ENGAGE-AF: Me too! Or four, rather… edoxaban represents yet another alternative to warfarin in patients with atrial fibrillation

This entry is the fourth part of a series on late-breaking clinical trials from the American Heart Association Scientific Sessions 2013. For a list of all reviewed trials, click here.

Summary:
In the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE-AF) trial [1], patients with atrial fibrillation and a CHADS₂ score of > 2 were randomized in a double-blind, double-dummy fashion to either high-dose edoxaban (60 mg daily), low-dose edoxaban (30 mg daily), or warfarin titrated to an INR of 2-3. Patients with an estimated creatinine clearance (CrCl) < 30 mL/min and those taking dual antiplatelet therapy were excluded. The dose of edoxaban was halved if patients were < 60 kg, had a CrCl of 30-50 mL/min, or if a strong p-glycoprotein inhibitor (i.e., dronedarone, quinidine, verapamil) was added. Notable baseline characteristics include median age of 72, history of stroke in 28.3% and heart failure in 57.4%; over three-fourths of patients had a CHADS₂ score < 3. The median time in therapeutic range (TTR) for those on warfarin was 68.4%.

In terms of the primary endpoint of stroke or systemic embolism, both doses of edoxaban were non-inferior to warfarin (1.18% with high-dose edoxaban and 1.61% with low-dose edoxaban vs. 1.50% with warfarin [p < 0.001 and p = 0.005, respectively]). While a trend favoring edoxaban was observed in the superiority analysis, it did not reach statistical significance. Rates of major bleeding were lower with both doses of edoxaban (2.75% and 1.61% with high and low-dose edoxaban vs. 3.34% with warfarin, both p < 0.001), as were rates of intracranial hemorrhage. Gastrointestinal bleeding (GI) was higher with edoxaban. Improvements in several key secondary endpoints were also observed with edoxaban, including death from cardiovascular causes. Patients receiving the lower dose of edoxaban had a higher rate of ischemic strokes, while rates were similar among those on warfarin and high-dose edoxaban.

Commentary:
With a few exceptions, the findings of ENGAGE-AF are almost identical to those observed in the comparison of rivaroxaban, another factor Xa inhibitor, and warfarin in the ROCKET-AF trial [2]. Most experts argue that is not possible to compare the new oral anticoagulants with each other because none were studied head-to-head. While this is true from the standpoint of academic purity, it does little to guide the clinician when faced with the challenge of selecting an agent in an individual patient. For this latter case, a discussion of the similarities and differences are important.

Similarities between ENGAGE-AF and ROCKET-AF include:

• Trial design: both were randomized, double-blind, double-dummy trials
• Inclusions/exclusions: similar thresholds for renal function, high-risk exclusions (e.g., patients on concomitant dual antiplatelet therapy were excluded) 
• Drug dosing: once daily dosing vs. warfarin titrated to an INR of 2-3 
• Efficacy: both shown to be non-inferior to warfarin 
• Safety: both safer than warfarin in the severest of safety endpoints (fatal bleeding, intracranial hemorrhage), but higher rates of GI bleeding

A few key differences:

• Study population: on average, the patients enrolled in ENGAGE-AF were healthier than those in ROCKET-AF, as demonstrated by lower median CHADS₂ scores and fewer patients with a history of stroke or heart failure
• Warfarin management: warfarin was more optimally managed in ENGAGE-AF based on a TTR of 68.4% compared to 55% in ROCKET-AF; that being said, INR control is closely related to overall health status, so the fact that the INR was less problematic in the healthier population of ENGAGE-AF is not altogether surprising 
• Safety endpoints: although both drugs reduced the incidence of severe bleeding, rivaroxaban was similar to warfarin in the primary safety endpoint of major bleeding, whereas edoxaban was safer in ENGAGE-AF 
• Transition at study termination: the investigators of ENGAGE-AF should be applauded for the lessons learned from ROCKET-AF, where rebound thrombotic events were observed among patients being transitioned from rivaroxaban to open-label warfarin at conclusion of the trial. At the end of ENGAGE-AF, a carefully monitored transition from edoxaban to warfarin was performed, resulting in no differences in rebound thrombotic events 
• Differences in secondary endpoints: edoxaban showed improvements in some secondary endpoints (e.g., cardiovascular death, other composites)

So now that edoxaban will represent the fourth alternative to warfarin, what are clinicians to do? To be honest, it is my personal opinion that edoxaban offers few if any clinical advantages to rivaroxaban. Despite being studied in a healthier population (i.e., where differences in drug metabolism and clearance are less likely to complicate management), edoxaban was still only non-inferior to warfarin. While it was safer than warfarin in terms of major bleeding, this could again be attributed to the healthier nature of the patient population. Both rivaroxaban and edoxaban reduced the incidence of the severest safety endpoints – fatal bleeding and intracranial hemorrhage.

