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n o t e

Pharmacodynamic response to warfarin after conversion of atrial fibrillation or flutter

to sinus rhythmMelissa C. staats and MiChael e. ernst

Melissa C. Staats is Pharm.D. candidate, College of Pharmacy, Uni-versity of Iowa, Iowa City. Michael E. Ernst, Pharm.D., is Professor (Clinical), Department of Pharmacy Practice and Science, College of Pharmacy, and Department of Family Medicine, Carver College of Medicine, University of Iowa.

Address correspondence to Dr. Ernst at the Department of Family Medicine, 01291-A PFP, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242 (michael-ernst@uiowa.edu).

Purpose. The results of an evaluation of the impact of restoring sinus rhythm on warfarin sensitivity are reported.Methods. A retrospective review of the records of all patients (n = 46) with atrial fibrillation or flutter who underwent car-dioversion or ablation procedures to restore sinus rhythm at a large medical center during a 27-month period was con-ducted. Patient data covering the 3-month periods before and after the procedures were reviewed to identify the warfarin doses required to maintain International Normalized Ratio (INR) values in the recom-mended range of 2.03.0. Within-individual preprocedure and postprocedure mean weekly warfarin doses for two periods (zero to four weeks and an expanded period of four weeks3 months) were compared us-ing paired t tests.Results. The average weekly warfarin

Presented as a student poster at the ASHP Midyear Clinical Meet-ing, New Orleans, LA, December 6, 2011.

The authors have declared no potential conflicts of interest.

Copyright 2012, American Society of Health-System Pharma-cists, Inc. All rights reserved. 1079-2082/12/0701-1158$06.00.

DOI 10.2146/ajhp110609

dose during the four-week preprocedure period was not significantly different from the doses during the four-week and expanded postprocedure periods. The av-erage weekly doses during the four-week and expanded postprocedure periods were significantly less than those used in the expanded preprocedure period (p = 0.004 and p = 0.046, respectively).Conclusion. Warfarin dosages required to maintain a goal INR of 2.03.0 were relative-ly stable in the four weeks before and after procedures to convert atrial fibrillation or flutter to sinus rhythm. Changes in the weekly warfarin dose requirement of 10% after the procedures were implemented in a small proportion of patients. The mean weekly warfarin dose was significantly lower in the three months after than in the three months before the procedure.Am J Health-Syst Pharm. 2012; 69:1158-61

Atrial fibrillation and atrial flutter are commonly occurring car-diac arrhythmias.1,2 As they have the potential to cause hemodynamic instability and thromboembolic events, these arrhythmias are associ-ated with significant morbidity, mor-tality, and health care costs. Practice guidelines currently recommend anticoagulation with warfarin, with a goal International Normalized Ratio (INR) of 2.03.0, for three to four weeks before and after conversion to sinus rhythm in patients experienc-ing atrial fibrillation for periods of >48 hours or of an unknown dura-tion.3 Patients preparing to undergo elective cardioversion are thus in-tensively and regularly monitored to ensure that INR values remain within the goal range. The extent to which the restoration of sinus rhythm af-fects warfarin sensitivity is unknown. Since cardiac output is reduced in atrial fibrillation, it is possible there is a downstream effect on hepatic perfusion that may subsequently influence the pharmacodynamic response to hepatically metabolized drugs such as warfarin.

Clinical pharmacists are frequent-ly responsible for managing warfarin therapy in patients with atrial fibril-lation or flutter pending procedures to restore sinus rhythm. The purpose of the study described here was to evaluate the impact of restoring sinus rhythm on warfarin mainte-

nance requirements. Specifically, we sought to determine (1) whether the within-patient mean warfarin dos-age required to maintain INR values within the goal range of 2.03.0 was significantly different before and after the restoration of sinus rhythm and (2) if a significant difference was

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noted, the magnitude and direction of the dosage change. Such informa-tion could help improve the safety of warfarin management in patients with atrial fibrillation or flutter.

MethodsA waiver of consent was obtained

from the institutional review board at our facility to perform this retro-spective chart review. A computer-ized search of the electronic medical record (EMR) system was performed to identify individuals with atrial fib-rillation or flutter who were followed by the anticoagulation management service (ACMS) and whose records indicated a Current Procedural Ter-minology code for elective cardio-version or ablation between May 1, 2009 (the go-live date for the EMR system), and August 1, 2011. Among the 85 such cases identified, 16 were excluded from the study because the atrial fibrillation or flutter sponta-neously converted to sinus rhythm, warfarin therapy was not admin-istered before a conversion proce-dure, or pacemaker placement was performed. Of the remaining 69 pa-tients, 48 had undergone cardiover-sion and 14 had undergone ablation procedures; of those patients, 16 were excluded because their cardioversion or ablation procedure was unsuc-cessful. A procedure was considered unsuccessful if conversion to sinus rhythm did not occur during the procedure or if the rhythm reverted to atrial fibrillation or flutter before a postprocedure INR determination. After those exclusions, the evaluable study population consisted of 46 patients.

