Apixaban approved: Now, which anticoagulant to use?

January 21, 2013

New York, NY - With the recent approval of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) in most major countries for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF), all three of the new oral anticoagulants are now available for this indication, leaving doctors with the dilemma of which one to use in which patients.

Being the first oral alternatives to warfarin, with all its limitations, these three new agents—the thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim); and the two factor Xa inhibitors, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and apixaban—are expected to revolutionize stroke prevention in AF.

Dr Alexander Turpie

But do these drugs really herald the end of warfarin, and how do doctors decide which of the three new agents to use? Two experts have quite different views of the situation.

Dr Alexander Turpie (McMaster University, Hamilton, ON), a thrombosis specialist, is very positive about the new agents, saying they have major advantages over warfarin and should be used in preference to warfarin in most cases.

In contrast, Dr Larry Goldstein (Duke Stroke Center, Durham, NC) believes they should have a more restricted role, for the time being.

"I would say that they are a very reasonable option for patients who are compliant but cannot maintain a stable INR on warfarin," he said. "But if a patient is stable on warfarin and is managing well with home monitoring, I don't think there is an overwhelming need to switch them."

Turpie points out that while warfarin is very effective, it has many limitations, including the need for monitoring and regular dose adjustments, as well as many interactions, which he says "are preventing around half the people who should be taking oral anticoagulants from receiving such therapy.

"These new drugs overcome these limitations and should vastly increase the number of patients able to take oral anticoagulants," he said. "Most patients and doctors now want to use one of these new agents instead of warfarin."

Reduction in ICH: A big advantage

In addition to the practical advantages of the new drugs, they have a major clinical benefit in that all three agents were associated with lower rates of intracranial hemorrhage (ICH) compared with warfarin in phase 3 trials.

Turpie says that this factor alone is enough for him to choose one of the new drugs in preference to warfarin.

"Even when I think just about the 2500 patients in my clinic who are taking warfarin for life, I know that one in 300 of them will have a ICH per year no matter how well controlled they are," he said. "Now with the new drugs, this can be reduced to one in 500 to 600. That is a big deal."

Goldstein agrees that this is a strong argument in favor of the new drugs, but he counters that the lack of an antidote also has to be taken into consideration. "That means if an ICH does occur, there may be no way to stop it."

Turpie would like to put most of his AF patients on these new drugs. "There are obvious exceptions, such as those patients with mechanical heart valves in whom they are contraindicated," he notes, but apart from this, the major deciding factor for him will be the patient's ability to pay.

"I will suggest one of these new drugs for my new patients, and when my existing patients come in for a review, I will suggest they switch if they can afford it," he said. He adds that the patients themselves are also very keen to take one of the new agents. "Many patients are not waiting for a review and are coming in and asking for the new drugs."

Limited role for warfarin?

Dr Larry Goldstein

He believes warfarin has only a limited role now. "It is still needed for heart-valve replacement patients because of the negative dabigatran data, and it will still be used in severe rheumatic valvular disease, as there are no data on the new agents yet, but I think its time is over in AF."

Goldstein, however, is far more cautious. He says he understands the urge to use these new drugs extensively given the positive clinical-trial results, but he cautions that there are many complex issues to be considered.

"None of the studies had a very long follow-up, so long-term use of these agents is still somewhat of an unknown, and most clinicians know that drugs need to be out in the big wide world for a while before we know everything about them," he said.

He pointed out that, while one of the main advantages of the new agents is the lack of requirement for monitoring because they are used at a fixed dose, this also has a flipside.

"It means that we don't know if patients are actually taking their drugs," he says. "If a patient presents with an acute thrombotic stroke, we may want to give [tissue plasminogen activator] tPA. If they are on warfarin we can assess their blood coagulation levels with a simple blood test, but this is not possible with the new drugs. If we don't know if there is active drug on board or not, it makes the tPA decision very difficult."

He added that this is slightly easier with dabigatran than with the factor Xa inhibitors, as dabigatran increases clotting time, although it isn't known if this correlates with clinical effect. But there is no test for rivaroxaban and apixaban.

"So while the monitoring of warfarin is a nuisance, it does mean the patient is having regular contact with a medical professional, which helps with adherence."

Compliance is key

Adherence is especially important with these new anticoagulants, as they all have relatively short half-lives. Goldstein says that it is vitally important that patients are fully compliant with the new drugs, more so than with warfarin, which has a much longer half-life.