Compared to the other new oral anticoagulants apixaban and dabigatran, my feelings on edoxaban are similar to rivaroxaban, which I wrote about in this entry in November 2011 and again in October 2012. I still tend to favor apixaban as my first-line alternative to warfarin based on it having the most comparative advantages, although I would still consider dabigatran in younger patients with normal renal function. The whole notion that the once daily dosing made possible by rivaroxaban, and now edoxaban, is more ideal for less compliant patients is still a dangerous proposition (see my note at the end of the selection tool posted in October 2012). For patients likely to miss doses, a once daily drug that only lasts half a day actually offers less protection from stroke and systemic embolism than one taken twice daily.

Bottom line:
Edoxaban is non-inferior to warfarin for preventing stroke and systemic embolism in patients with atrial fibrillation while reducing the risk of major bleeding.

References

1. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093–104.
2. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883–91.

Selecting an oral anticoagulant in patients with atrial fibrillation: an evidence-based guide for clinicians

Choosing the most appropriate oral anticoagulant has become a challenging decision in the management of patients with atrial fibrillation and one that often generates significant discussion on rounds. Unfortunately, no trial has compared all of the available options head-to-head, so data must be extrapolated from several sources, all while attempting to incorporate patient-specific characteristics that might make one strategy better than another.  Because the topic comes up so frequently, I developed the following algorithm to help guide my recommendations and thought I would share.

This information is also available in PDF format.

Figure 1. Evidence-based algorithm for choosing an oral anticoagulant in atrial fibrillation (Click image for a larger version)
Abbreviations: OACs oral anticoagulants, GI gastrointestinal, CAD coronary artery disease, INR international normalized ratio, CrCl creatinine clearance

Clinical Rationale (also included in the PDF)
Each point below corresponds to a section of the algorithm shown above.

