Download With Third-Degree Atrioventricular Block Rate and

Effect of Cilostazol on the Ventricular Escape
Rate and Neurohumoral Factors in Patients
With Third-Degree Atrioventricular Block
Koji Kodama-Takahashi, Akira Kurata, Kiyotaka Ohshima, Kozo
Yamamoto, Shigeki Uemura, Seiichiro Watanabe and Takeru Iwata
Chest 2003;123;1161-1169
DOI 10.1378/chest.123.4.1161
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Effect of Cilostazol on the Ventricular
Escape Rate and Neurohumoral Factors
in Patients With Third-Degree
Atrioventricular Block*
Koji Kodama-Takahashi, MD; Akira Kurata, MD; Kiyotaka Ohshima, MD;
Kozo Yamamoto, MD; Shigeki Uemura, MD; Seiichiro Watanabe, MD; and
Takeru Iwata, MD
Study objectives: This study assessed whether the antiplatelet agent cilostazol, which has potent
cyclic nucleotide phosphodiesterase type-3 inhibitory activity, affects the ventricular escape rate
and neurohumoral factors in patients with third-degree atrioventricular block.
Design: Prospective, but nonrandomized, study.
Setting: Cardiology division of an acute care hospital.
Patients: We studied 12 patients with third-degree intra-His or infra-His atrioventricular block
who were in functional class II or III of the New York Heart Association classification. None of the
patients had experienced Adams-Stokes attacks.
Interventions: These patients were given cilostazol orally at a dose of 200 mg daily for at least 1
week.
Measurements and results: Before and after treatment with cilostazol, continuous 24-h ECG
monitoring and measurement of plasma natriuretic peptide concentrations were performed.
Cilostazol significantly increased the mean (ⴞ SEM) total 24-h QRS count from 57,300 ⴞ 2,800 to
74,400 ⴞ 3,200 beats (p ⴝ 0.001) and significantly decreased the maximum geometric mean R-R
interval over a 24-h period from 1,900 ms (95% confidence interval [CI], 1,700 to 2,100 ms) to
1,600 ms (95% CI, 1,400 to 1,900 ms; p ⴝ 0.02), although none of the patients showed the
abolishment of the atrioventricular conduction abnormalities. The total 24-h count of premature
ventricular beats was not different before treatment (15 beats; 95% CI, 5 to 44 beats) and after
treatment (12 beats; 95% CI, 5 to 30 beats; p ⴝ 0.57). Treatment with cilostazol significantly
decreased the concentration of plasma atrial natriuretic peptide from 88 pg/mL (95% CI, 49 to
160 pg/mL) to 51 pg/mL (95% CI, 32 to 80 pg/mL; p ⴝ 0.007) and of brain natriuretic peptide
from 166 pg/mL (95% CI, 71 to 389 pg/mL) to 77 pg/mL (95% CI, 30 to 178 pg/mL; p ⴝ 0.02).
Conclusions: Cilostazol significantly increased the ventricular escape rate and significantly
decreased the level of circulating natriuretic peptides. Thus, cilostazol could be safely given to
selected patients over the short term with third-degree atrioventricular block.
(CHEST 2003; 123:1161–1169)
Key words: cilostazol; phosphodiesterase inhibitor; plasma natriuretic peptide; third-degree atrioventricular block
Abbreviations: ANP ⫽ atrial natriuretic peptide; BNP ⫽ brain natriuretic peptide; CI ⫽ confidence interval;
FS ⫽ fractional shortening; NYHA ⫽ New York Heart Association; PRA ⫽ plasma renin activity
(6-[4-(l-cyclohexyl-1H-tetrazol-5-yl)buC ilostazol
toxy]-3,4-dihydro-2(1H)-quinolinone) was approved for marketing in Japan in 1988, as an antiplatelet agent to improve ischemic symptoms, such
as pain and cold sensation, that were caused by
chronic arterial occlusive diseases.1
*From the Department of Internal Medicine, Yawatahama General Hospital, Yawatahama, Japan.
Manuscript received July 13, 2001; revision accepted August 12,
2002.
www.chestjournal.org
In 1999, this agent was approved by the US Food
and Drug Administration for the treatment of intermittent claudication. Cilostazol inhibits human platelet aggregation by potent cyclic nucleotide phosphodiesterase type-3 inhibitory activity.2,3 Cilostazol
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Koji Kodama-Takahashi, MD, Department of
Internal Medicine, Yawatahama General Hospital, 1-638 Ohira,
Yawatahama-shi, Ehime 796-8502, Japan; e-mail: koji0911@
sage.ocn.ne.jp
CHEST / 123 / 4 / APRIL, 2003
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1161
does not interrupt the adhesion of platelets to the
vascular wall at the initial step in thrombus formation.1 Thus, it has been thought that cilostazol is less
For editorial comment see page 978
likely to cause a tendency for bleeding. After treatment with cilostazol, bleeding time is not noticeably
prolonged.
