Apixaban Approved: Now Which Anticoagulant to Use?

With the recent approval of apixaban in most major countries for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF), all 3 of the new oral anticoagulants will now be 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 3 new agents — the thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim), and the 2 factor Xa inhibitors, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) — are expected to revolutionize the field of stroke prevention in AF.

But do these drugs really herald the end of warfarin, and how do doctors decide which of the 3 new agents to use? Medscape Medical News spoke to 2 experts with quite different views of the situation.

Alexander G.G. Turpie, MD, emeritus professor of medicine at McMaster University, Hamilton, Ontario, Canada, 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, Larry B. Goldstein, MD, professor of neurology at Duke Stroke Center, Durham, North Carolina, 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 [international normalized ratio] 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."

Dr. Turpie points out that although warfarin is very effective, it has many limitations, including the need for monitoring and regular dose adjustments, as well as many interactions. These interactions, 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 3 agents were associated with lower rates of intracranial hemorrhage (ICH) compared with warfarin in the phase 3 trials.

Dr. 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 1 in 300 of them will have an ICH per year no matter how well controlled they are," he said. "Now with the new drugs, this can be reduced to 1 in 500 to 600. That is a big deal."

Dr. 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 considered. "That means if an ICH does occur, there may be no way to stop it."

Dr. Turpie would like to prescribe these new drugs for most of his patients with AF. "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?

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."

Dr. 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 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 told Medscape Medical News.

He pointed out that although a main advantage of the new agents is the lack of requirement for monitoring because they are used at a fixed dose, this also has a flip side.

"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 tPA [tissue plasminogen activator]. 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 X inhibitors because dabigatran increases clotting time, although whether this correlates with clinical effect is unknown. 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."

Adherence Is Key

Adherence is especially important with these new anticoagulants because they all have relatively short half-lives. Dr. Goldstein says that it is vitally important that patients are fully adherent 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, so put themselves at a large increase in risk of stroke."

Dr. Goldstein further points out that although the new agents have far fewer interaction issues than warfarin, some other drugs 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.

Dr. Turpie and Dr. Goldstein have different views on the bleeding risks with the new agents and the fact that no antidotes are available as yet. Dr. 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 Dr. 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 is 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 your patient is a good candidate for one of the new agents, how do you to choose which one to go for?

On the basis of clinical trial data, all 3 new agents seem to have advantages over warfarin. But they have somewhat different profiles.

Dr. Goldstein noted that although all 3 showed a reduction in ICH versus warfarin, dabigatran was the only one that actually showed a significant reduction in thrombotic stroke; apixaban was the only one that showed a mortality reduction and a reduction in major bleeding. Gastrointestinal bleeding was increased with dabigatran and rivaroxaban but was not significant with apixaban.

Table. Major Results of Phase 3 Trials of New Anticoagulants vs Warfarin in AF

Drug/Trial	Efficacy: Stroke/Thromboembolism	Hemorrhagic Stroke	Major Bleeding
Dabigatran in RE-LY	34% reduction	74% reduction	Similar
Rivaroxaban in ROCKET	Noninferior to warfarin	40% reduction	Similar
Apixaban in ARISOTLE	20% reduction	50% reduction	30% reduction

ARISTOTLE = Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; RE-LY =  Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation. 

Other issues that need to be considered include the dosing schedule .Rivaroxaban has the advantage of a once-daily dose, whereas dabigatran and apixaban are given twice daily.

Dr. Goldstein pointed out that renal insufficiency is an issue with all 3 new drugs, and they all need to be modified if creatinine clearance is low, whereas warfarin can be used in patients with renal failure.

In terms of which drug to select, Dr. Goldstein said, "As there 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 [gastrointestinal] problems, and can they pay for the drugs. The doctor needs to have a long conversation with the patient about all these issues before deciding if any of these drugs are suitable and then which one "

Dr. Turpie believes all 3 drugs are very similar, and most of the differences seen in the clinical trial results are due to differences in trial design, numbers, and patients recruited rather than the drugs themselves.

"Having said that, the factor X 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 either rivaroxaban or apixaban may be a better choice than dabigatran."

It has been suggested that rivaroxaban may not be quite as effective as the others because the trial just showed noninferiority to warfarin rather than superiority (as seen with the other 2 agents), but rivaroxaban did show superiority in an on-treatment analysis.

"If you look at the venous trials then rivaroxaban looks the best of the 3," Dr. Turpie points out. "I think the 2 factor X inhibitors are practically the same. However, rivaroxaban's once-daily dosing schedule may be preferable to many patients."

Dr. Turpie is a consultant for Bayer and is on the speaker's bureau for Johnson & Johnson and Boehringer Ingelheim. Dr. Goldstein has disclosed no relevant financial relationships.

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Cite this: Apixaban Approved: Now Which Anticoagulant to Use? - Medscape - Jan 18, 2013.