"Patients are at increased risk of an embolic event, even if they just miss one dose of these new agents. I have personally seen this happen," he said. "This is a big issue, especially as these drugs will be used by a relatively elderly population. Doctors really have to drum this home to their patients. Whereas with warfarin, missing one dose probably wouldn't have much effect."

He adds that the cost of the new agents will exacerbate this problem. "These drugs are expensive. I worry that some patients may say they can afford them and start taking them and then decide not to continue because of the cost and not tell their doctor, putting themselves at a large increase in risk of stroke."

Goldstein further points out that, although the new agents have far fewer interaction issues than warfarin, there are other drugs that should not be taken at the same time. These include P-glycoprotein (PGP) inhibitors with dabigatran and both PGP inhibitors and CYP3A4 inhibitors with the factor Xa inhibitors.

Turpie and Goldstein have different views on bleeding risks with the new agents and the fact that no antidotes are available as yet. Turpie says he is "not too worried" about these issues.

"The regulatory agencies seem happy with the bleeding data," he said. "It is well-known that doctors report side effects more rigorously with new drugs. We see bleeding with warfarin all the time but don't often report it."

But Goldstein believes the lack of an antidote is a problem. "While these drugs do have short half-lives, so their effects will wear off relatively quickly, this is not sufficient when a patient is bleeding into the brain or experiencing another type of life-threatening bleed. You just can't wait for it to stop under those circumstances. There have been some suggestions of giving purified clotting factors and prothrombin complex concentrate, but these have not been properly tested clinically."

Which one to choose?

So, having decided that a patient is a good candidate for one of the new agents, how does a physician choose which one to go for?

Based on clinical-trial data, all three new agents seem to have advantages over warfarin—but each has a somewhat different profile.

Goldstein noted that, while all three showed a reduction in ICH vs warfarin, dabigatran was the only agent that showed a significant reduction in thrombotic stroke, whereas apixaban was the only agent that showed reductions in mortality and major bleeding. Gastrointestinal (GI) bleeding was increased with dabigatran and rivaroxaban but was not significant with apixaban.

Major results of phase 3 trials of new anticoagulants vs warfarin in AF

Drug/t rial
S troke/thromboembolism
Hemorrhagic stroke
Major bleeding
Dabigatran / RE-LY
34% reduction
74% reduction
Rivaroxaban / ROCKET-AF
Noninferior to warfarin
40% reduction
Apixaban / ARISTOTLE
20% reduction
50% reduction
30% reduction

Other issues that need to be taken into consideration include the dosing schedule, with rivaroxaban having the advantage of a once-daily dose, whereas dabigatran and apixaban are given twice daily.

Goldstein pointed out that renal insufficiency is an issue with all three new drugs, and they all need to be modified if creatinine clearance is low, whereas warfarin can be used in renal failure.

In terms of which drug to select, Goldstein said: "As there are no direct comparative studies, we have to rely on indirect comparisons, which is far from ideal. I think you have to look at all the nuances from the trials and select the drug that is most appropriate for each individual patient.

"Things to consider are: Will they be compliant? Will once a day be much more preferable to twice a day? What other drugs are they taking? Do they have issues with bleeding or GI problems? And can they pay for the drugs? The doctor needs to have a long conversation with the patient about all of these issues before deciding if any of these drugs are suitable, and then, which one."

Turpie believes that all three drugs are very similar, and most of the differences seen in clinical trials are due to differences in trial design, numbers, and patients recruited, rather than the drugs themselves.

"Having said that, factor Xa inhibitors probably have the edge in terms of off-target toxicity. They are less dependent than dabigatran on renal elimination and appear to have fewer GI side effects," he noted. "So I would say that, if a patient has renal insufficiency or is prone to GI side effects, then rivaroxaban or apixaban may be a better choice than dabigatran."

It has been suggested that rivaroxaban may not be quite as effective as the other agents, as the ROCKET trial showed just noninferiority to warfarin, rather than superiority shown with the other two agents in RE-LY (dabigatran) and ARISTOTLE (apixaban), but rivaroxaban did show superiority in an on-treatment analysis.

"If you look at the venous trials, then rivaroxaban looks the best of the three," Turpie points out. "I think the two factor Xa inhibitors are practically the same. However, rivaroxaban's once-daily dosing schedule may be preferable to many patients."

Turpie is a consultant for Bayer and is on the speaker's bureau for Johnson & Johnson and Boehringer Ingelheim . G oldstein declared no conflicts of interest .


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