1. For patients with a known history of atrial fibrillation (AF), decisions regarding oral anticoagulation should consider previous management strategies, including relative degree of success. Evidence indicates that patients who are successfully anticoagulated with warfarin may continue to do well with warfarin compared to those who are newly initiated on therapy or transitioned to other agents [1,2]. Notably, this trend has not been observed in patients transitioned from warfarin to the higher dose (150 mg) of dabigatran [3].
2. In the landmark trials comparing the new oral anticoagulants (OACs) rivaroxaban or dabigatran to warfarin, the mean INR time in therapeutic range (TTR) for patients randomized to warfarin ranged from 55% to 64% [2,3]. A mean TTR in the mid-60% range is generally considered the gold standard when comparing an agent to warfarin, which explains why the low TTR observed in ROCKET-AF was such a major criticism of the trial.  While a mean TTR in the mid-60% range represents the global management of patients on warfarin therapy, some centers are able to achieve much higher mean TTR values. How successfully a patient has been (or could be) managed on warfarin therapy should be factored into management decisions, as none of the new OACs have been compared to warfarin in patients with higher TTR ranges.
3. Patients who have been successfully managed on warfarin therapy should still be presented with the option of transitioning to a new OAC if they find the monitoring and lifestyle restrictions (e.g., diet) associated with warfarin therapy to be inconvenient.  Most guideline authorities recognize the importance of including patients in this management decision.  However, the limitations of these new agents (many of which are included in this document) should be fully disclosed to patients prior to making a decision about anticoagulation therapy.
4. The following is a list of several important limitations with the new OACs.
• Valvular heart disease. Patients with valvular heart disease were specifically excluded in the major trials comparing the new OACs with warfarin.  Because these patients are generally at higher thromboembolic risk (especially those with certain types of prosthetic valves), it is unknown whether the new OACs provide a degree of anticoagulation comparable to warfarin in these settings.
• Extreme body weights (< 60 kg or > 120 kg). The mean body weight of patients in the trial comparing dabigatran to warfarin was 82.5±19.4 kg and the mean BMI of patients in the trial comparing rivaroxaban to warfarin was 28 ± 3 kg/m²; patients at the very extremes of these body weight ranges have not been well-studied [2,3].  Doses of other anticoagulants (e.g., enoxaparin) are adjusted by weight, so it is unknown whether the new OACs provide a comparable degree of anticoagulation in patients with extremely low or high body weights at the fixed doses studied in randomized trials.
• History of significant gastrointestinal hemorrhage.  In the trials comparing rivaroxaban or dabigatran to warfarin, both agents were associated with significantly increased rates of gastrointestinal hemorrhage.  While this fact is a well-known adverse effect of dabigatran, some clinicians may be unaware that similar risks were observed with rivaroxaban.
• Active or advanced liver disease.  Patients with active or advanced liver disease, including those with evidence of coagulopathy (e.g., elevated INR at baseline), were excluded from major trials comparing the new OACs to warfarin. Furthermore, rivaroxaban undergoes significant hepatic metabolism and is known to accumulate in patients with significant hepatic impairment [4].
• Dual antiplatelet therapy for coronary artery disease required. Few patients on dual antiplatelet therapy (i.e., aspirin plus a P₂Y₁₂ receptor inhibitor) were included in the major trials comparing the new OACs to warfarin [2,3]. Of those that were, few if any were on the combination of aspirin and prasugrel (a combination associated with a higher risk of major and fatal bleeding at baseline) and none were on ticagrelor.  Therefore, for patients at a lower risk of stroke and in whom the risk of bleeding associated with the addition of warfarin is thought to outweigh the potential benefit, it may be reasonable to use only dual antiplatelet therapy for the critical period after the index event (including whether a coronary stent was placed) and then transition to warfarin after that time. While the combination of aspirin and clopidogrel is inferior to warfarin for stroke prevention in the setting of atrial fibrillation, it does provide some degree of protection while these patients are recovering from an acute event [1,5].  For patients with a higher risk of stroke due to atrial fibrillation, it may be reasonable to use the combination of aspirin, a P₂Y₁₂ inhibitor, and warfarin targeted to a less aggressive INR goal (i.e., 2 – 2.5), a recommendation recently incorporated into management guidelines for non-ST segment elevation myocardial infarction [6]. Emerging data indicates that these patients may also be safely managed with a P₂Y₁₂ inhibitor and warfarin alone, although these results have not been fully published nor included in clinical practice guidelines.
• Other conditions. Patients with other conditions that may influence drug metabolism (e.g., advanced heart failure), where monitoring of anticoagulation status may be necessary to ensure ongoing safety, should still be considered for warfarin therapy.  Use of currently available measurements of anticoagulation status (e.g., prothrombin time, ecarin clotting time, activated partial thromboplastin time, etc.) to guide therapy with the new OACs has not yet been well-validated.
5. Cost is an important consideration when initiating therapy with a new OAC, as issues related to access and ability to pay are some of the most significant contributors to patient non-adherence. The new OACs are generally more expensive than warfarin, even for patients with health insurance and prescription drug coverage, including (in most cases) when the expenses associated with warfarin monitoring and follow-up are also considered.  The manufacturers of the new OACs have some financial assistance programs available, and these should be considered for those patients who are unlikely to do well with warfarin but who are also unable to afford a new OAC.
6. Renal impairment may be the most important limitation with the use of the new OACs.
• End-stage renal disease.  Both dabigatran and rivaroxaban should be avoided in patients with severe renal impairment (creatinine clearance [CrCl] < 15 mL/min) due to the risk of drug accumulation.
• Severe impairment. Patients with moderate renal impairment (CrCl 15-60 mL/min) may be considered for therapy with a new OAC.  While an adjusted dose of dabigatran is available in those patients with some degree of renal impairment (CrCl 15-30 mL/min), data to support its use is derived from pre-clinical trials and pharmacokinetics rather than prospective evidence.  Therefore, this guideline recommends rivaroxaban in those patients, as the dose adjusted for renal impairment (15 mg daily, for CrCl 15-50 mL/min) was included in the large trial comparing it to warfarin [2].
• Moderate impairment. For patients with moderate renal impairment, age should become an additional consideration regarding which new OAC to choose, as equations commonly used to predict renal function are far less accurate in older patients, especially those with low body weight (i.e., muscle mass).  The inaccuracy of these equations may help explain why increased rates of hemorrhage have been observed with dabigatran in older patients (see additional explanation in Part G below).
• Mild impairment or normal. For patients with normal renal function or only mild renal impairment, dabigatran should be used preferentially over rivaroxaban, as it showed clinical superiority to warfarin in the large randomized control trial comparing the two agents.  At a dose of 150 mg twice daily, dabigatran demonstrated improvements in the composite endpoint of stroke and systemic embolism (as well as several secondary endpoints) with a comparable degree of overall bleeding and less bleeding in several key subgroups (including intracranial hemorrhage).  On the other hand, rivaroxaban was shown as only being non-inferior to warfarin in the primary analysis of its comparison trial with a lower incidence of overall bleeding. Therefore, this guideline gives preference to dabigatran, except in cases where its advantages over warfarin are less likely (e.g., renal impairment, older age), making rivaroxaban a more ideal choice.
7. As mentioned above, estimates of renal function are less predictable as patients age.  As a result, older patients with adequate renal function (as predicted by the Cockcroft-Gault or other equations) may actually have a significant degree of renal impairment.  In these patients, the risk of accumulation with dabigatran may outweigh its potential benefits, making rivaroxaban a more ideal choice.  Additionally, a post hoc analysis of the RE-LY trial as well as pooled data from adverse event reports indicates that the risk of major bleeding associated with dabigatran increases significantly in older patients.7 Although various age thresholds for avoiding dabigatran have been proposed (e.g., > 75 years, > 85 years), the median age of patients experiencing adverse events with dabigatran is around 80 years, so this threshold was chosen for this tool.  Even if patients have normal renal function or mild impairment, caution should still be exerted when initiating dabigatran in patients over the age of 80 years given the limited ability to estimate renal function in this patient population.

