Las Vegas—During a “bloody debate” at the American Society of Health-System Pharmacists 2012 Midyear Clinical Meeting, four experts argued fervently in favor of one of four oral anticoagulants for stroke prevention in treatment-naive patients with atrial fibrillation (AF). In this issue, Pharmacy Practice News presents a summary of the debate.
There are several advantages to using dabigatran (Pradaxa, Boehringer Ingelheim) over the other anticoagulants for patients with AF. Because of its 12- to 17-hour half-life, if one of the two daily doses of dabigatran is missed, patients are still covered for a significant part of the day. Furthermore, unlike the other novel oral anticoagulants, only 35% of metabolized dabigatran binds to protein, making it dialyzable in cases of emergent or life-threatening bleeding.
Dabigatran was approved in October 2010; rivaroxaban (Xarelto, Janssen) entered the market nearly one year later; and apixaban (Eliquis, Bristol-Myers Squibb) only recently received approval. I would argue we have more valuable experience using dabigatran and don’t yet know what skeletons are in the closet for the other agents.
Dabigatran is the only agent that, based on trial results, can be said to be superior to warfarin for prevention of ischemic strokes. findings from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial showed that only 1.11% of the large group of individuals receiving 150 mg of dabigatran twice daily suffered a stroke or systemic embolism compared with 1.69% of warfarin recipients (P<0.001) (N Engl J Med 2010;363:1875-1876). Furthermore, the annual mortality rate with 150 mg of dabigatran was 3.64%, compared with 4.13% with warfarin (P=0.051).
With dabigatran, most of the time there is no need to use a bridging agent in patients scheduled to undergo surgery. In RE-LY, dabigatran was administered an average of 49 hours prior to surgery, compared with an average 114 hours (87-144 hours) with warfarin (P=0.001). finally, the American Heart Association (AHA)/American Stroke Association (ASA) guidelines recommend dabigatran 150 mg twice daily as an effective alternative to warfarin for the prevention of first and recurrent stroke in patients with nonvalvular AF, at least one additional risk factor, and a creatinine clearance (CrCl) greater than 30 mL per minute. The American College of Chest Physicians (ACCP) guidelines also state that dabigatran 150 mg twice daily can be used “rather than adjusted-dose vitamin K antagonist therapy” for patients with AF.
Dr. Gulseth on warfarin: The infrastructure and training needed to use warfarin is quite extensive. In fact, many health systems have an anticoagulation service in large part because warfarin is a challenge to dose and manage.
Dr. Gulseth on rivaroxaban: Rivaroxaban is associated with a 3.15% rate of gastrointestinal (GI) bleeding, compared with 2.16% for warfarin (N Engl J Med 2011;365:883-889). Furthermore, although it was not statistically significant, data from ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial fibrillation) suggest that the overall bleeding rate could be even higher in the elderly, even when dose adjustments are made.
Dr. Gulseth on apixaban: The apixaban data are quite strong. We will have to watch for new data with this drug and see what is learned as experience accumulates.
Rivaroxaban has a rapid onset of action, once-daily dosing for stroke prevention in AF and few drug interactions, and it is approved for a wide range of indications.
Importantly, the ROCKET-AF trial of rivaroxaban included high-risk patients with a history of stroke, transient ischemic attack (TIA) or systemic embolism, or two or more of the following: heart failure, hypertension, age above 75 years and diabetes mellitus. The mean CHADS2 (Congestive heart failure, Hypertension, Age>75, Diabetes, Stroke or TIA ) score of 3.48 in the trial was a full point higher than the mean score in trials of dabigatran and apixaban (N Engl J Med 2011;365:883-891; N Engl J Med 2011;365:981-992).
The per-protocol analysis of ROCKET-AF data found that rivaroxaban reduced the cumulative incidence of stroke or systemic embolism by 21% compared with warfarin (P<0.001). Rates of major and clinically relevant bleeding events were similar between the two groups, but the number of bleeding-related deaths and intracranial hemorrhages were 50% and 33% lower, respectively, than the rates of these complications in the warfarin arm (P≤0.02 for both).
A small, double-blind, crossover study showed that rivaroxaban’s effects can be reversed using prothrombin complex concentrates (PCCs) (Circulation 2011;124:1573-1579). That study included 12 healthy participants randomized to receive either rivaroxaban 20 mg or dabigatran 150 mg, both twice daily, followed by randomization to infusion of either placebo or PCC. PCC reversed the prothrombin time in rivaroxaban recipients but did not reverse the effects of dabigatran.
finally, the novel once-daily formulation of rivaroxaban promises greater adherence and better disease control. To quote the late C. Everett Koop, MD, “drugs don’t work in patients who don’t take them.”
Dr. Clark on dabigatran: The open-label design of RE-LY weakens the strength of the evidence in support of dabigatran. Moreover, the risk for myocardial infarction is 28% higher with dabigatran than with warfarin (Am J Med 2010;123:785-789). Another issue I’ve seen is that many warfarin patients who switch to dabigatran pop these pills into their pill boxes, unaware that the medication needs to be kept in the original packaging to maintain short-term stability.
Dr. Clark on warfarin: To be used effectively, warfarin requires a high time-in-the-therapeutic range (TTR). However, most centers still do not know their own TTR and tend to overestimate it. Even with optimal warfarin management, the risk for intracranial hemorrhage remains significant.
Dr. Clark on apixaban: Results from the ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation) trial are impressive [See next section for a summary of the ARISTOTLE data].