It has been demonstrated4 that cilostazol has
positive chronotropic and dromotropic effects in
patients with supraventricular bradyarrhythmia, such
as those with sick sinus syndrome, and in those patients
with Wenckebach-type atrioventricular block. However, there have been no reports on the effects of
cilostazol on atrioventricular conduction or on the
QRS rate of the escape pacemaker in patients with
third-degree atrioventricular block. This prospective,
but nonrandomized, study was designed to assess
whether the administration of oral cilostazol can
affect the ventricular escape rate and neurohumoral
factors in patients with third-degree atrioventricular
block.
Materials and Methods
Patient Population
Twenty-two consecutive patients with idiopathic third-degree
atrioventricular block who were admitted to our hospital between
April 1998 and March 2001 were screened for enrollment in this
study. Atrioventricular block was labeled as idiopathic when there
were no diseases that could precipitate atrioventricular block, such
as inflammatory or infiltrative disease, cardiac tumors, toxicity of
drugs (particularly His-Purkinje system depressant drugs, such as
those for arrhythmia) or electrolyte (particularly potassium)
disturbances. The following studies were performed as a baseline:
(1) physical examination, including measurement of the BP at
rest with the patient in a supine position; (2) standard 12-lead
ECG and continuous 24-h ECG monitoring; (3) chest radiograph; (4) blood tests; (5) echocardiography; and (6) His bundle
recording.
Patients were selected for this study if they had experienced
subjective symptoms that were attributable to third-degree atrioventricular block at the intra-His or infra-His levels. However,
patients with dyspnea, which is indicative of functional class IV of
the New York Heart Association (NYHA) classification, and
syncope were not included. Patients with prior myocardial infarction, atrial fibrillation/flutter, other significant heart diseases (eg,
valvular or congenital heart disease), or renal dysfunction with
serum creatinine levels of ⬎ 1.5 mg/dL also were excluded.
In 7 of 22 patients, it was necessary to insert a temporary
transvenous right ventricular pacemaker just after hospital admission because of recurrent Adams-Stokes attacks or severe dyspnea that was indicative of functional class IV of the NYHA
classification. These seven patients were excluded from this
study. Similarly, oral or IV administration of ␤-adrenergic receptor agonists (eg, isoproterenol), adenosine-receptor antagonists
(eg, theophylline), and vagolytic agents (eg, atropine) were given
to three other patients who had near-syncope or pulmonary
congestion with pleural effusion that was attributable to third-
degree atrioventricular block. These three patients also were
excluded from the study. Five of the remaining 12 patients, who
had already been treated with these drugs for ⬎ 1 week at the
time of hospital admission, were included in this study. The
remaining seven patients had received no drugs that had chronotropic effects. Ultimately, 12 patients (five men and seven
women; mean [⫾ SD] age, 79 ⫾ 3 years; range, 58 to 92 years)
formed the study group. Eligible patients provided written
informed consent.
Study Protocol
Cilostazol, 100 mg twice daily, was given orally to all patients
for a minimum of 1 week (mean duration, 2.9 ⫾ 1.0 weeks; range,
1 to 12 weeks). Data for the following variables that were
obtained at the initial examination were used as follow-up
variables after treatment with cilostazol: chest radiograph cardiothoracic ratio; standard 12-lead ECG and 24-h ECG findings;
concentrations of plasma natriuretic peptides; and the percentage
of fractional shortening (FS) assessed by echocardiography.
It has been reported that an increase in plasma natriuretic
peptide concentrations may represent a compensatory mechanism to the hemodynamic disadvantage of atrioventricular asynchrony, such as ventricular pacing in patients with third-degree
atrioventricular block.5 Therefore, we selected plasma natriuretic
peptide concentrations as follow-up variables in this study. Blood
samples were collected after the patients had rested in a supine
position for at least 15 min, and concentrations of plasma atrial
natriuretic peptide (ANP) and brain natriuretic peptide (BNP)
were measured with a commercial kit (Sumitomo Laboratory;
Tokyo, Japan). In addition, plasma renin activity (PRA) and
concentrations of plasma aldosterone, epinephrine, and norepinephrine were measured with the same commercial kit. The
laboratory reference ranges for these concentrations are as
follows: plasma ANP, ⬍ 43.0 pg/mL; plasma BNP, ⬍ 18.4 pg/mL;
PRA, 0.3 to 2.9 ng/mL/h; plasma aldosterone, 30 to 159 pg/mL;
plasma epinephrine, ⬍ 80 pg/mL; and plasma norepinephrine,
90 to 420 pg/mL.