Note: Some contend that the once daily dosing of rivaroxaban provides it with a significant clinical advantage to dabigatran, especially in patients with poor medication adherence.  However, this is not yet supported by the literature and may be a risky proposition given the increased rates of thromboembolic events observed in patients transitioning from rivaroxaban to warfarin following the conclusion of ROCKET-AF [2].  Additionally, it is generally thought that medication adherence is not significantly impacted until patients are required to take medications three times a day and many patients with atrial fibrillation are already taking other medications twice daily (e.g., certain beta blockers, antiarrhythmics, antihypertensives, etc.).  Finally, based on pharmacokinetic comparisons between dabigatran and rivaroxaban (e.g., duration of action, termination half-life), dabigatran may provide a similar degree of thromboembolic protection compared to once daily rivaroxaban even if doses are missed (although this is not yet based on evidence from the literature).

As always, comments and suggestions (and disagreements, of course!) welcomed.

References

1. Connolly S, Pogue J, Yusuf S, et al; for the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006 Jun 10;367(9526):1903-12.
2. Patel MR, Mahaffey KW, Califf RM, et al; for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91.
3. Connolly SJ, Ezekowitz MD, Wallentin L, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51.
4. Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol. 2012 Feb;26(1):27-32.
5. Wann LS, Curtis AB, Yancy CW; et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011 Jan 11;57(2):223-42.
6. Jneid H, Anderson JL, Zidar JP, et al. 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012 Aug 14;60(7):645-81.
7. Eikelboom JW, Wallentin L, Yusuf S, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011 May 31;123(21):2363-72.

Update: Deja vu in ATLAS ACS-2: rivaroxaban in the subset of patients with ST-segment elevation myocardial infarction

In an article posted on theheart.org last week highlighting the results of several late-breaking clinical trials revealed at the 2012 European Society of Cardiology (ESC) meeting, experts again debated the utility of adding low-dose rivaroxaban (2.5 mg twice daily) to dual antiplatelet therapy in patients with acute coronary syndromes (ACS). The discussion involved a pre-specified sub-analysis of ATLAS ACS 2 [1], a trial that randomized patients with ACS who were already receiving aspirin and clopidogrel to either rivaroxaban or placebo.  A sub-analysis of the patients with ST-segment elevation myocardial infarction (STEMI) found a small but marginally significant reduction in major adverse cardiovascular events (absolute risk reduction 1.9%, HR 0.81 (95% CI 0.65-1.00), p = 0.047) with rivaroxaban. However, as observed in the overall cohort of patients with ACS, this benefit was accompanied by a significant increase in several types of bleeding (details unavailable at this time).

