New Oral Anticoagulants in AF: What to Do in Clinical Practice

March 27, 2012

March 27, 2012 (Updated April 11, 2012 ) (Chicago, Illinois) — In a talk on the new oral anticoagulants entitled "Putting it all together: What should we do now?" Prof John Camm (St Georges Hospital, London) attempted to make some recommendations on how these new drugs should be incorporated into clinical practice.

Noting that dabigatran (Pradaxa, Boehringer Ingelheim) is now available worldwide, rivaroxaban (Xarelto, Bayer) is starting to reach the market, and apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) is awaiting approval, Camm told a packed session on the last day of theAmerican College of Cardiology (ACC) 2012 Scientific Sessions: "It is a difficult task to put together all the data in a field that is so highly dynamic."

Prof John Camm

He stressed that warfarin was an extremely effective drug for stroke prevention in AF patients, reducing stroke by 68% and mortality by 26%. But about 60% of patients never get warfarin, around half of patients who do get it stop taking it, and of those who still take it only half are in therapeutic range. So only a small minority are well treated.

In trying to decide who to should receive the new drugs, Camm pointed out that they all had very short half-lives, which will be hazardous if patients are noncompliant. And renal function is another key factor that needs to be taken into account.

Comparing the Trials

He noted that the new drugs are associated with superior or similar stroke rates to warfarin, but all have shown reduced intracranial hemorrhage. In terms of major bleeding, rivaroxaban and dabigatran 150 mg are similar to warfarin but apixaban and dabigatran 110 mg show less major bleeding than warfarin.

He cautioned that these between- and within-trial comparisons were very hazardous, as there were major differences between the trials. For example, the ROCKETtrial with rivaroxaban included much higher-risk patients, so the time in therapeutic range was lower. "'But as we will probably never have head-to-head trials of the new drugs, these between-trial comparisons will have to do when trying to select which drug to use."

Concentrating on dabigatran, which is the main drug in use at present, Camm said, "It is now clear that there is a small but definite signal of MI with dabigatran vs warfarin, but this is far outweighed by its benefits. However, this has made some clinicians wary."

He noted that the main American and European Society of Cardiology (ESC) guidelines have suggested that the new drugs are "alternatives to warfarin," while new Canadian guidelines and those just announced by the ACCP have made the jump to the new agents being "preferred to warfarin."

Camm highlighted the obvious first groups of patients who should be candidates for the new drugs as:

  • Patients unwilling to take warfarin.

  • New patients naive to oral anticoagulation.

  • Those with unstable INRs on warfarin.

However, he cautioned that in the third group, it was imperative to establish that the unstable INR was not due poor compliance.

Finally, patients who are stable on warfarin could still be switched to one of the new drugs, but these may not be the highest priority at present, he suggested.

In choosing between the two new drugs so far available--dabigatran and rivaroxaban--Camm made the following points:

  • Some people prefer a once-daily dosage (ie, rivaroxaban).

  • Dabigatran should be avoided in severe renal failure. Renal function is not so much of a problem with rivaroxaban but it still needs to be considered.

  • Only the low dose of dabigatran should be used with the P-glycoprotein (Pgp) inhibitor verapamil, and close clinical surveillance is recommended especially in patients with renal impairment with quinidine and amiodarone. Dabigatran should not be used with dronedarone.

  • Dabigatran can be dialysed out of the system; rivaroxaban cannot.

  • For ACS patients, there are better data for rivaroxaban (in low dose) from theATLAS trial.

  • There is concern over the higher dose of dabigatran in the elderly.

Which Dose of Dabigatran?

On which dose of dabigatran to use in which patients, Camm pointed out that the FDA chose not to approve the 110-mg dose as it couldn't find a group of patients in whom the net clinical benefit was better on 110 mg than on 150 mg.

But he noted that in Asia the 110-mg dose is standard, probably because they are smaller people and have traditionally erred toward a lower anticoagulant status.

