Appropriate Use of Dabigatran in Geriatric Patients: An Interview With Eugene Yang, MD

On October 19, 2010, the US Food and Drug Administration (FDA) approved dabigatran (Pradaxa) to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, making it the first new oral anticoagulant to reach the US market in more than 50 years. The FDA approved dabigatran for this indication based on the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which randomly assigned 18,113 patients to receive dabigatran 150 mg twice daily (n=6076), dabigatran 110 mg twice daily (n=6015), or warfarin (n=6022) titrated to achieve an international normalized ratio of 2.0 to 3.0.¹ Although both dabigatran dosages were found to be noninferior to warfarin, the superiority of the dabigatran 150-mg regimen over both the warfarin and dabigatran 110-mg regimens led the FDA to approve the 150-mg dose of dabigatran. In addition, the FDA approved a 75-mg twice-daily dose for patients with severe renal impairment (creatinine clearance, 15-30 mL/min/1.73 m²), despite an absence of clinical trial efficacy and safety data.

Serious side effects have been associated with dabigatran use, in particular, bleeding complications. To reduce the risk of stroke while minimizing adverse events associated with dabigatran use, physicians must carefully decide for whom it is an appropriate treatment, said Eugene Yang, MD, clinical associate professor of medicine, University of Washington Medical Center, Seattle, in a product theater presented at the 2012 American Geriatrics Society annual meeting. Clinical Geriatrics^® (CG) had the opportunity to discuss the use of dabigatran in greater detail with Dr. Yang. 

CG: In February 2012, the American College of Chest Physicians (ACCP) published its new guidelines on antithrombotic therapy and prevention of thrombosis. What stance do these guidelines take with regard to the use of dabigatran?

Dr. Yang: The new ACCP guidelines recommend using dabigatran as the first-line oral anticoagulant for patients who are at high risk of stroke (eg, CHADS₂ score, ≥2) over the use of adjusted-dose vitamin K antagonists, such as warfarin.² This decision was based solely on the results of the RE-LY trial.¹ For intermediate-risk patients (eg, CHADS₂ score, 1), oral anticoagulants are recommended over antithrombotic therapies (eg, aspirin or clopidogrel); however, no specific guidance on which oral anticoagulant to use first is offered. One important remark from the guidelines that warrants clarification is that dabigatran is not contraindicated for patients who have severe renal impairment (creatinine clearance, <30 mL/min/1.73 m²). The FDA approved a 75-mg twice-daily dose for patients with creatinine clearances between 15 mL/min/1.73 m² and 30 mL/min/1.73 m². This dosage was approved based on pharmacokinetic modeling, not on clinical safety or outcome data.

How does the ACCP’s stance compare with that of other organizations, such as the American College of Cardiology (ACC) and the American Heart Association (AHA)?

Last year, the ACC, AHA, and Heart Rhythm Society (HRS) released a focused update on dabigatran for managing atrial fibrillation.³ The ACCP statement was stronger by positioning dabigatran as a first-line treatment for high-risk patients with nonvalvular atrial fibrillation. The guidelines by the cardiology societies are more tempered and give dabigatran a Class I indication as an alternative to vitamin K antagonists for patients with risk factors for stroke. They also specify that dabigatran use should be limited to patients who do not have a prosthetic heart valve, hemodynamically significant valvular heart disease, severe renal failure (creatinine clearance, <15 mL/min/1.73 m²), liver disease, or bleeding disorders. Most of these contraindications are based on the exclusion criteria from the original RE-LY trial.¹

It has been established that elders, particularly those 75 years and older, have an increased risk of adverse effects following use of dabigatran. What measures should clinicians take to ensure the safety of these patients?