As I describe in a previous entry on the results of ATLAS ACS 2, I am still not sure it is worth pursuing the addition of rivaroxaban in patients with ACS until we know its risk versus benefit profile in combination with aspirin and one of the newer P2Y12 inhibitors prasugrel or ticagrelor.  Although, given the results of another trial revealed at ESC 2012, perhaps we should be dropping aspirin from the "triple therapy" strategy anyway.

What is perhaps an even more challenging scenario, as the article goes on to discuss, is what to do when patients have multiple indications for anticoagulation or are already receiving rivaroxaban for a different indication and have an ACS event.  The appropriate dose of rivaroxaban depends on indication -- 10 mg once daily for prophylaxis of venous thromboembolism following major orthopedic surgery, 15 mg twice daily for the treatment of deep vein thrombosis or pulmonary embolism (assuming the agent will be approved for these indications based on the results of the two EINSTEIN investigations [2,3]), or 20 mg daily for atrial fibrillation (15 mg once daily if impaired renal function). If someone has an ACS event that requires dual antiplatelet therapy and is already taking rivaroxaban for one of these indications, do we reduce the dose to 2.5 mg twice daily given that higher doses are already known to increase the risk of bleeding in this population [4]?

I suppose nobody has any definitive answers to these and other challenging clinical scenarios that will soon be at our doorstep, but one thing I do know for sure -- what an exciting time to be practicing in the area of cardiology.

Note: the 2.5 mg twice daily dose of rivaroxaban was up for approval by the US Food & Drug Administration earlier this year, but failed to gain the indication for use in acute coronary syndromes.

References

1. Mega JL, Braunwald E, Gibson CM; for the ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 2012; 366:9-19.
2. The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010; 363:2499-2510.
3. The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012; 366:1287-1297.
4. Mega JL, Braunwald E, Gibson CM, et al; for the ATLAS ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009 Jul 4;374(9683):29-38.

Going to ground: risk of falls and oral anticoagulation

LAW #2: GOMERS GO TO GROUND.

In The House of God, a 1970s novel detailing his experience as a first-year medical resident, Samuel Shem (a pseudonym for Stephen Bergman, MD), cites the above axiom as one of the Laws of the House of God taught to him by a senior resident known only as The Fat Man.  The rule itself refers to the propensity of elderly patients to fall or fall from their hospital beds, and like many concepts from the novel that have made their way into the medical vernacular, an assessment of fall risk remains an important evaluation in both hospitalized and ambulatory patients and often significantly impacts the strategies of care offered or delivered to them.

One of the most common scenarios during which a discussion of fall risk occurs is when determining the appropriate antithrombotic strategy for an elderly patient with atrial fibrillation (assuming their annual risk of stroke warrants oral anticoagulation, as determined by the CHADS₂ and/or CHA₂DS₂-VASc score).  The risk of major hemorrhage associated with a traumatic fall is often cited as a reason not to provide full anticoagulation, but evidence from the literature indicates these risks are often overestimated; more importantly, the preference for aspirin in many of these patients is unlikely to ameliorate these risks.

For example, in the Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA) [1], patients over the age of 75 years (mean 81.5 years) with atrial fibrillation were randomized to aspirin 75 mg daily or adjusted-dose warfarin (INR goal 2-3); after a mean follow-up period of nearly 3 years, adjusted-dose warfarin was associated with a reduction in the number of total strokes compared to aspirin (3.4% versus 1.6%, respectively, p = 0.003), a difference that was largely driven by a difference in ischemic strokes (2.5% versus 0.8%, p = 0.0004).  More importantly, the benefits observed with warfarin were not accompanied by an increase in major hemorrhage or hemorrhagic stroke. In another analysis [2], the risk of falls among elderly patients with atrial fibrillation was not found to be a major contributor to the hemorrhagic events associated with warfarin -- in fact, a patient would need to fall nearly 300 times in a single year for the risks to outweigh the potential benefits.