We obtained continuous 24-h ECG recordings using modified V1
and V5 leads. Because bipolar leads were used, the output was the
potential difference between positive and negative inputs. The
positive electrodes were placed in the conventional positions of V1
and V5 for modified V1 and V5 leads, respectively. The negative
electrode was placed on the upper end of the sternum. Maximum
heart rate, mean heart rate, minimum heart rate, maximum R-R
interval over a period of 24 h, 24-h total QRS counts, and 24-h total
counts of premature ventricular complexes were assessed.
Two-dimensionally targeted, M-mode echocardiographic studies were carried out with the subjects in the left lateral decubitus
position. To measure the left ventricular cavity and wall thickness, an M-mode scan of the left ventricle with the ultrasound
beam aimed just below the tips of the mitral valve leaflets was
recorded on strip chart paper. The following variables were
measured according to the American Society of Echocardiography and Penn conventions6: left ventricular end-diastolic and
end-systolic dimensions; and interventricular septal and left ventricular posterior wall thickness at end-diastole. As a marker of left
ventricular function, the percentage of FS was used. The percentage of FS was estimated from the following formula:
% FS 共%兲 ⫽ 100 ⫻ 共LVEDD ⫺ LVESD兲 / LVEDD,
where LVEDD is the left ventricular end-diastolic dimension,
and LVESD is the left ventricular end-systolic dimension.
His bundle recordings were performed to delineate the site of
atrioventricular block. The multipolar electrode catheter was
inserted into the right femoral vein and was advanced fluoroscop-
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ically across the tricuspid valve into the right ventricle. Then, the
catheter was slowly pulled back until potentials of right atrium,
His bundle, and right ventricle appeared. When the His deflection did not follow the atrial deflection, but preceded the
ventricular deflection, a block site was defined as the supra-His
level. When the His deflection followed the atrial deflection, but
did not precede the ventricular deflection, a block site was
defined as the infra-His level. When His deflections were split
into two parts, that is, when the first His deflection followed the
atrial deflection, and the second one preceded the ventricular
deflection, a block site was defined as the intra-His level.
Statistical Analysis
All data were tested for normality with the Shapiro-Wilks
statistic. The distribution of the maximum R-R interval over a
24-h period, the 24-h total count of premature ventricular beats,
and the plasma concentrations of neurohumoral factors was
skewed but approximated well to a normal distribution following
logarithmic transformation. The data are expressed as the mean
⫾ SEM, unless otherwise specified. For logarithmically transformed variables, geometric means (95% confidence intervals
[CIs]) were used. Data comparisons were made with paired or
nonpaired Student t tests when appropriate. In addition, simple
linear regression analysis was performed to describe the relationship between the change in the P (atrial) rate and the change in
the QRS (ventricular) rate in response to the administration of oral
cilostazol. All tests were two-tailed, and a p value of ⬍ 0.05 was
assumed to represent statistical significance. The maximum R-R
intervals over a 24-h period before the administration of cilostazol
for patients 2 and 10 were 15,600 ms and 10,500 ms, respectively.
These data were well outside the range of the distribution for the
other 10 patients, when outlying observations were tested with the
Smirnov-Grubbs statistic. We therefore excluded these data from
the analysis.
Results
Baseline Characteristics
Of 12 patients, 6 had cardiovascular diseases that
required drug therapy (hypertension, 4 patients;
hypertension and vasospastic angina pectoris, 1 patient; and stroke, 1 patient). The period between the
onset of third-degree atrioventricular block and
treatment with oral cilostazol ranged from 1 to 208
weeks. Before treatment with cilostazol, oral ␤-adrenergic receptor agonists were administered to five
patients. Three of these patients received adenosinereceptor antagonists orally. These drugs were administered before hospital admission. Eight patients
were in functional NYHA class II, and four patients
were in functional NYHA class III. Six patients had
block sites at intra-His levels, whereas the other six
had block sites at infra-His levels. The details of the
baseline clinical characteristics are shown in Table 1.