Older patients are at higher risk for major bleeding when taking dabigatran versus warfarin based on a subanalysis of the RE-LY trial.⁴ Major bleeding was increased by about 20% for patients aged 75 years and older who were taking dabigatran versus warfarin. A majority of the bleeding was gastrointestinal. Patients older than 75 years who were on dabigatran had 80% more bleeding from this source, compared with their age-matched counterparts who were on warfarin. In addition, renal impairment, which progresses with age, is also a risk factor for adverse events, including bleeding. The severity of renal impairment in older patients is often underestimated; some patients may be exposed to higher concentrations of dabigatran, especially as their creatinine clearances approach 30 mL/min/1.73 m².

To minimize adverse events and identify appropriate candidates for dabigatran, it is imperative to take a thorough medical history that focuses on bleeding disorders. In particular, lower gastrointestinal bleeding problems should be identified, such as rectal bleeding from hemorrhoids, radiation proctitis from prostate cancer treatment, or diverticular disease. Among the small number of patients in the RE-LY trial who underwent endoscopy for gastrointestinal bleeding events, a higher proportion of patients on dabigatran than on warfarin had lower gastrointestinal bleeding,  at 47% versus 25%, respectively.¹ Therefore, patients who disclose a history of gastrointestinal bleeding are probably not ideal candidates for dabigatran. Bleeding risk can be estimated using scoring systems such as HAS-BLED,⁵ which can provide guidance when deciding whether patients are good candidates for therapy with any oral anticoagulant.

Frequent monitoring of kidney function is critical and should be performed when clinically indicated in all patients. Because 80% of dabigatran is renally excreted, kidney function will significantly impact the peak and trough levels of the drug.¹ In addition, because routine monitoring of the anticoagulant effect of dabigatran is not performed, heightened sensitivity to kidney function assessment is even more vital. Patients who have unstable kidney function or severe kidney disease, with creatinine clearance approaching 30 mL/min/1.73 m², may not be suitable candidates for dabigatran. Of note, the Cockroft-Gault formula was used to estimate the creatinine clearance of patients in the RE-LY trial and should be used for all patients to assess and monitor renal function.¹ A recent registry from New Zealand published a letter in the New England Journal of Medicine outlining bleeding events that it identified during the first 2 months of dabigatran use.⁶ The registry included approximately 7000 patients and reported a total of 78 bleeding events. Of these cases, 44 were analyzed and 32 patients were found to have at least mild renal impairment. Prescriber error was presumed to be the cause of 25% of these bleeding events, with six patients inappropriately receiving dabigatran despite having severe renal impairment.

Certain drugs, most notably aspirin and clopidogrel, have been shown to increase the risk of bleeding when used concomitantly with dabigatran. Should these agents be discontinued or their dosages lowered before dabigatran therapy is initiated? Do any agents contraindicate the use of dabigatran?

The bleeding subanalysis of the RE-LY trial found that patients on dual antiplatelet therapy (DAPT) with the dabigatran 150-mg twice-daily dose had a 40% higher risk of major bleeding versus patients on dabigatran alone.⁶ It should be noted that patients on DAPT and warfarin had a 50% higher risk of major bleeding versus patients on warfarin alone. Careful consideration is paramount when using these agents in any combination. For example, patients undergoing elective percutaneous coronary intervention for coronary artery disease should preferentially receive a bare metal stent if it is appropriate, as this option minimizes the exposure to DAPT with an oral anticoagulant, reducing the risk of major bleeding. In all cases, the lowest dose of aspirin should be used, as clinically indicated (eg, 3-6 months after drug-eluting stent implantation). Many decisions are individualized to each patient based on the potential benefit of antiplatelet therapies to reduce cardiovascular events while minimizing the risk of adverse events. Unfortunately, we don’t have clinical studies to determine when single or dual antiplatelet therapy is appropriate in combination with dabigatran for patients with stable coronary artery disease or peripheral vascular disease. These agents do not preclude the use of dabigatran, but should be used with caution, similar to how patients are assessed who require warfarin or another vitamin K antagonist.

Is warfarin a better choice than dabigatran for some patients? If so, in whom?

As noted previously, patients with a history of gastrointestinal bleeding or severe renal impairment (creatinine clearance, <30 mL/min/1.73 m²) are likely better candidates for warfarin than dabigatran. In addition, patients who have unstable renal function or whose kidney function is deteriorating rapidly may also be better served by warfarin since the anticoagulant effect can be closely and accurately monitored.