Given the alternatives now afforded by the new oral anticoagulants apixaban, dabigatran, and rivaroxaban -- which are arguably safer than warfarin in appropriately selected patients -- the benefits associated with full anticoagulation are even more likely to outweigh the hemorrhagic risks commonly attributed to falls. In fact, when it comes to intrancranial hemorrhage, the most devastating complication of a traumatic fall, each of the new oral anticoagulants is associated with a markedly lower risk compared to warfarin -- a difference in absolute risk per year of 0.24%, 0.44%, and 0.20% with apixaban, dabigatran, and rivaroxaban, respectively [3-5].

Thus, as the population continues to age and the incidence of atrial fibrillation grows, it is likely that discussions involving the appropriate antithrombotic strategy in elderly patients with this condition will only become more frequent as time goes on. While every patient should be evaluated for their individual risk of stroke and hemorrhage, we should be cautious not to potentially deny them the benefits of oral anticoagulation in favor of an antithrombotic strategy (i.e., aspirin) that is definitively less effective but also unlikely to ameliorate the risk of hemorrhage associated with a traumatic fall.

References

1. Mant J, Hobbs FD, Murray E; for the BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007 Aug 11;370(9586):493-503.
2. Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med. 1999 Apr 12;159(7):677-85.
3. Granger CB, Alexander JH, Wallentin L, et al; for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92.
4. Connolly SJ, Ezekowitz MD, Wallentin L, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51.
5. Patel MR, Mahaffey KW, Califf RM, et al; for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91.

Rivaroxaban management guideline posted on ClotConnect

A guideline we developed for the practical management of rivaroxaban at our institution (click here for the PDF) was recently posted on ClotConnect, an educational website for patients and health care providers developed by the Hemophilia and Thrombosis Center at the University of North Carolina at Chapel Hill.  Rivaroxaban is an oral factor Xa inhibitor indicated for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation as well as for the prevention of venous thromboembolism following orthopedic surgery.  In the guideline, we provide recommendations on the following:

• Considerations for initiation of therapy (dosing and administration, monitoring parameters, cost considerations)
• Conversions to and from other anticoagulants, including unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and warfarin
• Perioperative management
• Management of hemorrhagic events
• Patient education

I should disclose that many of the recommendations included in this document have been extrapolated from pharmacokinetic and pre-clinical investigations, as there is little other evidence in the literature to help guide clinicians in the practical management of rivaroxaban.  As such, the content is subject to evolve significantly as we gain more experience with it and the other new oral anticoagulants.  In the meantime, we hope this resource will be useful in assisting other institutions and individual providers who are already using rivaroxaban in clinical practice. 

Special thanks goes to all the other collaborators on this project, including Melissa Hunter and Stacy Miller, who were final year student pharmacists at the time of its creation; Abbie Miller, PharmD, BCPS; and Stephan Moll, MD.

Deja vu in ATLAS ACS 2: rivaroxaban in acute coronary syndromes

Another major trial that emerged out of the 2011 American Heart Association meeting last month was ATLAS ACS 2 [1], which evaluated the addition of rivaroxaban (Xarelto^®) to dual antiplatelet therapy in patients with acute coronary syndromes (ACS).  A reduction in major cardiovascular events was demonstrated in the group randomized to rivaroxaban therapy, but this benefit was accompanied by an increase in major nonfatal bleeding.

The rationale behind ATLAS ACS 2 is similar to WARIS II [2], a study conducted in 2002 which randomized patients to aspirin, warfarin, or both following an acute myocardial infarction (MI). The study demonstrated that warfarin given alone or in combination with aspirin reduced major cardiovascular events (largely driven by reductions in reinfarctions and thromboembolic strokes) but was associated with an increase in major nonfatal bleeding.  However, the practice never really caught on. First, the addition of warfarin seemed impractical and inconvenient for the majority of patients who presented following an MI.  Secondly, as the results of WARIS II were being finalized, the CURE trial was published [3], paving the way for dual antiplatelet therapy as the new standard of care in patients with ACS.  Given the follow-up and monitoring required for long-term warfarin therapy, the addition of clopidogrel to aspirin seemed like a more attractive strategy for reducing major cardiovascular events following ACS.  Since that time, no robust randomized prospective trials have specifically investigated the addition of warfarin to dual antiplatelet therapy for the purpose of improving outcomes in ACS, so the practice was largely abandoned before it ever began.