The Effects of Cilostazol on Standard 12-Lead
ECG and Holter Monitoring Data
During the administration of cilostazol, none of
the patients required the insertion of a temporary
transvenous right ventricular pacemaker or the new
administration of ␤-adrenergic receptor agonists,
phosphodiesterase inhibitors other than cilostazol,
or vagolytic agents because of uncontrollable heart
failure or Adams-Stokes attacks.
There was a significant positive linear correlation
between the change in P rate and the change in QRS
rate on the standard 12-lead ECG in response to oral
cilostazol (r ⫽ 0.59; p ⫽ 0.04) [Fig 1]. Patients 2 and
10, in whom long ventricular standstill (ie, a maximum R-R interval of ⬎ 10 s before treatment with
cilostazol) had been seen, were not excluded from
the study because the long ventricular standstill had
developed during sleep and, therefore, did not produce an Adams-Stokes attack. In 5 of 12 study
patients, atrioventricular synchrony, which was dis-
Table 1—Baseline Characteristics*
Block Site
NYHA
Functional
Class
1/89/M
Infra-His
III
8
2/89/M
Intra-His
III
12
3/77/F
4/91/M
Infra-His
Intra-His
II
III
52
208
5/80/M
Infra-His
II
56
6/74/F
7/85/F
8/92/F
Infra-His
Intra-His
Intra-His
II
III
II
8
3
2
9/73/M
10/73/F
11/64/F
12/58/F
Intra-His
Infra-His
Intra-His
Infra-His
II
II
II
II
156
3
11
1
Patient/Age,
y/Sex
Period Between
Onset and
Treatment, wk
␤-Adrenergic
Receptor Agonists
Adenosine-receptor
Antagonists
Yes (isoprenaline,
60 mg/d)
Yes (orciprenaline,
30 mg/d)
No
Yes (isoprenaline,
60 mg/d)
Yes (procaterol,
50 ␮g/d)
No
No
Yes (isoprenaline,
60 mg/d)
No
No
No
No
Yes (theophylline,
200 mg/d)
No
Cardiovascular Diseases
Stroke
Hypertension
No
Yes (theophylline,
200 mg/d)
Yes (theophylline,
200 mg/d)
No
No
No
Hypertension
Hypertension
Angina pectoris, hypertension
None
None
No
No
No
No
None
Hypertension
None
None
None
*M ⫽ male; F ⫽ female.
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1163
Figure 1. Relationship between change in the 12-lead ECG P rate and those of the QRS rate in
response to oral cilostazol administration (r ⫽ 0.59; p ⫽ 0.04).
cerned by baseline Holter monitoring data analysis,
was seen transiently before treatment with cilostazol.
On follow-up Holter monitoring, the duration of the
synchrony was prolonged in three of the patients and
remained unchanged in one of the patients after
treatment with cilostazol. In the fifth patient, atrioventricular synchrony disappeared after treatment
with cilostazol. Of the seven patients with no atrioventricular synchrony documented on baseline Holter
monitoring before treatment with cilostazol, synchrony
was transiently obtained after treatment with cilostazol in only one patient and was not obtained at all in
the remaining six patients. None of the patients
showed abolishment of the atrioventricular conduction abnormality.
Overall, cilostazol significantly increased the
mean total 24-h QRS count from 57,300 ⫾ 2,800
to 74,400 ⫾ 3,200 beats (p ⫽ 0.001), as is shown in
Figure 2. The mean heart rate (before treatment,
41 ⫾ 2 beats/min; after treatment, 50 ⫾ 2 beats/min;
p ⫽ 0.0005) and minimum heart rate (before
treatment, 30 ⫾ 3 beats/min; after treatment,
40 ⫾ 2 beats/min; p ⫽ 0.0006) significantly increased
after treatment with oral cilostazol, whereas maximum
heart rate did not change (before treatment, 61 ⫾ 4
beats/min; after treatment, 75 ⫾ 7 beats/min;
p ⫽ 0.09). On the other hand, the maximum R-R
interval over a 24-h period decreased significantly from
1,900 ms (95% CI, 1,700 to 2,100 ms) to 1,600 ms (95%
CI, 1,400 to 1,900 ms; p ⫽ 0.02) [Fig 3]. The total 24-h
count of premature ventricular beats did not change
(before treatment, 15 beats [95% CI, 5 to 44 beats];
after treatment, 12 beats [95% CI, 5 to 30 beats];
p ⫽ 0.57). Representative 24-h heart-rate trendgrams
are shown in Figures 4 and 5.
