January 17th, 2013
Revisiting Novel Anticoagulants in Atrial Fibrillation
John Ryan, MD and Christian Thomas Ruff, MD, MPH
With all that’s changed in the swiftly evolving world of novel anticoagulants, we invited Christian Thomas Ruff, MD, MPH, and Andrew E. Epstein, MD to answer our questions—and yours—on the use of these agents in patients with AF. Do you agree with their perspectives? What questions do you have for them or for your colleagues here at CardioExchange?
Dr. Ryan: Has the availability of new anticoagulants expanded the number of AF patients that you are anticoagulating? How are you deciding which anticoagulant to start with in these patients?
Dr. Ruff: There is a real systemic failure in our healthcare community to anticoagulate patients with atrial fibrillation who are at risk for stroke. I believe the addition of the 3 currently approved novel anticoagulants (dabigatran, rivaroxaban, and apixaban) will eventually translate into a greater proportion of eligible patients being treated; it certainly has in my practice for two main reasons: First, there are many patients who simply refuse to take warfarin because they don’t like the inconvenience of frequent INR monitoring or are concerned about the numerous food and drug interactions that interfere with their dosing. The second, and I think most compelling reason, is that all the new agents are significantly safer than warfarin with respect to intracranial bleeding (approximately a 50% reduction), which is the most feared and devastating complication of anticoagulant therapy.
About initiating anticoagulant therapy, I have found it easier to start a novel anticoagulant in a recently diagnosed treatment-naive patients with AF than to switch a patient who has been stable on warfarin for several years. As far as which agent to start with, I think all the novel anticoagulants are more similar than they are different. They are all at least as effective as warfarin in preventing strokes, and they are all vastly safer with respect to intracranial hemorrhage. There are several differences, however, that do influence which agent I prescribe. Some patients strongly prefer once a day medication and, and rivaroxaban is the only novel anticoagulant that can be dosed this way. In patients with renal dysfunction, I would be inclined to start rivaroxaban or apixaban because they have dose adjustments that were tested in their respective clinical trials and also allow dose adjustment in patients with more mild renal dysfunction compared with dabigatran.
Dr. Epstein: In addition to the points highlighted by Dr. Ruff, the randomized trials clearly showed remarkable efficacy of the novel anticoagulants. However, the risks of any therapy have to always be considered. First, it is highly unlikely that a direct comparison of the new anticoagulants will ever be done. Thus, we will have to choose between one or another based on pharmacokinetics, convenience, and perhaps formulary availability. Substudy analyses are also important: there are data from RE-LY that cardioversion may be safely performed on dabigatran, from ROCKET AF that patients with particularly high CHADS2 scores, especially from prior stoke benefit from rivaroxaban, and from ARISTOTLE that apixaban decreases not only the risk of stroke and bleeding but also of death, the latter not reaching statistical significance in either RE-LY or ROCKET AF. Second, there has been interest in the HAS-BLED score that quantifies the risk for bleeding. This score should not be used to find reasons to not anticoagulate. Instead, it should be employed to identify patients for whom extra precautions be undertaken to minimize the risk for bleeding. Third, I am concerned that although the elderly often have the most to gain from the new anticoagulants, they are also the patients at greatest risk for bleeding, especially if renal function is labile with drugs cleared by the kidneys. For such patients, warfarin should be considered.
Dr. Ryan: Some of the hesitancy surrounding novel anticoagulants remains the lack of reversibility. How do you counsel your patients regarding this, especially in light of the increased risk of intracranial bleed?
Dr. Ruff: Although I think it is important to continue to develop reversal agents for the novel anticoagulants, I don’t think the lack of such an agent is sufficient reason to avoid using a novel anticoagulant. As for intracranial bleeding, even in warfarin-treated patients it is far better to prevent this side effect than to use a reversal agent once a bleed occurs. As I mentioned, the novel anticoagulants reduce intracranial bleeding by approximately 50%, which will have a much more substantial clinical impact than the use of a reversal agent. Also, the anticoagulant effect of the novel agents is much shorter than warfarin. Although it varies according to the specific agent and the patient’s renal function, most of the anticoagulant effect of these drugs disappears after 48 hours. If a serious bleed occurs, providing supportive measures and waiting 1-2 days will be adequate in the vast majority of cases.
Dr. Epstein: Recall that for every intracranial hemorrhage, over 20 ischemic strokes are prevented. And since strokes resulting from atrial fibrillation cause greater morbidity and mortality than do strokes from other causes, the risk-benefit ratio clearly favors anticoagulation.
Dr. Ryan: Have you found the price points of new anticoagulants restrictive for patients?
Dr. Ruff: I think that price is one of the most important factors that has hindered uptake of the novel agents. Although these drugs may well be “cost-effective” in complicated analyses that focused on the costs and benefits to society at large, it is the out of pocket expense for the drugs that really matters to patients, and the new agents are substantially more expensive than warfarin. This is an especially important issue for anticoagulants because the guidelines for stroke prevention in patients with AF recommend indefinite, potentially life-long therapy. For each patient considering anticoagulant options, I have a frank conversation about the pros and cons of all of the agents and this discussion includes cost. I find it helpful to contact the patient’s pharmacy to get the actual cost for that individual as it varies depending on his or her insurance policy. Having a patient start a new anticoagulant and stop because they realize they can’t afford can result in serious safety risks for patients.
