BAFS: New anticoagulants may outshine warfarin, but questions remain
BOSTON--Novel anticoagulants--dabigatran, rivaroxaban, apixaban and edoxaban--will begin replacing warfarin treatment for stroke prevention in atrial fibrillation, with dabigatran being the first; however, understanding how the agents compare with each other must still be determined, Jeffrey Weitz, MD, of McMaster University in Hamilton, Ontario, said Jan. 14 during a presentation at the Boston AF Symposium (BAFS).

Choices of antithrombotic therapy for stroke prevention include: antiplatelet agents, aspirin, aspirin plus clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and anticoagulants.

But because warfarin therapy has several limitations—a slow onset of action, genetic variation in metabolism, food and drug interactions and a narrow therapeutic index—other compounds, like dabigatran (Pradaxa, Boehringer Ingelheim) are becoming FDA approved.

“These limitations mean that we need to do frequent INR monitoring to ensure that we have a therapeutic anticoagulant effect because two low, and patients are at risk for stroke, and too high, a patient is at risk for bleeding,” said Weitz.

Weitz says that the CHADS2 scoring system is “simplistic,” and can help physicians decide whether a patient requires an anticoagulant or whether the risk of stroke is low enough to consider using aspirin, or even no therapy. However, he says that the big “conundrum” is the patient who has a CHADS2 score of one, where there is “equipoise between an antiplatelet agent like aspirin, or an anticoagulant.”

While Weitz said that warfarin was developed to reach multiple targets, the new anticoagulants, were developed to chart specific enzymes, like dabigatran, which targets thrombin. The newer agents have a more rapid onset of actions that achieve peak drug levels within two to three hours, have half-lives that permit once or twice daily administration and a have degree of renal discretion.

“In contrast to warfarin, new agents have a rapid onset set of actions, they can be given in fixed doses, there are few drug-to-drug interactions and we don’t have to do routine coagulation monitoring,” he added.

How do the new oral anticoagulants compare with warfarin?
“Dabigatran in the lower 110 mg dose regiment is noninferior to wafarin, while the higher 150 mg dose is superior to warfarin in terms of reducing stroke and systemic embolism,” offered Weitz.

In fact, dabigatran reduced the rates of intracranial bleeding by two-thirds when compared to warfarin. In addition, the higher 150 mg dose of dabigatran was more effective than warfarin in all CHADS2 categories, while the lower dose had similar effects to warfarin.

But what have we learned about the differences of dabigatran versus warfarin? asked Weitz. The benefits of dabigatran over warfarin are available in all levels of time in therapeutic range and at all levels of warfarin control; however, the benefits are greatest in patients who have the lowest time in therapeutic range.

Weitz said, “The better patients do with warfarin management, the less they will benefit from dabigatran and the poorer they do with wafarin management, the greater the benefit you will see with dabigatran.”

In certain patient populations, like the elderly, dabigatran may decrease the risk of stroke and intracranial bleeding, but increase the risk of extracranial (GI) bleeds. Currently, Health Canada has approved the 110 mg dose of dabigatran for patients over the age of 80 and for those who are at a high risk of bleeding.

But who is not a candidate for dabigatran then? “I would say that for those patients who are very stable on warfarin and have a good time in therapeutic range; there is really no argument to change.

However, patients with a CrCI less than 15 ml/min, who have severe hepatic dysfunction, a high risk of GI bleeding or a mechanical valve, should not be placed on dabigatran.

And while patients on dabigatran may fare better than some patients on warfarin, Weitz said, there are still many unanswered questions about dabigatran’s usage. For example, will dyspepsia lead to discontinuation? How will we manage patients with a history of GI bleeding? And will the short half-life obviate need for an antidote?

While the ROCKET, ARISTOTLE and ENGAGE trials will assess the efficacy and safety of rivaroxaban (Xarelto, Bayer), apixaban (Pfizer/Bristol-Myers Squibb) and edoxaban (Daiichi Sankyo), respectively. Weitz says while it will be “difficult to compare apples to oranges,” comparing these agents will be helpful for future usage.

Already, data has shown that rivaroxaban, while non-inferior to warfarin for efficacy, has similar rates of ischemic stroke, major bleeding, and MI, but reduces ICH. However, rivaroxaban’s advantage over warfarin is “less clear,” said Weitz.

Developers of apixaban had to cease the Phase 3 APPRAISE-2 trial that enrolled patients with acute coronary syndrome (ACS) because data showed that there is an increase in bleeding risk in those administered the drug.

Even while these drugs have potential for becoming the new wave of anticoagulation therapy, Weitz says costs, compliance and how we treat bleeding rates will need to be assessed.

Despite the issues, Weitz concluded that “new oral anticoagulants are poised to replace warfarin for stroke prevention in AF … in fact it’s already happening.”