In seven patients who did not receive any drugs
before cilostazol administration, cilostazol significantly
increased the mean total 24-h QRS count from
58,400 ⫾ 3,700 to 76,600 ⫾ 3,600 beats (p ⫽ 0.03).
The mean heart rate (before treatment, 41 ⫾ 3
beats/min; after treatment, 49 ⫾ 3 beats/min;
p ⫽ 0.02) and the minimum heart rate (before treatment, 30 ⫾ 3 beats/min; after treatment, 37 ⫾ 2
beats/min; p ⫽ 0.003) also significantly increased
after treatment with oral cilostazol, whereas the
maximum heart rate did not change (before treatment, 65 ⫾ 6 beats/min; after treatment, 85 ⫾ 10
beats/min; p ⫽ 0.17). The maximum R-R interval
over a 24-h period decreased from 2,000 ms (95%
CI, 1,700 to 2,500 ms) to 1,800 ms (95% CI, 1,400 to
2,200 ms), but this difference was not statistically
significant (p ⫽ 0.12). Also, the total 24-h count of
premature ventricular beats was not different (before treatment, 14 beats [95% CI, 2 to 96 beats];
after treatment, 8 beats [95% CI, 2 to 30 beats];
p ⫽ 0.30). In the remaining five patients, who had
received drugs ⬎ 1 week before the administration
of cilostazol, cilostazol significantly increased the
mean total 24-h QRS count from 55,800 ⫾ 4,900 to
71,300 ⫾ 5,900 beats (p ⫽ 0.01). The mean heart
rate (before treatment, 41 ⫾ 3 beats/min; after treatment, 51 ⫾ 5 beats/min; p ⫽ 0.04) and minimum
heart rate (before treatment, 29 ⫾ 7 beats/min; after
treatment, 43 ⫾ 5 beats/min; p ⫽ 0.02) also signifi-
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Figure 2. Chart showing individual (E) and mean changes (f) in
the total 24-h QRS count before and after treatment with oral
cilostazol, in patients with third-degree intra-His or infra-His
atrioventricular block. The overall change observed was statistically significant (p ⫽ 0.001). Error bars indicate SEM.
cantly increased after treatment with oral cilostazol,
whereas the maximum heart rate did not change
(before treatment, 54 ⫾ 2 beats/min; after treatment, 62 ⫾ 6 beats/min; p ⫽ 0.31). The maximum
R-R interval over a 24-h period decreased from
1,800 ms (95% CI, 1,300 to 2,500 ms) to 1,400 ms
(95% CI, 1,000 to 1,900 ms), but the difference just
failed to reach statistical significance (p ⫽ 0.06). The
total 24-h count of premature ventricular beats did
not change (before treatment, 18 beats [95% CI, 7 to
49 beats]; after treatment, 23 beats [95% CI, 5 to 106
beats]; p ⫽ 0.75).
The Effects of Cilostazol on the Concentrations of
Plasma Natriuretic Peptides
As shown in Figures 6 and 7, the oral administration of cilostazol significantly decreased the concentration of plasma ANP from 88 pg/mL (95% CI,
49 to 160 pg/mL) to 51 pg/mL (95% CI, 32 to
80 pg/mL; p ⫽ 0.007) and decreased the concentration of BNP from 166 pg/mL (95% CI, 71 to
389 pg/mL) to 77 pg/mL (95% CI, 30 to 178 pg/mL;
p ⫽ 0.02).
Four patients were classified into a good-response
group according to Holter monitoring data, as mentioned above. Three of the patients were those who
had experienced transient atrioventricular synchrony
before treatment with cilostazol, which improved after
treatment. One of the patients experienced atrioventricular asynchrony before treatment with cilostazol
and experienced a transient synchrony after treatment
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Figure 3. Chart showing individual changes (E, F) and geometric mean changes (f) in the maximum R-R interval over a 24-h
period before and after treatment with oral cilostazol in patients
with third-degree intra-His or infra-His atrioventricular block.
The overall change observed was statistically significant
(p ⫽ 0.02). The data represented as F were excluded from the
analysis. Bars indicate 95% CIs.
with cilostazol. The eight remaining patients were
classified as the poor-response group. In the goodresponse group, oral cilostazol administration decreased the concentration of plasma ANP from
80 pg/mL (95% CI, 9 to 728 pg/mL) to 34 pg/mL
(95% CI, 11 to 99 pg/mL) and the concentration of
BNP from 127 pg/mL (95% CI, 6 to 2,980 pg/mL) to
33 pg/mL (95% CI, 3 to 402 pg/mL). However, these
differences were not significant (p ⫽ 0.17 and
p ⫽ 0.16, respectively). On the other hand, in the
poor-response group, oral cilostazol administration
significantly decreased the concentration of plasma
ANP from 93 pg/mL (95% CI, 51 to 171 pg/mL) to
62 pg/mL (95% CI, 39 to 97 pg/mL; p ⫽ 0.003), and
the concentration of BNP from 189 pg/mL (95% CI,
79 to 451 pg/mL) to 110 pg/mL (95% CI, 34 to
301 pg/mL; p ⫽ 0.03).