Dr. Epstein: Dr. Ruff raised the issue of stopping a new anticoagulant and changing to warfarin. We need to be aware that this action carries important risk for stroke during the transition. In the ARISTOTLE study patients were switched from study drug to warfarin at the end of the trial. During this transition there was an increased risk for stroke likely due to subtherapeutic anticoagulation in the cross-over period. Thus, withholding anticoagulants is not without risk. The package inserts for these drugs give guidance on how to manage transition between anticoagulants and bridging therapy for surgical procedures.
8 Responses to “Revisiting Novel Anticoagulants in Atrial Fibrillation”
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I have heard about a controversy saying that rivaroxaban pharmacokinetics (half-life: 5-9h in younger, 11-13h in elderly pts) would not support its once a daily use, despite good results in clinical trials. What do you think about that? Thank you.
You ask a very good question. There are two important point. The first is that it is certainly true that the half-life of rivaroxaban, as well as all the novel anticoagulants, will vary primarily due to differenes in renal function as all of the agents have some degree of renal clearance. The elderly generally have diminished renal funtion compared to younger patients which probably explains most of the difference in half life.
The second part of your question is more complicated. Although all the agents have a relatively similar half life some are dosed twice daily and others once daily. The biologic effect of balancing the prevention of thrombosis without causing excess bleeding is not a simple correlation with half life. For example, it may be the extent and duration of anti-Xa or anti-IIa activity that matters most.
Importantly, all of these agents underwent extensive dose ranging studies as part of their development which included various dose strengths and testing of once and twice daily dosing. For each agent, the selected dose strength and frequency had the best combination of laboratory and clinical data. In my own practice, I feel very comfortable prescribing rivaroxaban once daily with the appropriate dose adjustment as needed in patients with impaired renal function.
Thank you very much, Dr Ruff!
The PK/PD studies showed a more desirable benefit-risk profile at twice daily dose of rivaroxaban. Yet, once daily dose was studied in ROCKET-AF. One has to wonder to what extent marketing considerations (compliance advantage with single dosing) were involved in this decision. Twice daily dosing was evaluated for the other 2 OACs, consistent with the PK/PD studies.
This was one of the major discussion points at the FDA Ad Com panel on rivaroxaban for NVAF indication. I have yet to hear a compelling scientific reason for once daily dose used in ROCKET-AF trial.
Agree with Sanjay. There is much wider variability in peak/trough ratio with once daily dosing vs twice daily dosing of rivaroxaban (specifically referring here to the anticoagulation status of the patient). I have often wondered whether the transition to warfarin at the end of ROCKET-AF, and the attendant bounce in stroke/death, could have been the result of the decision to dose OD in the trial, or whether it was because it was not correctly overlapped with initiation of warfarin. The consequence of this, for patients having procedures and requiring interruption of rivaroxaban therapy without bridging, remains to be seen, but one might predict more embolic events in that setting. My prediction: when we see large pharmacoepidemiological studies comparing these 3 NOACs head-to-head, there will be large differences in stroke rates between the groups. As well, it should be pointed out that in ROCKET-AF, TTR with warfarin was about 55%.
It would be helpful if Sanjay could shed further light on some of these issues, based on his experience on the panel.
Excess events at the end of the trial with rivaroxaban could be explained by either increased rebound hypercoagulability (less likely) or inadequate anticoagulation (more likely) as there was no formal transition or bridging plan. There was evidence of both under-anticoagulation (HR of 1.7 for ischemic events) as well as over-anticoagulation (HR of 1.65 for bleeding events) in the rivaroxaban-treated group during post-treatment transition with warfarin. Accordingly, this resulted in a boxed warning from the FDA warning that treatment discontinuation places patients at increased risk for stroke, and that patients should undergo bridging therapy with other anticoagulants.
After discontinuing rivaroxaban, start with warfarin and parenteral anticoagulant at the time of the scheduled next dose of rivaroxaban. Since rivaroxaban can increase INR, do not use INR to initiate bridging therapy.
Given the half-life of rivaroxaban is similar to apixaban and shorter than dabigatran (both drugs dosed twice daily), and given the PK/PD results, it is difficult to justify the once daily dose.
I would like to emphasize Sanjay’s point that at the end of ROCKET trial the excess risk of stroke in patients randomized to rivaroxaban was almost certainly due to the the lack of an appropriate transition strategy. Most patient went on to VKA therapy and it took a longer time to reach a therapeutic range than patients randomized to warfarin who were simply continuing open label warfarin (or other VKA). This excess risk has nothing to do with once or twice daily dosing as the exact same excess risk of stroke was seen in the ARISTOTLE trial with apixaban which is dosed twice daily. If a patient is on a new anticoagulant and it is being stopped with a plan to transition to VKA a bridging strategy is necessary until patient obtain a therapeutic INR.
I have no patience with regard to the reluctance to transition to either: rivaroxaban (my preferred agent), apixaban (too new to be acceptable) or dabigatran ( trashed because of stupid issues, but very useful). The transition criteria are straightforward with regard to each agent — and ALL, ALL — are preferable to warfarin and INR; with regard to instituting the new agents is a no brainer, if the INR is < 3. . Reversbility is an issue, but a silly one — anyone who has had to reverse warfarin knows how difficult and unreliable that may be. 4-component prothrombin complex concentrates will reproducibly reverse both rivaroxaban and warfarin "toxicitity," the latter for an indeterminable interval, depending upon the prior dose — the former, for the foreseeable future. If the patient remains at risk of recurrent VTE, follow-up anticoagulation is necessary.