Given the complex thrombotic risk associated with ACS, the addition of rivaroxban was expected to provide a similar benefit as warfarin in WARIS II, but without the cumbersome monitoring and follow-up required (and perhaps a lower incidence of certain types of bleeding) -- but given the evolution of antiplatelet therapy, is ATLAS ACS 2 simply a case of deja vu?

In ATLAS ACS 2, rivaroxaban was added to dual antiplatelet therapy comprised of aspirin and clopidogrel (and in a few instances, ticlopidine). However, some would argue that we have entered an era where clopidogrel will be gradually phased out in favor of the newer antiplatelet agents prasugrel (Effient^®) and ticagrelor (Brillinta^®) (or, at the very least, its use will be primarily reserved for the minority of patients who are not candidates for other therapies).  While I anticipate this process will take years to occur, several recently published guidelines already reflect this shift in practice -- the 2011 European guidelines for non-ST elevation myocardial infarction (NSTEMI) recommend prasugrel and ticagrelor as first-line therapy in appropriate patients and the 2011 US guidelines for percutaneous coronary intervention (PCI) recommend these agents as reasonable alternatives to clopidogrel.

So, while the addition of low-dose rivaroxaban appeared to benefit patients in ATLAS ACS 2, is this simply the modification of a standard of care that is already on its way out?  Prasugrel is clearly associated with increased rates of bleeding versus clopidogrel. While ticagrelor is associated with a similar incidence of bleeding overall, it had higher rates of bleeding in certain key subgroups, including intracranial hemorrhage and non-CABG related major bleeding.  Therefore, given the incidence of bleeding already associated with newer antiplatelet therapies, the risks of adding rivaroxaban to these emerging standards of care may actually outweigh its benefits. Moreover, if a clinician's reasoning for avoiding prasugrel or ticagrelor in a specific patient is related to concerns for bleeding, the addition of long-term rivaroxaban seems even more unlikely.

With the patent for clopidogrel set to expire late in the second quarter of next year, it will likely remain a standard of care for many patients in the US for some time.  If patients who would otherwise be candidates for prasugrel or ticagrelor are placed on clopidogrel for financial considerations, I cannot imagine any financially justifiable advantages of adding rivaroxaban -- an agent that will probably only be available as a brand name product for the next decade or more.

Either way, it is still too early to tell how ATLAS ACS 2 will influence the management of patients with ACS. However, if history (i.e., WARIS II) has taught us anything, the addition of rivaxoban in patients with ACS may also be a practice that is abandoned before it ever begins...

References

1. Mega JL, Braunwald E, Gibson CM; for the ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. N Engl J Med. 2011 Nov 13.
2. Hurlen M, Abdelnoor M, Arnesen H, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-74.
3. The CURE Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345: 494-502.

Rivaroxaban approved for stroke prevention in atrial fibrillation

Earlier today, representatives from the US Food & Drug Administration (FDA) announced that the agency had approved the oral factor Xa inhibitor rivaroxaban (Xarelto^®) for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The decision follows several months of controversy, as FDA reviewers initially recommended against its approval in atrial fibrillation while the FDA Cardiovascular and Renal Drugs Advisory Committee voted in its favor.

The approval is based on the results of the ROCKET-AF trial, which found that rivaroxaban was just as effective (i.e., non-inferior) to warfarin for the prevention of stroke and systemic embolism in patients with non-valvular AF. Bleeding events were comparable between the two agents, although patients on rivaroxaban had less severe bleeding events, including fewer intracranial hemorrhages and fewer cases of fatal bleeding.

The results of ROCKET-AF have been the subject of harsh criticism, including the fact that patients randomized to warfarin had a time in therapeutic range (TTR) of only 55%. While no official threshold exists, most consider TTR > 60-65% as being the gold standard when making comparisons to warfarin. Critics of the trial have also expressed concerns over the increased incidence of thromboembolic events in patients who discontinued therapy or were transitioned from rivaroxaban to another anticoagulant.

