Zhenguo Liu, MD, PhD
A 67-year-old woman with medical history of hypertension and type 2 diabetes was evaluated at the emergency department for sudden onset of right facial dropping and slurred speech. No other complaints. Her blood pressure was 146/82 mm Hg with heat rate 78 bpm and irregular. Her 12-lead ECG upon arrival in the emergency room showed atrial fibrillation with ventricular rate of 74. A head CT scan and carotid ultrasound examination were unremarkable. Her symptoms were resolved 12 hours later. A transesophageal echocardiogram revealed a dilated left atrium, moderate mitral regurgitation, and mild global left ventricular hypokinesis with an estimated ejection fraction of 45%. No apparent thrombus was identified in her left atrial appendage. No right to left shunt was present. A subsequent coronary angiogram demonstrated non–flow-limiting lesions. Attempts were made to convert her to normal sinus rhythm without success. She was sent home with a β-blocker, ACE inhibitor, baby ASA, and Coumadin (warfarin). The patient has been doing well since then.
COMMENTS AND DISCUSSION
Atrial fibrillation (AF) is the most common cardiac arrhythmia with a growing prevalence due to an aging population. One of the major issues for AF is stroke and systemic embolism in patients at high risk that are associated with significant morbidity and mortality as well as medical cost. Existing data demonstrate that oral anticoagulation is highly cost-effective for the prevention of stroke and systemic embolism in high-risk patients, but not for those with a low risk of stroke. Coumadin or warfarin is one of the commonly used oral anticoagulation agents for the prevention and treatment of thromboembolism in patients with AF or atrial flutter.1,2
MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS FOR COUMADIN
• Coumadin or warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, including factors II, VII, IX, and X, and the anticoagulant proteins C and S.
• Anticoagulation effect generally occurs within 24 hours after oral administration. Its peak anticoagulant effect may be delayed for 72 to 96 hours. The duration of action of a single dosing is 2 to 5 days. The effective half-life ranges from 20 to 60 hours with a mean of about 40 hours.
• Coumadin is essentially absorbed completely after oral administration, with its peak concentration usually within 4 hours of administration. Approximately 99% of the drug is bound to plasma proteins with a small distribution volume.
• The elimination of coumadin is almost entirely by hepatic cytochrome P-450 enzymes that may vary based on patient’s age and ethnic background. Asian patients may require lower initiation and maintenance doses.
INDICATIONS FOR COUMADIN THERAPY IN AF PATIENTS
• Due to significant risk for stroke and systemic embolism, anticoagulation therapy is recommended for high-risk AF patients. Patient characteristics and risk factors have been used for stroke risk stratification, known as CHADS2 (1 point for each of the following: Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, and 2 points for previous Stroke or transient ischemic attack) and recently CHA2DS2-VASc (1 point for Congestive heart failure, Hypertension, 2 points for Age ≥75 years, 1 point for Diabetes, 2 points for previous Stroke, transient ischemic attack, or thromboembolism, 1 point for Vascular disease, Age 65 to 75 years, and female Sex category) as shown in Table 27-1. The ACC/AHA/HRS/ESC recommends that AF patients with a CHADS2 score of ≥1 should be treated with oral anticoagulation (such as Coumadin with international normalized ratio [INR] 2-3) if no contraindications exist.1-5
TABLE 27-1 Factors for Establishing the Risk of Stroke in AF Patients
• Oral anticoagulation therapy (such as Coumadin with INR 2-3) is recommended for AF patients before and after cardioversion for at least 4 weeks regardless of their CHADS2 score.
• Systemic anticoagulation such as Coumadin with INR 2-3 is recommended for all patients for at least 2 months following an AF ablation procedure. Continuation of systemic anticoagulation more than 2 months following ablation should be based on the patient’s risk factors, including assessment with CHADS2 or CHA2DS2VASc score, and other risk factors for stroke and not on the amount of AF or type (paroxysmal, persistent or long-standing persistent AF) of AF.
MANAGEMENT OF PATIENTS WITH HIGH INR
If a patient’s INR is high (≥4.0) or Coumadin therapy needs to be reversed clinically, an algorithm could be followed as suggested by Garcia and Crowther6 and as shown in Figure 27-1.
FIGURE 27-1 Suggested algorithm for the management of patients with international normalized ratio (INR) over 4. Abbreviation: IV, intravenously. (Modified with permission from Garcia DA, Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation. 2012;Jun 12;125(23):2944-2947).
ALTERNATIVES TO ANTICOAGULATION WITH COUMADIN
• Dabigatran (Pradaxa) and rivaroxaban (Xarelto) are new anticoagulants approved for the prevention of thromboembolic events in AF patients. There is no need for laboratory monitoring for INR or dietary restrictions. However, these agents carry the bleeding risks similar to that of Coumadin and are without a reliable reversal agent.7
• Combined therapy with clopidogrel (Plavix) and aspirin may occasionally be considered if the patient is not a suitable candidate for Coumadin or dabigatran or rivaroxaban. But this dual antiplatelet therapy is less effective for the prevention of thromboembolic events.
CONCOMITANT TREATMENT WITH COUMADIN AND ANTIPLATELET AGENTS
• Triple therapy with Coumadin and aspirin plus clopidogrel has increased risk for bleeding with no significant benefit on reducing thromboembolic risk in AF patients.8,9
• Double therapy with Coumadin and one antiplatelet agent (aspirin or clopidogrel) increases the risk for early bleeding (within 90 days after initiation).
1. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm. 2012;9(4):632-696.e21.
2. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-198.
3. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-272.
4. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost. 2012;107(6):1172-1179.
5. Taillandier S, Olesen JB, Clémenty N, et al. Prognosis in patients with atrial fibrillation and CHA2DS2-VASc Score = 0 in a community-based cohort study. J Cardiovasc Electrophysiol. 2012;23(7):708-713.
6. Garcia DA, Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation. 2012;125(23):2944-2947.
7. Brem E, Koyfman A, Foran M. Review of recently approved alternatives to anticoagulation with warfarin for emergency clinicians. J Emerg Med. 2013;45(1):143-149.
8. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation. 2013;127(5):634-640.
9. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation. 2012;126(10):1185-1193.