Limitations of novel oral anticoagulants challenge their widespread use

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Even though novel oral anticoagulants present an “amazing opportunity to improve stroke prevention in atrial fibrillation”, according to Peter Kowey (chief of Cardiology at Main Line Heath and professor of Medicine and Clinical Pharmacology, Jefferson Medical College, Philadelphia, USA), there are still several limitations that affect their widespread use.

Kowey presented on the limitations of novel oral anticoagulation, highlighting issues such as monitoring, discontinuation, lack of reversal agents and lack of long-term data at the AF Symposium in Orlando, USA (9–11 January 2014).

“We have been through some interesting times with these drugs [novel oral anticoagulants]. Some of us thought there was going to be a therapeutic revolution when they were approved, but clearly it has not happened and there are a number of reasons for that. Among those are their limitations,” noted Kowey.

Because of the numerous limitations of warfarin-including slow onset and offset of action, genetic variation in metabolism, multiple food and drug interactions and a narrow therapeutic window-Kowey pointed out that pharmaceutical companies have come up with therapeutic alternatives. He said: “They have gone through complicated and costly development programmes and four compounds [apixaban, dabigatran, rivaroxaban and edoxaban] have emerged.” He continued, “Doctors have been bombarded with a lot of information about these drugs, and I think there is a good deal of confusion. We have not been educating our primary care physician or patients as we should.”

Kowey said that data from the IMS Health National Disease and therapeutic Index 2007–2011 show that the amount of anticoagulant use in 2011 had not gone up compared with 2007. “We have not anticoagulated people who should have been anticoagulated, and we have not made a significant dent in the use of warfarin,” he noted. “Warfarin is still the most commonly used anticoagulant in the USA, accounting for 50 to 70% of new starts, so we still have a lot of work to do. We still have many clinical challenges with novel oral anticoagulants.”

He continued, “The new drugs are more expensive than warfarin, but there are other issues regarding reversibility and monitoring.”


Monitoring

Kowey commented that there is yet no way of establishing the intensity of anticoagulant effect in clinical practice. Available tests do not have precision to support dose tritation. “The point is moot since none of the novel oral anticoagulants were developed using titratable dosing based on extent of anticoagulation, but the lack of validated metrics interferes with peri-procedural management.”


Discontinuation

A second problem for all oral anticoagulants is discontinuation. Kowey said that discontinuation of all anticoagulants (including warfarin) is “hazardous.” “The luxury we have with novel oral anticoagulants is that the time to onset and offset is short, such that patients can be anticoagulated quickly. Yet, it is very important for everyone to be aware that when you stop any anticoagulant, you expose the patient to risk,” he commented. “Because of their short half-life, novel oral anticoagulants are a bridging blessing but a switching hazard, particularly when moving patients from a new agent back to warfarin.”

Discontinuing novel oral anticoagulants specifically for surgical and catheter procedures “is a bit of a conundrum,” said Kowey. “We do not have comprehensive information, for example, on catheter ablation to be able to guide physicians as to when to stop and to start novel oral anticoagulants for these procedures.” He commented that there are little data on the continuous use of novel oral anticoagulants through catheter ablation procedures. “Fortunately we will begin to see some clinical trial information to answer these questions but it is going to take a while for those data to mature,” he said.


Lack of reversal agents

Another limitation is that there are no specific reversal agents for any of the new oral anticoagulants as of yet. “This is probably one of the biggest push backs I get from primary care doctors and patients: What happens if I bleed? What are you going to do?” he said. According to Kowey there is a “very strong effort” right now to develop reversal agents. The problem is, he noted, “We do not currently have a good read on what will be required in the regulatory arena to bring these drugs to market. How much evidence is needed to bring a new agent forward? Do you simply need to prove that you can stop bleeding, do you need some surrogate benefit like a reduction in transfusion requirement reduction. Or will you need hard endpoints to judge the efficacy and safety of these reversal agents.”

He noted that there is going to be a Cardiovascular Safety Research Consortium Think Tank in Washington, in April, to discuss these issues. Kowey commented that the lack of reversal agents “should not necessarily dissuade physicians from using the novel oral anticoagulants because they were superior on mortal and major bleeding endpoints even without the availability of revearsal agents.”


Lack of long-term data

Kowey pointed out that patients who receive noval oral anticoagulants have not been followed for long-periods. Some toxicity “will only become manifest when patients have been on these drugs for a long time,” he noted. According to Kowey, dabigatran is the exception to date, having shown long-term and consistent efficacy and safety in the RELIABLE extension study. “Information about safety and efficacy is important, but even more so is adherence, durability of effect, and switches,” he said.

“Most importantly, we still do not have head to head trials, so physicians must use clinical judgment when choosing among the anticoagulants.”

Kowey also referred to some other gaps such us the lack of data in pregnant/lactating women, in children, and in African Americans. There are also no studies regarding atrial fibrillation after cardiac surgery or what to do when an atrial fibrillation patient has an acute coronary syndrome, deep vein thrombosis or joint replacement.

He concluded that although novel anticoagulants present an “amazing opportunity to improve care,” they also present “a set of unique challenges.” He continued, “We still have a long way to go, and much to understand to improve the quality of care of patients, specifically to prevent strokes associated with atrial fibrillation. Much more work will be required to refine their use and to ultimately gain wider acceptance.”

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