The differences in the concentrations of plasma
ANP and BNP before and after the administration of
cilostazol were greater in the good-response group
than in the poor-response group, but these differences were not statistically significant (p ⫽ 0.15 and
p ⫽ 0.22, respectively).
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Figure 4. Twenty-four-hour heart rate trendgrams obtained from patient 5 before treatment (top) and
after treatment (bottom) with cilostazol. The heart rate was almost constant throughout the day both
before and after treatment, although cilostazol administration increased the heart rate by about
10 beats/min. The constant heart rate was due to third-degree atrioventricular block with neither the
abrupt cessation of escape beats nor atrioventricular synchrony.
Other Follow-up Variables
The mean systemic systolic BP tended to decrease
after treatment with oral cilostazol (before treatment,
152 ⫾ 6 mm Hg; after treatment, 146 ⫾ 7 mm Hg),
but this difference was not statistically significant
(p ⫽ 0.13). Oral cilostazol did not change the chest
radiograph cardiothoracic ratio (before treatment,
53 ⫾ 2%; after treatment, 54 ⫾ 2%; p ⫽ 0.55), or the
percentage of FS assessed by echocardiography (before
treatment, 44 ⫾ 1%; after treatment, 43 ⫾ 1%;
p ⫽ 0.27). In addition, PRA and concentrations of
plasma aldosterone, epinephrine, and norepinephrine
did not change after the administration of cilostazol.
PRA was 0.7 ng/mL/h (95% CI, 0.3 to 1.7 ng/mL/h)
before treatment vs 1.4 ng/mL/h (95% CI, 0.8 to 2.5
ng/mL/h) after treatment (p ⫽ 0.07). The aldosterone
concentration was 36.3 pg/mL (95% CI, 30.0 to 43.9
pg/mL) before treatment vs 37.4 pg/mL (95% CI, 22.0
to 63.4 pg/mL) after treatment (p ⫽ 0.93). The epinephrine concentration was 38.0 pg/mL (95% CI, 22.4
to 64.4 pg/mL) before treatment vs 33.6 pg/mL (95%
CI, 23.5 to 48.1 pg/mL) after treatment (p ⫽ 0.68).
Figure 5. Twenty-four-hour heart-rate trendgrams before treatment (top) and after treatment
(bottom) with cilostazol that were obtained from patient 7. The heart rate was constant and was around
30 beats/min at baseline. After treatment, atrioventricular synchrony was seen between 4:00 pm (hour
16) and 4:00 am (hour 4), and between 1:00 pm (hour 13) and 4:00 pm (hour 16). During these periods,
the heart rate increased.
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Figure 6. Chart showing individual changes (E) and geometric
mean changes (f) in the plasma levels of ANP before and after
treatment with oral cilostazol in patients with third-degree
intra-His or infra-His atrioventricular block. The overall change
observed was statistically significant (p ⫽ 0.007). Bars indicate
95% CIs.
Finally, the norepinephrine concentration was 429.4
pg/mL (95% CI, 295.2 to 624.6 pg/mL) before treatment vs 484.8 pg/mL (95% CI, 349.2 to 673.0 pg/mL)
after treatment (p ⫽ 0.57).
Permanent Pacemaker Implantation
Ultimately, 9 of the 12 patients underwent permanent pacemaker implantation without discontinuing
cilostazol therapy, just after post-cilostazol administration tests were performed. No bleeding complications were seen during surgery. The remaining three
patients did not undergo pacing therapy because of
dementia (two patients) or poor general condition
(one patient). They continued receiving cilostazol in
addition to ␤-adrenergic receptor agonists and
adenosine-receptor antagonists. Patient 1 died of
aspiration pneumonia 4 months after receiving treatment with oral cilostazol. Patient 8 died suddenly 9
months after receiving treatment with oral cilostazol.
