You are evaluating a 63-year-old man with a history of paroxysmal atrial fibrillation (AF) in the office. His medical history of notable for hypertension, for which he takes hydrochlorothiazide and lisinopril, and diabetes, for which he takes a metformin. He has no history of congestive heart failure, stroke or transient ischemic attack, kidney or liver disease, or symptomatic peripheral vascular disease.
On review, he has never been treated for atrial fibrillation. Examination reveals a well-appearing man. The cardiac examination reveals an irregularly irregular rhythm with normal rate and without murmurs, rubs, or gallops. No carotid or abdominal bruits are appreciated. Brisk, even distal pulses are noted in all extremities without brachioradial delay. You note no skin rashes or ecchymoses. Laboratory evaluation from a recent outpatient visit reveals normal serum creatinine, liver function tests, and complete blood count. A 12-lead EKG done in your clinic reveals AF with an average ventricular rate of 78 per minute.
Upon completion of your evaluation, he mentions that he is generally healthy and wants to avoid frequent blood draws and testing if possible. Because he is already taking other medications, he also wants to avoid medications with complicated and/or frequent dosing schedules.
Which of the following therapies is most appropriate for the patient’s atrial fibrillation?
Show Answer
The correct answer is: E. Novel factor specific anticoagulant
Based on current guidelines, the most appropriate therapy for this patient is treatment with an anticoagulant – either warfarin or a factor-specific oral anticoagulant.
Anticoagulation is important in paroxysmal AF because independent on duration or frequency of AF, there is data to suggest these patients are at similar risk for embolic events as those with persistent AF.1,2
Individual decisions to initiate anticoagulation therapy should be dictated by risk stratification using the validated CHADS2 score.3,4 Based on the latest guidelines from the American College of Chest Physicians (ACCP) and the European Society of Cardiology (ESC) guidelines1,5 anticoagulation is not indicated in patients with CHADS2 score of 0, but should be considered for patients with scores of 1 or higher without clear contraindications to therapy. This patient has the risk factors of hypertension and diabetes, resulting in a CHADS2 risk score of 2 and at least a 4% annual stroke risk. This clear indication for anticoagulation makes CHOICE A incorrect and the use of warfarin or a factor-specific oral anticoagulant recommended.6 There is evidence that in patients with atrial fibrillation and stroke risk factors, oral anticoagulation is more efficacious than single anti-platelet agents like aspirin monotherapy and superior to aspirin + clopidogrel combination therapy.7,8 Therefore CHOICE B and CHOICE C are also incorrect.
It is important to recognize that while straightforward, the CHADS2 score possesses several limitations. It does not include a number of common stroke risk factors, and there have been questions about both the patient populations and risk factor definitions from which it was derived.9,10 As a result, it may underestimate risk in certain populations, the ESC now recommends using the CHADS-VASc score – which also accounts for female gender, younger age (65-74 years old) and female gender –instead of the CHADS2 score for risk stratification. Our patient’s CHADS2-VASc is also 2, representing a strong indication for oral anticoagulation. Given his desire to avoid frequent blood draws and testing, a novel factor specific anticoagulant (CHOICE E) is more appropriate than warfarin (CHOICE D). Warfarin and other Vitamin K antagonists requiring frequent monitoring of the INR to ensure a therapeutic level of anticoagulation. However, since the factor specific anticoagulants have more predictable pharmacokinetic and pharmacodynamic responses, no routine monitoring of anticoagulation tests is required.
There are three currently available factor-specific anticoagulants that could be considered in this situation: dabigatran, rivaroxaban, and apixaban. Each has been shown via prospective studies in patients with non-valvular AF to be non-inferior and efficacious compared to warfarin.11-13 Beyond the strength of supporting evidence, several other factors should be considered when choosing between these novel agents.
First, clinicians must consider how mechanisms of clearance can drug levels and safety. Dabigatran is primarily excreted by the kidney, whereas the direct anti-Xa agents, rivaroxaban and apixaban, are excreted via the kidneys and the liver. Because the limitations in drug level monitoring and a lack of reversal agents, patients must be evaluated for pre-existing renal or hepatic disease to assess suitability for these medications. Based on currently available data,14-16 dabigatran and rivaroxaban are not recommended for patients with severe renal disease (CrCl <15 mL/min), while the anti-Xa anticoagulants are not recommended in patients with moderate to severe liver disease. The safety of apixaban was not evaluated for patients with CrCl <15 mL/min; hence apixaban should not be utilized in patients with severe renal insufficiency.
Second, adherence and desire/ability to adhere to medication schedules should also be considered. Dabigatran and apixaban are dosed twice daily, whereas rivaroxaban is dosed once daily and considered by some clinicians to be a good choice for patients who desire the most straightforward dosing regimens.
Lastly, health care providers should carefully review the concomittant therapies being administered to patients who are receiving an oral anticoagulant. While the factor specific oral anticoagulants have far fewer drug-drug interactions than warfarin, the recommendations regarding the use and dosing of these new agents in patients also taking drugs that inhibit or induce the P-glycoprotein transport and/or cytochrome P4503A4 isoenzyme system differ for the specific agents.14-16
These considerations are helpful in deciding the optimal treatment for our patient. He has normal renal and hepatic function, suggesting that any one of the three factor specific anticoagulants would be a good option.
References
You JJ, Singer DE, Howard PA, Lane DA, et al. 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):e531S-575S.
Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. J Am Coll Cardiol 2000; 35:183.
Gage BF, Waterman AD, Shannon W, et. al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864-70.
Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685.
Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation – developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33:2719-47.
Fuster V, Ryden LE, Cannom, DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2006; 48:854-906.
Connolly S, Pogue J, Hart R, et al. ACTIVE Writing Group of 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; 367:1903-12.
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation. Ann Intern Med 2007; 146(12):857-67.
Lip GY. Stroke in atrial fibrillation: epidemiology and thromboprophylaxis. J Thromb Haemost 2011; 9 (Suppl 1):344-51.
Keogh C, Wallace E, Dillon C, Dimitrov BD, Fahey T. Validation of the CHADS2 clinical prediction rule to predict ischaemic stroke. A systematic review and meta-analysis. Thromb Haemost 2011; 106:528-38.
Connolly SJ, Ezekowitz MD, Salim Y, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139-1151.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011; 365:883-891.
Agnelli G, Buller HR, Cohen A, et al. Apixaban for Extended Treatment of Venous Thromboembolism. N Engl J Med 2013; 368:699-708.