for renal dysfunction and low creatinine clearance are most frequently elected," Parikh noted.

In that regard, apixaban comes out on top due to needing dose adjustment least often and being the only one approved for use in patients on chronic hemodialysis, whereas dabigatran comes out on the bottom, Giugliano said.

"I personally believe that renal dysfunction is most challenging for dabigatran and so I tend to use one of the other NOACs in patients with labile or abnormal renal function," he told MedPage Today.

A novel oral factor Xa inhibitor that is hepatically cleared -- -- is under development and might solve that issue if it continues to pan out in VTE and nonvalvular atrial fibrillation.

Bleeding Risk

Most nonvalvular atrial fibrillation patients do have comorbidities, and for those on antiplatelet therapy for prevention in coronary artery disease that means thinking carefully about bleeding risk, Parikh noted.

"In my practice, when there are patients on dual-antiplatelet therapy, for example after drug-eluting stent placement if they're on aspirin and an a P2Y12 antagonist, I do not elect to use a novel anticoagulant," he said. "I think warfarin is probably the safest choice."

While highly controversial, Parikh said his group switches patients to aspirin, clopidogrel (Plavix), and warfarin after stenting if they come in on a NOAC. After 6 or 12 months, they will be moved to aspirin and a NOAC.

"We are trying to actively enroll these patients in studies so we can get a better sense of what the best regimens are for these patients," Kirtane added.

Studies like are open, albeit none yet are the needed head-to-head comparisons of NOACs, he noted, calling for independent institutions to get observational analyses and comparative research studies underway.

"As clinicians, we should not let marketing dictate which drugs we chose for our patients," Kirtane said.

The lack of clinically-available antidotes for the NOACs is also a concern that plays into the decision, Bonow said. "Many patients that I speak with are really concerned about that and in some cases would prefer warfarin because of the issue regarding reversibility should there be hemorrhaging."

Turning Off NOACs

But it is a misconception that the NOACs aren't reversible, Januzzi argued.

"While specific antidotes for each are on the very near horizon, they may be reversed with infusion of prothrombin complex concentrate," he told MedPage Today. "With the expected rapid approval of direct inhibitors of each drug -- which literally work within a matter of minutes -- this issue should be resolved once and for all."

Once reversal agents become commercial available, "then I don't think there's going to be that much of a role for warfarin at all" if patients aren't already on it and doing well, Kirtane said.

Some of the current confusion should clear up with experience, Parikh concluded. "But for now it's incumbent on the providers to understand the label and the indication for each of the individual agents and then customize the choice to each individual patient."

From the American Heart Association:

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