The remaining patient (patient 5) was alive and had
been receiving cilostazol therapy for 12 months at
the time of the last follow-up. No exacerbation of
heart failure or occurrence of Adams-Stokes attacks
was seen in the three patients who did not undergo
pacing therapy. The third patient was in functional
NYHA class I, although he was not very active.
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Figure 7. Chart showing individual changes (E) and geometric
mean changes (f) in the plasma levels of BNP before and after
treatment with oral cilostazol in patients with third-degree
intra-His or infra-His atrioventricular block. The overall change
observed was statistically significant (p ⫽ 0.02). Bars indicate
95% CIs.
Discussion
This study demonstrated that the short-term administration of cilostazol accelerated the rate of
escape rhythms in patients with third-degree atrioventricular block, although none of the patients
showed abolishment of the atrioventricular conduction abnormality. In addition, it was shown that the
drug decreased the concentrations of plasma natriuretic peptides.
Therapy for Third-Degree Atrioventricular Block
With advances in cardiac pacemaker technology
and the establishment of the therapeutic benefits of
cardiac pacing,7 permanent pacemaker implantation
has become the first-line treatment for patients with
symptomatic third-degree atrioventricular block.
However, careful consideration should be given to
performing this operation in patients with coexisting
dementia or poor general condition, such as the three
patients who did not undergo permanent pacing.
In patients with idiopathic third-degree atrioventricular block at intra-His or infra-His levels, drug
therapy is not expected to improve atrioventricular
conduction sufficiently. Oral, or preferably IV, cateCHEST / 123 / 4 / APRIL, 2003
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Copyright © 2003 by American College of Chest Physicians
1167
cholamine agents, such as isoproterenol, may be used
to accelerate the impulse of the escape pacemaker in
these patients, but it cannot be relied on for more than
a few hours or days without producing significant side
effects.8 Generally, these drugs are used for short-term
therapy until adequate pacing therapy can be established. The insertion of a temporary transvenous pacemaker as a bridge to permanent pacing is the most
effective strategy.9 However, such intervention is invasive. Moreover, the insertion of a temporary transvenous pacemaker often requires patients to stay in bed
until the implantation of a permanent pacemaker. Bed
rest should be avoided, particularly in the elderly, as it
can lead to complications like disuse muscle atrophy,
pulmonary thromboembolism, and delirium.
Effects of Cilostazol on Atrioventricular
Conduction and the Escape Pacemaker
In anesthetized dogs, cilostazol increases heart
rate and decreases BP dose-dependently.3 In humans, cilostazol produces a significant increase in
heart rate.10 It has been demonstrated4 that cilostazol has positive chronotropic effects in patients with
sick sinus syndrome and has positive dromotropic
effects in those with Wenckebach second degree
atrioventricular block.
In this study, cilostazol administration accelerated
the rate of the escape rhythm, although the atrioventricular conduction abnormality was not abolished in
any of the patients. By contrast, cilostazol administration significantly decreased the maximum R-R
interval over a 24-h period, even in two patients with
a maximum R-R intervals of ⬎ 10 s. The total 24-h
count of premature ventricular beats did not change
after treatment with oral cilostazol. Furthermore, no
bleeding complications were seen during surgery in
patients who underwent permanent pacemaker implantation without discontinuing cilostazol. The incidence of adverse events requiring the discontinuation of cilostazol is very low in general.1,11,12 Thus,
cilostazol could be safely given to selected patients
with third-degree atrioventricular block over the
short term.
In patients with symptomatic third-degree atrioventricular block at intra-His or infra-His levels, a
rapid increase in QRS rate often is needed. Niki and
Mori13 demonstrated that the rapid onset of action of
oral cilostazol is advantageous. In humans, cilostazol
is promptly absorbed, with a maximum plasma concentration observed 3 to 4 h after oral administration.14 The heart rate increases within 6 h of the
administration of oral cilostazol, although this is too
long a delay for patients with symptomatic thirddegree atrioventricular block. None of the patients
included in this study required chronotropic support,
even during this period. Therefore, there may have
been a bias due to flaws in the study design or patient
selection. However, cilostazol might make invasive
and risky procedures, such as temporary pacing,
unnecessary until permanent pacemaker implantation in some patients with symptomatic third-degree
atrioventricular block at intra-His or infra-His levels.
In addition, the usefulness of cilostazol in accelerating the rate of the escape rhythm may allow more
time to evaluate the need for permanent pacing, although resolution of the symptoms caused by atrioventricular block must be observed.