Of the pivotal trials for the three novel oral anticoagulants, apixaban’s ARISTOTLE trial was the largest, with 18,201 participants (N Engl J Med 2011;365:981-992). ARISTOTLE found 1.27% and 2.13% annual rates of stroke or systemic embolism, and major bleeding, respectively, with apixaban 5 mg twice daily (2.5 mg twice daily for participants above 80 years of age, below 60 kg or with creatinine >1.5 mg/dL). The rates of both outcome measures were significantly lower in the apixaban arm than in the warfarin arm (P<0.05). Apixaban is the only novel oral anticoagulant that has been shown to significantly reduce annual all-cause mortality compared with warfarin (3.52% vs. 3.94%; P=0.047).
Indirect comparisons show that apixaban is associated with lower rates of stroke, systemic embolism and major bleeding compared with rivaroxaban, and less major bleeding compared with dabigatran 150 mg twice daily. Furthermore, 0.75% of patients in ARISTOTLE had GI bleeding, compared with 1.5% of those treated with dabigatran 150 mg and 3% of those treated with rivaroxaban in trials of those agents.
With a 25% renal excretion rate, apixaban is the best option in patients with renal impairment. The renal excretion rate for unmetabolized drug is 92% with warfarin, 80% with dabigatran and 33% with rivaroxaban. Apixaban is effective regardless of renal function or the method used to determine CrCl (Eur Heart J 2012;33:2821-2830). In fact, the greatest risk reduction in major bleeding in ARISTOTLE was seen in renally impaired patients.
finally, apixaban is the most cost-effective of all the oral anticoagulants. The estimated annual cost of treating a patient receiving apixaban, not including the price of the drug itself, is $1,599 (J Med Econ 2012;15:776-785). Cost data for other anticoagulants were as follows: warfarin, $2,084; dabigatran, $1,905; rivaroxaban, $1,995.
Dr. Nutescu on dabigatran: All of the data on dabigatran show an increased incidence of acute coronary events with the drug (Arch Intern Med 2012;172:397-402). Furthermore, real-world data show a 9% rate of major bleeding that is nearly three times the rate reported in clinical trials (J Am Coll Cardiol 2012;59:E602).
Dr. Nutescu on rivaroxaban: In ROCKET-AF, rates of stroke were higher following rivaroxaban discontinuation during transition to warfarin (N Engl J Med 2011;365:883-891). Therefore, if rivaroxaban is discontinued in anticipation of surgery or invasive procedures, the interim period should be minimized and shorter-acting anticoagulants, such as unfractionated heparin, should be considered to bridge the gap.
Dr. Nutescu on warfarin: Warfarin is a poor option in patients with renal impairment. It also is associated with a high risk for bleeding complications. Whether these risks are offset by the lower rates of stroke and systemic thromboembolic events is up for debate.
Warfarin is an established therapy with a large body of evidence backing up its efficacy in reducing stroke risk in patients with nonvalvular AF. Data include results from five randomized controlled studies including 3,691 patient-years of treatment. Cumulatively, these trials confirm that warfarin reduces the risk for stroke by nearly 70% (Arch Int Med 1994;154:1449-1457).
Unlike with the new agents, which still are not completely understood, with warfarin, clinicians have a wealth of experience in special subpopulations. For example, we know we can use it along with other antiplatelet agents. This is an important point, given that one-third of our nonvalvular AF patients have coronary artery disease.
We also know that the effects of warfarin can be reversed using a number of agents, including vitamin K, fresh frozen plasma, PCCs and recombinant activated factor VIIa. In contrast, the newer oral anticoagulants have effects that either cannot be reversed or require costly agents or longer hospital stays including hemodialysis for reversal.
We have a lot of experience with tests such as the international normalized ratio to monitor warfarin and individualize the therapy. Tailoring treatment is particularly important in those who are receiving multiple medications or have clinical conditions that may require dosing modifications. In contrast, the new agents have fixed doses. With a fixed dose, what do we do in unique patients, for example those with obesity or renal failure? We don’t know, partly because we do not have a good test or understanding of how to use test values to adjust therapy.
There may be some valid reasons to switch to one of the newer oral anticoagulants, but many patients cannot tolerate these newer medications. At our clinic, half of those who have switched to dabigatran returned to warfarin because of vomiting, bleeding or fatigue, among other issues.
finally, warfarin is the only oral anticoagulant with level 1A support in guidelines for the prevention of stroke in nonvalvular AF (Circulation 2011;123:e269-367). The strong recommendation based on high-quality evidence is a testament to warfarin’s superiority.
Dr. Dager on dabigatran: There are significant safety concerns with dabigatran. In a summary of serious adverse events that occurred during the first quarter of 2011, the Institute for Safe Medication Practices pointed to 932 serious adverse events suspected to be related to dabigatran. These included 120 deaths, 65 of which were due to hemorrhagic strokes, as well as 505 additional hemorrhages (www.ismp.org/quarterwatch/pdfs/2011Q1.pdf).
Dr. Dager on rivaroxaban: The FDA has placed a little black cloud over rivaroxaban by stating that nonadherence to the medication can actually lead to a rebound phenomenon that could include hypercoagulability. There also is evidence the drug may not be as effective as it is claimed to be in the upper quartiles of TTR (FDA Draft Briefing Document for the Cardiovascular and Renal Drugs Advisory Committee [CRDAC]; Sept 8, 2011).
Dr. Dager on apixaban: Apixaban requires twice-daily dosing and there is limited knowledge about how to reverse, monitor and adjust dosing for unique patient populations. For all the new agents, the effect of reduced drug adherence, use of a different dosing strategy for a particular indication and effects when used in populations not included in clinical trials need further clarification.
Dr. Gulseth is on the speakers’ bureaus for Boehringer Ingelheim and Janssen and also is a consultant for Janssen. Dr. Nutescu has received research support from Janssen and serves as a consultant for Daiichi-Sankyo and Janssen. Drs. Clark and Dager reported no relevant financial conflicts of interest.