Patient charts were abstracted for demographic data pertaining to sex, age, diagnosis, and type of procedure. Antiarrhythmic and rate control medications, blood pressure, and heart rate were also obtained for four-week periods before and after the procedure. Each INR measured in the three months leading up to and after the procedure was recorded

and matched to a corresponding weekly warfarin dose, as recorded in ACMS notes. From this information, average preprocedure and postproce-dure weekly doses for periods of up to four weeks and for an expanded time period (more than four weeks to three months) were calculated.

Paired t tests were performed using SPSS, version 19.0 (IBM Cor-poration, Armonk, NY), to compare within-individual continuous data such as the calculated mean weekly warfarin dose before and after car-dioversion procedures, blood pres-sure, and heart rate. Additionally, the percentage of patients who had a warfarin dosage change of 10% (in either direction) between the prepro-cedure and postprocedure periods was determined.

ResultsA total of 46 patients (mean age,

64.5 years) had at least one evaluable set of INR values for pairwise com-parison. Thirty-eight patients (83%) were men, and 31 (67%) underwent cardioversion as opposed to ablation. Their mean INR values in the four weeks before and four weeks after the restoration of normal sinus rhythm were 2.74 and 2.47, respectively (p = 0.039); the mean INR values in the

expanded data collection periods (more than four weeks and up to three months) before and after the procedure were 2.63 and 2.48, re-spectively (p = 0.185).

As shown in Table 1, no significant difference was found in the mean weekly warfarin dose between the four-week periods before and after ablation or cardioversion. Likewise, no significant difference was found in the mean weekly dose between the four-week period before either procedure and the expanded period (more than four weeks, up to three months) after the procedure. How-ever, a significant difference was found in the mean weekly warfarin dose between the expanded period before the procedures and the four-week period after the procedures and between the expanded periods before and after the procedures. Ten of 46 patients (22%) had a change in their mean weekly warfarin dose of 10% from the four-week period before the procedure to the end of the four-week postprocedure period. For the expanded periods, 5 of 27 patients (19%) had a change of the same magnitude in weekly warfarin dose.

No significant difference in mean systolic blood pressure was observed between the preprocedure and post-

Pair 1 27 0.02612.7258 0.046 4 wk3 mo before 39.8 16.2 4 wk3 mo after 38.4 17.4 Pair 2 46 0.94271.1540 0.840 4 wk before 33.3 16.2 4 wk after 33.2 16.2 Pair 3 34 0.50472.4059 0.004 4 wk3 mo before 37.3 16.2 4 wk after 35.8 16.2 Pair 4 37 2.28740.9290 0.397 4 wk before 34.4 16.7 4 wk3 mo after 35.0 16.9

Table 1.Pairwise Comparisons of Mean Weekly Doses of Warfarin Sodium Before and After Cardioversion or Ablation

Data Collection Period n

Mean S.D. Weekly Dose (mg)

95% Confidence Interval for Difference p

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procedure periods (118.6 and 114.8 mm Hg, respectively; p = 0.081). However, mean diastolic blood pres-sure and heart rate in the postproce-dure period (68.0 mm Hg and 67.4 beats/min) were significantly lower than in the preprocedure period (74.0 mm Hg and 88.3 beats/min; p < 0.001 for comparisons of both variables). Twelve patients (26%) had a medication change after an ablation or cardioversion procedure; the most common changes were dosage altera-tions for an agent intended to control the heart rate and the discontinu-ation of one medication. No clear association was observed between medication changes and warfarin dosage requirements.

DiscussionThere has been extensive research

on the numerous food and drug interactions that can affect war-farin pharmacodynamics, but to our knowledge, ours was the first study to address the effect of restoring sinus rhythm on warfarin require-ments. We found that although the mean weekly warfarin dose required to maintain an INR of 2.03.0 re-mained stable during the four-week periods before and after ablation or cardioversion, the mean weekly dose during the expanded preprocedure period differed significantly from that observed during both the four-week and expanded postprocedure periods. Further, a change of 10% in the weekly warfarin dose occurred in roughly one fifth of cases whether the comparison was between the four-week or the expanded preprocedure and postprocedure periods.

The rationale for our study was that warfarin dose requirements might change as a result of physi-ological alterations in hepatic blood flow and drug metabolism occurring when the cardiac rhythm is normal-ized and cardiac output is stabilized. The expected improvement in hemo-dynamic variables after the restora-tion of sinus rhythm should theoreti-

cally improve hepatic blood flow and possibly lead to increased warfarin dosage requirements. However, we found that warfarin sensitivity actu-ally increased and that the warfarin dosage requirement was lower in the postprocedure period. The biologi-cal explanation for these findings is unclear, but our observation of an association between hemodynamic improvement and increased warfar-in sensitivity is not the first.4,5 One simple potential explanation is that an improvement in hepatic blood flow after ablation or cardioversion has transient effects on soluble clot-ting factors, perhaps causing them to be cleared more quickly.

