note Warfarin

note

Pharmacodynamic response to warfarin

after conversion of atrial fibrillation or flutter
to sinus rhythm
Melissa C. Staats and Michael E. Ernst

trial fibrillation and atrial flutter

are commonly occurring cardiac arrhythmias.1,2 As they have
the potential to cause hemodynamic
instability and thromboembolic
events, these arrhythmias are associated with significant morbidity, mortality, 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 experiencing atrial fibrillation for periods of
>48 hours or of an unknown duration.3 Patients preparing to undergo
elective cardioversion are thus intensively and regularly monitored to
ensure that INR values remain within
the goal range. The extent to which
the restoration of sinus rhythm affects 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.

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 cardioversion or ablation procedures to
restore sinus rhythm at a large medical
center during a 27-month period was conducted. 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 recommended 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 using paired t tests.
Results. The average weekly warfarin

Clinical pharmacists are frequently responsible for managing warfarin

therapy in patients with atrial fibrillation 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-

Melissa C. Staats is Pharm.D. candidate, College of Pharmacy, University 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).

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Am J Health-Syst PharmVol 69 Jul 1, 2012

dose during the four-week preprocedure

period was not significantly different
from the doses during the four-week and
expanded postprocedure periods. The average 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 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.
Am J Health-Syst Pharm. 2012; 69:1158-61

nance requirements. Specifically, we

sought to determine (1) whether the
within-patient mean warfarin dosage 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

Presented as a student poster at the ASHP Midyear Clinical Meeting, New Orleans, LA, December 6, 2011.
The authors have declared no potential conflicts of interest.
Copyright 2012, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/12/0701-1158$06.00.
DOI 10.2146/ajhp110609

note Warfarin

noted, the magnitude and direction

of the dosage change. Such information could help improve the safety
of warfarin management in patients
with atrial fibrillation or flutter.
Methods
A waiver of consent was obtained
from the institutional review board
at our facility to perform this retrospective chart review. A computerized search of the electronic medical
record (EMR) system was performed
to identify individuals with atrial fibrillation or flutter who were followed
by the anticoagulation management
service (ACMS) and whose records
indicated a Current Procedural Terminology code for elective cardioversion 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 spontaneously converted to sinus rhythm,
warfarin therapy was not administered before a conversion procedure, or pacemaker placement was
performed. Of the remaining 69 patients, 48 had undergone cardioversion and 14 had undergone ablation
procedures; of those patients, 16 were
excluded because their cardioversion
or ablation procedure was unsuccessful. 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 postprocedure 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 Corporation, Armonk, NY), to compare
within-individual continuous data
such as the calculated mean weekly
warfarin dose before and after cardioversion procedures, blood pressure, and heart rate. Additionally,
the percentage of patients who had a
warfarin dosage change of 10% (in
either direction) between the preprocedure and postprocedure periods
was determined.
Results
A total of 46 patients (mean age,
64.5 years) had at least one evaluable
set of INR values for pairwise comparison. 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, respectively (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. However, a significant difference was
found in the mean weekly warfarin
dose between the expanded period
before the procedures and the fourweek 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 fourweek 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-

Table 1.

Pairwise Comparisons of Mean Weekly Doses of Warfarin Sodium

Before and After Cardioversion or Ablation
Data Collection
Period

Mean S.D.
Weekly Dose (mg)

95% Confidence
Interval for
Difference

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

Am J Health-Syst PharmVol 69 Jul 1, 2012

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note Warfarin

procedure periods (118.6 and 114.8

mm Hg, respectively; p = 0.081).
However, mean diastolic blood pressure and heart rate in the postprocedure 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 alterations for an agent intended to control
the heart rate and the discontinuation of one medication. No clear
association was observed between
medication changes and warfarin
dosage requirements.
Discussion
There 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 requirements. We found that although the
mean weekly warfarin dose required
to maintain an INR of 2.03.0 remained 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 fourweek 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 fourweek or the expanded preprocedure
and postprocedure periods.
The rationale for our study was
that warfarin dose requirements
might change as a result of physiological alterations in hepatic blood
flow and drug metabolism occurring
when the cardiac rhythm is normalized and cardiac output is stabilized.
The expected improvement in hemodynamic variables after the restoration of sinus rhythm should theoreti1160

cally improve hepatic blood flow and

possibly lead to increased warfarin
dosage requirements. However, we
found that warfarin sensitivity actually increased and that the warfarin
dosage requirement was lower in the
postprocedure period. The biological 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 clotting factors, perhaps causing them to
be cleared more quickly.
Our unexpected results prompted
us to speculate on additional possible mechanisms. First, the effects of
increased cardiac output on hepatic
blood flow are not definitively established; some researchers have suggested that increased cardiac output
may actually reduce hepatic blood
flow because of the fractional redistribution of blood flow.6,7 Such a reduction 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 stunning) after cardioversion, which
is thought to explain the observed
delay in the improvement of ejection fraction and exercise capacity.9-11
Although the effects of this phenomenon 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 sensitivity during this transient period.
A possible nonphysiological explanation for our findings may lie
in the periprocedural management
protocol at our institution, which requires that patients have a minimum

Am J Health-Syst PharmVol 69 Jul 1, 2012

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 restarts. Thus, clinicians may have been
reluctant to adjust a warfarin dosage 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 influenced 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 warfarin requirements. To our knowledge, no hemodynamic studies have
examined the effects of arrhythmia
and conversion to sinus rhythm on
hepatic perfusion and drug metabolism. Given the small sample size,
our findings should be considered
hypothesis-generating results that
did not prove a specific cause-andeffect relationship but rather showed
an association; thus, further basic
physiological research should be
performed, and confirmation of our
findings should be sought within a

note Warfarin

much larger sample. This will also enable better evaluation of factors associated with the likelihood that significant dosage changes will be required in the periprocedure period.
Conclusion
Warfarin 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.
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