A Simple Scheme to Initiate Oral Anticoagulant
Treatment in Outpatients With Nonrheumatic
Atrial Fibrillation
Vittorio Pengo, MD, Alessandra Biasiolo, DSci, and Cinzia Pegoraro, MD
A
trial fibrillation (AF) is a common arrhythmia
associated with an increased incidence of stroke,
1
which is significantly reduced with oral anticoagulant
treatment.
2
Diagnosis of AF is often made by means
of ambulatory electrocardiography, with oral antico-
agulant treatment initiated on an outpatient basis. The
most popular protocol to initiate warfarin treatment
considers prothrombin time-international normalized
ratio (PT-INR) determinations every day for the first 4
days.
3
This protocol was shown to be effective in a rela-
tively young group of inpatients but not in older groups.
4,5
Moreover, the inconvenience of daily monitoring of
treatment renders this scheme impractical for outpa-
tients with AF. We have recently developed a scheme
for early indication of warfarin maintenance dose on
the basis of PT-INR at day 3 after 2 consecutive daily
10-mg doses of warfarin.
6
However, it was recently
shown that a 5-mg loading dose produces less excess
of anticoagulation,
7
reinforcing the advice to initiate
anticoagulation on an outpatient basis with an antici-
pated maintenance warfarin dose of 4 to 5 mg/day.
8
Because excess anticoagulation and older age are as-
sociated with increased bleeding complications,
9
we
decided to shift from the total 20-mg warfarin dose in
2 days (induction scheme) into a total of 20 mg of
warfarin administered over 4 consecutive days. Simi-
lar to the induction scheme, we then established a
correlation between the INR on the fifth day and the
warfarin maintenance dose.
•••
From January 1998 to June 1999, all consecutive
patients with nonrheumatic AF referred to the Throm-
bosis Center of the Padova Civic Hospital for initia-
tion of oral anticoagulant treatment were considered
for the study; no patient was receiving heparin when
evaluated for the study. Patients were excluded if they
(1) were treated with drugs known to interfere with
warfarin (in particular amiodarone, which is often
prescribed to these patients), (2) had an associated
disease known to affect coagulation, (3) had a relative
contraindication to treatment, (4) had undergone a
previous course of anticoagulant treatment, (5) had a
basal INR that was above 1.2, or (5) refused their
informed consent to participate. All patients followed
the basic educational program at the center. Patients
received a prescription of 5 mg/day of warfarin for 4
consecutive days. PT-INR determination was sched-
uled on the fifth day. Dose prescription on the fifth day
was freely decided by the doctor in charge. Thereafter,
the date of the next PT-INR determination and pre-
scription was recommended to be 1 week apart for
the first 2 weeks.
INR determinations were obtained by using recom-
binant thromboplastin (Instrumentation Laboratory,
Milan, Italy) and an Electra 1400 coagulometer
(Hemoliance, Milan, Italy) with an International Sen-
sitivity Index value close to 1.0, certified for each
batch by the manufacturer and a national authority.
External quality control and clinical and laboratory
follow-up of patients attending the center were in line
with the recommendations of the ltalian Federation of
Anticoagulation Clinics.
10
Follow-up was continued
for up to 3 months to establish the warfarin mainte-
nance dosage; the warfarin dose was considered to be
stabilized when the INR values were between 2.0 and
3.0 (therapeutic range) on 3 consecutive occasions, 1
week apart. Major and minor bleedings as well as
thromboembolic complications were recorded and de-
fined as previously reported.
9,11
The relation between the INR at day 5 (after 4
consecutive daily doses of 5 mg of warfarin) and the
weekly maintenance dose of warfarin in patients was
evaluated. To test the validity of an early maintenance
dose, an additional group of patients with nonrheu-
matic atrial fibrillation were prescribed the predicted
maintenance dose after 4 days of treatment according
to the obtained scheme.
To expedite estimation of the warfarin mainte-
nance dose, each patient’s INR value on day 5 was
plotted against the weekly maintenance dose. The best
fit was obtained by means of minimal squares. The
mean warfarin dosage in groups of patients was com-
pared by the unpaired t test with Welch’s correction.
The agreement between the estimated and actual
maintenance dose was assessed by plotting the data
according to Bland and Altman.
12
•••
From a total of 105 candidate outpatients with AF,
14 were excluded (8 for associated interfering drugs, 3
for basal INR 1.2, and 3 for an associated dilated
cardiomyopathy). After informed consent, the remain-
ing 91 patients (mean age 71 years, range 42 to 88)
received 5 mg/day of warfarin for 4 consecutive days.
Fifty-four (59%) were men, and major risk factors for
systemic embolism (hypertension, reduced left ven-
tricular ejection fraction, previous stroke) were
present in 50 (55%), 21 (23%), and 9 (10%) patients,
respectively. Thirty patients were not included in data
analysis; 16 of these patients completed the 3 months
From the Department of Clinical and Experimental Medicine, Cardiol-
ogy Section, University of Padova, Padova, Italy. Dr. Pengo’s address
is: Department of Clinical and Experimental Medicine, Thrombosis
Center, University of Padova School of Medicine, “Ex Busonera”
Hospital, via Gattamelata, 64 I-35128 Padova, Italy. E-mail:
vittorio.pengo@unipd.it. Manuscript received May 29, 2001; revised
manuscript received and accepted July 6, 2001.
1214 ©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matter
The American Journal of Cardiology Vol. 88 November 15, 2001 PII S0002-9149(01)02069-0