Position Paper Addresses New Anticoagulants in AF and ACS

CLINICAL CONTEXT

New oral anticoagulants offer the promise of reductions in important cardiovascular outcomes with fewer complications for the patient. The authors of the current review analyze the pharmacology of these agents. Dabigatran etexilate, a direct inhibitor of thrombin, is eliminated unchanged primarily by the kidneys, and it requires dosage adjustment for patients with moderate impairments in renal function and also among patients older than 80 years. There is no specific reversal agent for overdose with dabigatran, and administration of coagulation factors may be insufficient in reversing its anticoagulant effects.

Inhibitors of factor Xa include rivaroxaban, apixaban, and edoxaban. These medications have greater interactions with the cytochrome metabolism in the liver, and they are administered once or twice daily. Again, there is no specific reversal agent for overdose with these agents, but administration of fresh frozen plasma or other coagulation factors should reverse their anticoagulant effects compared with dabigatran.

The current position paper by De Caterina and colleagues highlights studies of these 4 medications in the management of atrial fibrillation (AF) and acute coronary syndromes (ACS).

STUDY SYNOPSIS AND PERSPECTIVE

In a "position paper" on the new oral anticoagulants, a group of experts from the European Society of CardiologyWorking Group on Thrombosis are enthusiastic about the new agents in AF, but not so impressed with their use in ACS [1].

Apixaban favored in AF

While the authors welcome all three new drugs as attractive alternatives to warfarin, they come down in favor ofapixaban as having the best data in AF.

They write: "Apixaban is currently the best-documented alternative to both warfarin and aspirin for stroke prevention in a broad population with AF." They add: "Apixaban has been shown to be superior compared with warfarin concerning the reduction of stroke and mortality in combination with a reduction in major bleeding, with a bleeding risk similar to that of low-dose aspirin, and with better tolerability than both these alternatives, albeit with no reduction in ischemic stroke compared with warfarin."

On dabigatran, they say: "Dabigatran 150 mg is also a well-documented alternative to warfarin based on its reduction of hemorrhagic stroke as well as of ischemic stroke and systemic embolism, with a similar risk of major bleeding and a reduced risk of intracranial bleeding." They note, however, that dabigatran is associated with some specific side effects, "such as an increased rate of dyspepsia and gastrointestinal bleeding, a trend toward an increased risk of myocardial infarction, and a dependence on normal or only moderately impaired renal function for its elimination." But they add that lower doses allow for tailoring of treatment in older patients and/or those with poor renal function.

The authors say rivaroxaban once daily is "a third alternative to warfarin in AF," having been "documented to be noninferior concerning stroke prevention and major bleeding, with a lower risk of intracranial but a higher rate of gastrointestinal bleeding in this population. Rivaroxaban has the advantage of a convenient once-daily regimen, which may improve adherence."

To heartwire , lead author of the position paper, Dr Raffaele De Caterina (G d'Annunzio University, Chieti, Italy), commented: "We are comparing data from different trials, so these are indirect comparisons, and therefore it is difficult to reach any firm conclusions. But if I had to rank the results of the three major trials in AF, I would putARISTOTLE with apixaban at the top, with RE-LY (dabigatran) second and ROCKET (rivaroxaban) third."

But he added: "Rivaroxaban has the advantage of a once-daily dosing, so if there is any issue of compliance, the physician may favor this agent. Rivaroxaban is also the one studied in the most indications, having the most data in [deep venous thrombosis] DVT and ACS."

De Caterina said he was "very excited" about all three new drugs. "They are easier to use than warfarin, and they all show lower rates of intracranial hemorrhage [ICH], with less or comparable bleeding. If cost were no object, I think they should almost completely replace warfarin, especially after we accrue more experience with them. We have after all really only one year of experience in clinical practice with just one of these drugs — dabigatran."

De Caterina says he is not overly concerned by the reports of bleeding with dabigatran, which seem to have flooded in during its initial time on the market. "These drugs are anticoagulants. You expect to see some bleeding. But I don't think the bleeding rates are any higher than what we see with warfarin. And the best data are that from the randomized trial, in which the bleeding rates were acceptable. In some of the cases of reported bleeding in clinical practice, dabigatran has been prescribed without proper attention to renal function or low weight. I believe that if you stick to the indications, bleeding will not be so frequently reported."