He concluded, "Although physicians traditionally like to err away from bleeding risk, I would recommend 150 mg as the standard dose of dabigatran, with 110 mg reserved for patients with reduced renal function or those over 80 years old."

Dr Jack Ansell

Also participating in the same ACC session, Dr Jack Ansell (Lenox Hill Hospital, New York), said he thought the FDA had made a mistake not approving the 110-mg dabigatran dose. "We've got into some trouble, as everyone is on the higher dose. I think they should reinstate the 110-mg dose."

In terms of health economics, Camm said there have been six or seven papers so far published on cost-effectiveness of dabigatran and one with rivaroxaban. "They all appear pretty consistent, and the health economic argument for the new drugs is good."

He added: "The [incremental cost-effectiveness ratio] ICER values are generally around $25 000 to $35 000, which is considered cost-effective. But there will be concerns if the new drugs are introduced too fast; budgets will be stretched."

England and Scotland Reach Different Conclusions

Camm highlighted a bizarre situation in the UK, where England and Scotland have made completely different decisions on the use of dabigatran despite considering exactly the same data.

In England, NICE is encouraging of its use, stating, "Dabigatran is an important development" and "the ICERs are within the range considered cost-effective," while the Scottish Healthcare Improvement agency says, "Warfarin remains the anticoagulant of choice, but dabigatran can be used in patients with poor INR control or those with allergies or intolerance to warfarin."

"So it is dabigatran for all in England and for very few in Scotland," Camm commented. "It is a confusing situation, but I am confident it will be resolved." He added: "The Scottish agency obviously thinks the cost impact of dabigatran is too great. But I believe their position is just a temporary measure to keep costs down."

Home-Managed Warfarin Can Be Good Option

In the same session at the ACC, Ansell made the point that patients with stable INRs in the therapeutic range may best be left on warfarin.

"If you are effective at managing warfarin, the benefits of the new drugs are not so great," he commented.

Ansell noted that patient self-testing of INRs, which is common in Europe and growing rapidly in the US, is an effective way of keeping people in therapeutic range and should translate into better outcomes.

He reported impressive results with the home monitoring of warfarin, in particular a new study presented at this meeting--STABLE--which represented the largest real-world experience with warfarin patients self-testing. In the retrospective analysis of almost 30 000 patients, time in therapeutic range was 69.7% in the overall population, climbing to 74% in those who performed weekly tests.

"This compares favorably to the time in therapeutic range for warfarin patients in the large studies of the new oral anticoagulants (around 64% or below). And other data have shown that when time in therapeutic range is above 70% with warfarin, then the cost-effectiveness of the new drugs is much lower, with warfarin starting to become more cost-effective," Ansell said.

"Warfarin is not going to go away. I would not change a stable patient doing well. But for new patients the new drugs are good options, and also possibly for some patients with unstable INR." But Ansell reiterated Camm's concerns that it is not a good move to put a noncompliant patient on the new agents. And he pointed out it can be very difficult to establish the reason for an unstable INR. "All patients will tell you they are taking their medicines, when in reality it can be very different."

Camm has served as an advisor or consultant for Actelion Pharmaceuticals, ARYx Therapeutics, Bristol-Myers Squibb, Cardiome Pharma, CV Therapeutics, Daiichi Sankyo, Menarini Group, Merck, Novartis, Sanofi, Servier, and Xention; served as a speaker or a member of a speaker's bureau for Cardiome Pharma, Daiichi Sankyo, Menarini Group, Pfizer, and Sanofi; received grants for clinical research from Bristol-Myers Squibb, Daiichi Sankyo, Sanofi, and Server; served as a member of the data safety monitoring board for Bristol-Myers Squibb, Novartis, and Servier; and served as an expert witness for Johnson & Johnson, Sanofi, and Servier. Ansell reports receiving consulting fees/honoraria from Boehringer Ingelheim, Daiichi Sankyo, Alere, Janssen, Pfizer, and Instrumentation Laboratories.