Cilostazol augments the increased beating rate of
isoproterenol-treated isolated guinea pig atria.3 In
this study, five patients had received ␤-adrenergic
receptor agonists before the administration of cilostazol. In these five patients, cilostazol increased the
total 24-h QRS count. Thus, cilostazol may be considered as an alternative or a supplement when
front-line drug therapy for chronotropic support,
such as the administration of ␤-adrenergic receptor
agonists, is insufficient.
The long-term effects of cilostazol on the escape
pacemaker in patients with third-degree atrioventricular block were not investigated in this study, although 3 of the 12 patients took the drug for at least
4 months. If cilostazol effectively resolved the symptoms caused by third-degree atrioventricular block
for a long period of time, as was the case in patient
5, cilostazol administration would obviate the need
for permanent pacemaker implantation, particularly
in patients with coexistent dementia or those in poor
general condition. The long-term chronotropic or
dromotropic effects of cilostazol in patients with thirddegree atrioventricular block must be clarified.
Effects of Cilostazol on Plasma Levels of
Natriuretic Peptides
In patients with third-degree atrioventricular block,
an increase in plasma ANP concentrations is mainly
caused by the increased atrial wall stretch that results
from the occurrence of atrial systole during ventricular
systole and from the increased cardiac preload due to
marked bradycardia. It is thought that ANP release
provides a mechanism for compensating for the hemodynamic disadvantage of atrioventricular asynchrony,5
through its ability to promote sodium and water excretion, to reduce systemic and pulmonary vascular resistance, and to modulate volume-regulating hormones.
On the other hand, it has been shown15 that atrial
contraction against closed mitral valves leads to left
atrial distension and increased pulmonary vascular
pressure, which affects the right ventricle and results in
the release of BNP. In addition, BNP might be cosecreted with ANP in response to the same stimuli.16
1168
Clinical Investigations
Downloaded from chestjournal.org on February 10, 2008
Copyright © 2003 by American College of Chest Physicians
In this study, the short-term administration of
cilostazol significantly decreased the concentrations
of plasma ANP and BNP, although Vardas et al17
have reported that short-term ventricular demand
pacing, which increases the QRS rate but leaves
atrioventricular asynchrony, does not change the
concentration of ANP. In 4 of 12 patients whose
atrioventricular synchrony improved transiently in
response to oral cilostazol administration, the transient atrioventricular synchrony might have slightly
decreased the atrial wall stretch and might have led
to a decrease in the plasma levels of natriuretic
peptides.18 On the other hand, even in the remaining
eight patients in whom atrioventricular synchrony
was not attained, was worsened, or remained unchanged, oral cilostazol significantly decreased the
concentration of plasma natriuretic peptides. In
these patients, volume expansion as a hemodynamic
disadvantage of both atrioventricular asynchrony and
slow escape rhythms might have been partially improved by an increased escape rhythm in response to
the administration of oral cilostazol. This might have
resulted in decreased plasma levels of natriuretic
peptides. Further studies using a larger number of
patients are needed to clarify the physiologic role of
natriuretic peptides under these circumstances.
Study Limitations
This study has some limitations. First, the sample
size was very small. Second, improvements in subjective symptoms were not followed, because the observation period was short in most patients studied. In
addition, exercise-tolerance testing was not performed,
because exercise worsens intra-His or infra-His atrioventricular block.8 Third, 3 of the 12 study patients did
not undergo permanent pacemaker implantation.
Fourth, neither patients who were in functional NYHA
class IV nor those who had experienced Adams-Stokes
attacks were included. Fifth, coronary angiography was
performed only in two study patients, who had no
atherosclerotic luminal narrowing in the epicardial
coronary arteries. Another limitation of this study was
that bleeding time was not investigated.
Conclusions
In patients with third-degree intra-His or infra-His
atrioventricular block who were in functional NYHA
class II or III and had not experienced Adams-Stokes
attacks, the impulse of the escape pacemaker was
increased and was made stable after treatment with
oral cilostazol. Together with these findings, cilostazol significantly decreased the level of circulating
natriuretic peptides. Thus, cilostazol could be safely
given to selected patients with third-degree atrioventricular block over the short term.
www.chestjournal.org
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CHEST / 123 / 4 / APRIL, 2003
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1169
Effect of Cilostazol on the Ventricular Escape Rate and Neurohumoral
Factors in Patients With Third-Degree Atrioventricular Block
Koji Kodama-Takahashi, Akira Kurata, Kiyotaka Ohshima, Kozo Yamamoto,
Shigeki Uemura, Seiichiro Watanabe and Takeru Iwata
Chest 2003;123;1161-1169
DOI 10.1378/chest.123.4.1161
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