Given that rivaroxaban is no more effective than warfarin and probably less effective than dabigatran (although the two have not been compared head-to-head), I anticipate Johnson & Johnson will market the drug based on its convenience (e.g., once daily dosing and no need for lab monitoring). The once daily dosing strategy still perplexes me, especially given that the drug's half life is only about 5-9 hours. Rivaroxaban is dosed twice daily in the management of deep venous thrombosis and pulmonary embolism, although it has not yet been approved for these indications in the US.

In terms of comparing it to existing alternatives, I would put rivaroxaban at a distant third, considering it primarily for those patients in whom compliance may be a limiting factor. However, the "rebound" effects observed in ROCKET-AF are troubling, so I would still make this recommendation with some trepidation. Another proposed advantage (details in a previous post) is that the effects of rivaroxaban can be reversed by prothrombin complex concentrate (PCC), a prohemostatic agent comprised of factors II, VII, IX, and X. However, whether the reversal of laboratory measurements (e.g., prothrombin time, endogenous thrombin potential) correlates with a clinically meaningful improvement in bleeding events is still unknown at this time.

The excitement over rivaroxaban will likely be eclipsed by the approval of apixaban, another factor Xa inhibitor and the latest to be compared to warfarin in patients with AF. Although apixaban is dosed twice daily, it was shown to be safer and more effective than warfarin, two features that have yet to be matched by any other anticoagulant to date. While no official word on its approval is currently available, I imagine it will only be a matter of time.

Another strike against dabigatran

In addition to two new oral anticoagulants vying to take its place as the alternative to warfarin in patients with atrial fibrillation (AF), dabigatran (Pradaxa^®) took another hit last month when one of the proposed strategies for reversing its anticoagulant effects was shown to be ineffective in a small study of healthy volunteers.

Last year, dabigatran was shown to be more effective than warfarin in the prevention of stroke and systemic embolism in patients with AF, a result that came with comparable rates of overall bleeding and lower rates of intracranial bleeding. Improved efficacy in the absence of increased bleeding was certainly a welcomed change, but the question remained -- if you have one, how do you manage it?

A colleague and I worked with one of our hematologists to develop guidelines for the management of dabigatran at our institution and our proposed initial strategy for the management of severe to life-threatening bleeding events included the administration of prothrombin complex concentrate (PCC), a prohemostatic agent comprised of coagulation factors II, VII, IX, and X. This decision was based on several factors, including some evidence indicating efficacy in animal models, lower thrombogenic potential compared to other factor products, and truthfully, the absence of compelling data indicating that anything else would be more effective.

Well, it appears PCC is probably not the right answer either... at least not according to the study published in Circulation last month. Twelve healthy volunteers were randomized in a double-blind, placebo-controlled fashion to receive either rivaroxaban (Xarelto^®) 20 mg twice daily or dabigatran 150 mg twice daily for 2.5 days (i.e., enough time to allow each agent to achieve steady state concentrations) followed by 50 units/kg of PCC or placebo. After a washout period, patients crossed over and the process was repeated. Coagulation assays were performed at baseline, at steady state for each anticoagulant, and after administration of PCC. The anticoagulant effect of rivaroxaban was reversed following administration of PCC, whereas the effect of dabigatran remained unchanged.

While the study was small and conducted in a limited patient population (and uses parameters that have not yet been standardized for measuring the anticoagulant effects of new oral anticoagulants), it does provide some insightful human data where we once had none.

The question is... well, now what? For the time being, we are in the process of revising the dabigatran management guidelines at our institution to no longer recommend the routine use of PCC. We are considering recombinant factor VIIa (rFVIIa) as a potential strategy for the management of severe or life-threatening bleeding events, an agent that comes with some limited animal data but also an increased thrombotic risk compared to PCC. Lower doses of rFVIIa are becoming more commonplace in practice, so that may help swing the risk-benefit ratio in its favor.

While this was a small win for rivaroxaban, it may have inadvertently been a victory for apixiban (Eliquis^®) as well. With a similar molecular mechanism of action, one would expect PCC to have similar effects on reversing the anticoagulant effects of apixiban. Given that it was recently shown to be superior to warfarin in nearly every conceivable way, the results of this study only further add to the possible advantages of its use in clinical practice.