Our unexpected results prompted us to speculate on additional pos-sible mechanisms. First, the effects of increased cardiac output on hepatic blood flow are not definitively estab-lished; some researchers have sug-gested that increased cardiac output may actually reduce hepatic blood flow because of the fractional redis-tribution of blood flow.6,7 Such a re-duction in hepatic blood flow could lead to increased warfarin sensitivity.

Second, not all patients experience an improvement in cardiac output after cardioversion to restore sinus rhythm; in fact, in more than one third of patients, there is a temporary decrease.8 This phenomenon may relate to transient atrial mechanical dysfunction (i.e., myocardial stun-ning) after cardioversion, which is thought to explain the observed delay in the improvement of ejec-tion fraction and exercise capacity.9-11 Although the effects of this phenom-enon on hepatic blood flow have not been directly examined, it may be that a temporary reduction in cardiac output reduces hepatic blood flow and leads to increased warfarin sen-sitivity during this transient period.

A possible nonphysiological ex-planation for our findings may lie in the periprocedural management protocol at our institution, which re-quires that patients have a minimum

of four weeks of consecutive INR values of 2.03.0 before undergoing cardioversion or ablation; if even one INR value is below the target range, the four-week monitoring period re-starts. Thus, clinicians may have been reluctant to adjust a warfarin dos-age downward before a procedure, since dosages producing INR values slightly above the target range would be unlikely to produce a subsequent INR below the target range and force a new four-week monitoring period. Evidence to support this hypothesis was provided by the slightly higher mean INR in the four weeks before the procedure compared with the four weeks after the procedure.

An important limitation of this study was the difficulty in isolating potential confounding factors, such as changes in vitamin K intake and adherence, that might have influ-enced warfarin requirements in the study cohort. However, given that all patients included in the analysis had four consecutive weekly INR values of 2.0 before cardioversion or ablation, their INR status could be considered more stable than is typical in the general population of patients receiving warfarin; thus, the likelihood of a significant influence by these confounders is as small as it can be in an uncontrolled study.

Another limitation of the study was that additional hemodynamic data (e.g., cardiac output, hepatic blood flow) were not available to help explain our findings about war-farin requirements. To our knowl-edge, no hemodynamic studies have examined the effects of arrhythmia and conversion to sinus rhythm on hepatic perfusion and drug metabo-lism. Given the small sample size, our findings should be considered hypothesis-generating results that did not prove a specific cause-and-effect relationship but rather showed an association; thus, further basic physiological research should be performed, and confirmation of our findings should be sought within a

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much larger sample. This will also enable better evalu-ation of factors associated with the likelihood that sig-nificant dosage changes will be required in the peripro-cedure period.

ConclusionWarfarin dosages required to maintain a goal INR of

2.03.0 were relatively stable in the four weeks before and after procedures to convert atrial fibrillation or flutter to sinus rhythm. Changes in the weekly warfarin dose requirement of 10% after the procedures were implemented in a small proportion of patients. The mean weekly warfarin dose was significantly lower in the three months after than in the three months before the procedure.

References1. Wyndham C. Atrial fibrillation: the most common arrhythmia.

Tex Heart Inst J. 2000; 27:257-67.2. Boyer M, Koplan BA. Atrial flutter. Circulation. 2005; 112:e334-6.3. Fuster V, Rydn LE, Asinger RW et al. ACC/AHA/ESC guidelines

for the management of patients with atrial fibrillation: execu-tive summary 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 and policy conferences (committee to develop guide-lines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Circulation. 2001; 104:2118-50.

4. Ageno W, Turpie AG. Exaggerated initial response to warfarin following heart valve replacement. Am J Cardiol. 1999; 84:905-8.

5. Rose JP, Rihn TL, Long SF. Warfarin sensitivity after mechanical heart valve replacement. Pharmacotherapy. 1998; 18:856-9.

6. Wilkinson GR. Pharmacokinetics of drug disposition: hemody-namic considerations. Annu Rev Pharmacol. 1975; 15:11-27.

7. Pang KS, Rowland M. Hepatic clearance of drugs. I. Theoretical considerations of a well-stirred model and a parallel tube model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J Pharmacokinet Biopharm. 1977; 5:625-53.

8. Upshaw CB. Hemodynamic changes after cardioversion of chronic atrial fibrillation. Arch Intern Med. 1997; 157:1070-6.

9. Khan IA. Transient atrial mechanical dysfunction (stunning) after cardioversion of atrial fibrillation and flutter. Am Heart J. 2002; 144:11-22.

10. Lipkin DP, Frenneaux M, Stewart R et al. Delayed improvement in exercise capacity after cardioversion of atrial fibrillation to sinus rhythm. Br Heart J. 1988; 59:572-7.

11. Van Gelder IC, Crijns HJ, Blanksma PK et al. Time course of hemodynamic changes and improvement of exercise tolerance after cardioversion of chronic atrial fibrillation unassociated with cardiac valve disease. Am J Cardiol. 1993; 72:560-6.

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