Which patients first?

On which patients should receive the new drugs, the position paper notes that patients already on long-term warfarin with well-controlled INRs and handling the monitoring without problems derive "uncertain overall advantages" from switching to the new oral anticoagulants, "and the arguments for changing treatment in such patients appear weaker than for other patient categories." It adds that warfarin may also be needed in several remaining conditions, such as intolerance of the new anticoagulants, very poor renal function, other needs for close monitoring of anticoagulation, and indications for which the new anticoagulants have not yet been studied.

De Caterina added: "There are definite advantages of these new drugs, but perhaps there are different priorities as to which patient groups should receive them first."

He said the obvious groups to start with are new patients just starting therapy; patients not well managed on warfarin — those with oscillating INRs and those who have been discouraged from using warfarin because of the risks of ICH — eg, patients with severe hypertension.

He added that another group of good candidates for the new drugs would be lower-risk patients who have not been receiving warfarin. On these patients he said: "There has been a perception that aspirin may be just as good as warfarin for these low-risk patients, but this is not the case. Warfarin is much more effective than aspirin in reducing stroke risk even in the low-risk patients. But many lower-risk patients are reluctant to take warfarin as they don't want to be bound to the health system with all the monitoring. The new drugs are a better option in this respect as no monitoring is required."

Not so enthusiastic in ACS

The paper is not so enthusiastic about use of the new anticoagulants in ACS patients.

It notes that two of the agents have been studied in large-scale trials in ACS with different results. Apixaban failed to significantly reduce ischemic events in APPRAISE-2, while a low dose of rivaroxaban succeeded in ATLAS-2. But it adds that a three- to fourfold excess in major and intracranial bleeding events was seen in both trials when the new anticoagulants were added to current antiplatelet treatment, which it says is a "major concern."

The authors point out that long-term treatment with the newer antiplatelet agents, prasugrel or ticagrelor, is associated with a reduction in ischemic events compared with clopidogrel in ACS, with only a relatively small (30%) increase in the risk of major bleeding compared with the new anticoagulants. And they suggest that use of prasugrel or ticagrelor instead of clopidogrel would therefore appear preferable to adding an oral anticoagulant.

De Caterina commented to heartwire : "The problem with ATLAS-2 is that the clopidogrel/aspirin combination may be outdated. Prasugrel and ticagrelor are replacing clopidogrel. Many doctors will want to ask what the comparison of rivaroxaban vs prasugrel or ticagrelor would have shown. We don't have the answer to that, but I would think the net clinical benefit seems to favor using the newer antiplatelets rather than rivaroxaban, as there would be less overall bleeding."

But he says there might be a place for the new anticoagulants in the longer-term treatment of ACS patients, when the initial treatment period with dual antiplatelet therapy is over — ie, one year after the event — and he would like to see a trial in this situation.

Reversal

Addressing the issue of reversal of these agents, which has been the subject of much concern, the position paper points out that there are currently no specific reversal agents or antidotes available.

In the case of overdose, it recommends oral administration of activated charcoal for adsorbing the drug from the stomach. Hemodialysis is advised for removing dabigatran from the blood, but not the other agents, which are more highly protein bound.

It recommends coagulation factors such as prothrombin complex concentrates or activated factor VII in cases of uncontrolled bleeding on all the new agents. It notes that in volunteers, prothrombin complex concentrate reverses rivaroxaban-induced prolongation of the prothrombin time, but whether it attenuates rivaroxaban-induced bleeding is unknown. It adds that because dabigatran is a thrombin inhibitor, administration of coagulation factors may not be wholly effective in reversing its effects, but even though prothrombin complex concentrate has little effect on dabigatran-induced prolongation of the activated partial thromboplastin time in volunteers or animals, it attenuates dabigatran-induced bleeding in animals.

References

1. De Caterina R, Husted S, Wallentin L, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes. ESC Working Group on Thrombosis — Task Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol 2012; 59:1413-1425.