Would you care to share any thoughts on some of the newer anticoagulants on the horizon?

As you know, there are several new oral anticoagulants in various stages of development and FDA approval status. The FDA approved rivaroxaban (Xarelto), a factor Xa inhibitor, at the end of last year. This agent has the benefit of once-daily administration, which may improve compliance. It also does not carry a higher risk of gastrointestinal side effects, such as dyspepsia, which have been reported with dabigatran use. However, in terms of the primary outcome of its main trial, 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), it was found to be noninferior to warfarin for stroke prevention, but did not demonstrate statistical superiority in the intention-to-treat analysis, despite being used in a very high-risk patient population with a relatively low percentage of warfarin patients consistently in the therapeutic range.⁷ Bleeding rates were similar to warfarin, but gastrointestinal bleeding events were substantially higher in the rivaroxaban arm. Nevertheless, it is an excellent alternative to warfarin for some patients.

The next closest agent to achieving approval is apixaban (Eliquis), although the FDA just announced a delay by requesting additional information on data management and verification from the pivotal ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial.⁸ Like rivaroxaban, apixaban is a factor Xa inhibitor, but requires twice-daily dosing. On the surface, it appears to have the most favorable efficacy and safety profile. In the ARISTOTLE trial, stroke risk was reduced by 21% over warfarin in an intention-to-treat analysis, a finding that reached statistical significance. More importantly, major bleeding rates were 31% lower in the apixaban arm versus the warfarin arm, and gastrointestinal bleeding events were also slightly lower in the apixaban arm. Patients older than 75 years had substantially lower rates of major bleeding on apixaban than on warfarin, yet they maintained a lower stroke risk. In addition, patients with moderate to severe renal impairment also had much lower rates of major bleeding on apixaban.⁸ While this therapy is very promising, especially for geriatric patients, the FDA delay certainly raises some concerns about the published data.

Edoxaban (Lixiana) is the third factor Xa inhibitor in clinical development. The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48) trial⁹ is the pivotal clinical trial comparing two once-daily doses of edoxaban versus warfarin in patients with nonvalvular atrial fibrillation. The study is ongoing, with completion of enrollment expected at the end of this year.  

Do you have any take-home messages for clinicians with regard to using dabigatran in elderly persons?

The key take-home message is appropriate patient selection. The more predictable pharmacokinetics of dabigatran obviates the need for routine monitoring of its anticoagulant effect. However, this benefit for our patients has led to more complacency and a false sense of security about its safety among providers who prescribe this medication. In fact, I believe more vigilance is required for patients on dabigatran to ensure that their renal function is stable and that they are not at high risk for adverse events, in particular, gastrointestinal bleeding. The geriatric patient is more likely to have chronic kidney disease and low body weight, both of which are potential risk factors for major bleeding. A comprehensive assessment of each patient is essential for determining if he or she is a suitable candidate for dabigatran therapy.

Disclosures:

Dr. Yang has received speaker honoraria from Boehringer Ingelheim, Janssen Pharmaceuticals, and Novartis. He has also served as a consultant or advisory board member to Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis.

References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med. 2010;363(19):1877]. N Engl J Med. 2009;361(12):1139-1151.

2. You JJ, Singer DE, Howard PA, et al; American College of Chest Physicians. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e531S-e575S.

3. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57(11):1330-1337.

4. Eikelboom JW, Wallentin L, Connolly SJ, 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;123(21):2363-2372.

5. QxMD. HAS-BLED score calculator. www.qxmd.com/calculate-online/cardiology/has-bled-score-bleeding-in-atrial-fibrillation. Accessed July 3, 2012.

6. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly [letter]. N Engl J Med. 2012;366(9):864-866.

7. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365(10):883-891.

8. Granger CB, Alexander JH, McMurray JJV, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.

9. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010;160(4):635-641.