(Circulation. 2001;103:1083.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Beneficial Effects of Pentoxifylline in Patients With Idiopathic Dilated Cardiomyopathy Treated With Angiotensin-Converting Enzyme Inhibitors and Carvedilol
Results of a Randomized Study
From the Department of Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa.
Correspondence to Daniel Skudicky, MD, Department of Cardiology, Baragwanath Hospital, PO Bertsham 2013, Johannesburg, South Africa. E-mail dskudi{at}icon.co.za
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—We previously reported beneficial effects of pentoxifylline, a xanthine-derived agent known to inhibit the production of tumor necrosis factor-
, in patients with idiopathic dilated cardiomyopathy
treated with diuretics, digoxin, and ACE inhibitors. Since then, 3
large clinical trials showed important clinical benefits of
ß-blockers in this population. Therefore, we designed the present
study to establish whether in patients with heart failure already
receiving treatment with ACE inhibitors and ß-blockers, the addition
of pentoxifylline would have an additive beneficial
effect. Methods and Results—In a single-center, prospective, double-blind, randomized, placebo-controlled study, 39 patients with idiopathic dilated cardiomyopathy were randomized to pentoxifylline 400 mg TID (n=20) or placebo (n=19) if they had a left ventricular ejection fraction <40% after 3 months of therapy with digoxin, ACE inhibitors, and carvedilol. Primary end points were New York Heart Association functional class, exercise tolerance, and left ventricular function. Patients were followed up for 6 months. Five patients died (3 in the placebo group). Patients treated with pentoxifylline had a significant improvement in functional class compared with the placebo group (P=0.01), with an increment in exercise time from 9.5±5 to 12.3±6 minutes (P=0.1). Left ventricular ejection fraction improved from 24±9% to 31±13%, P=0.03, in the treatment group.
Conclusions—In patients with idiopathic dilated cardiomyopathy, the addition of pentoxifylline to treatment with digoxin, ACE inhibitors, and carvedilol is associated with a significant improvement in symptoms and left ventricular function.
Key Words: cardiomyopathy • heart failure • apoptosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We previously reported beneficial effects of 6 months of treatment with pentoxifylline, a xanthine-derived agent known to inhibit the production of tumor necrosis factor-
(TNF-), in patients with idiopathic dilated
cardiomyopathy.1 Although the
mechanism of improvement is unclear, pentoxifylline reduced plasma
circulating levels of TNF-, a cytokine with negative inotropic
properties,2 3 and
Fas/APO-1,4 an
apoptosis-signaling surface receptor known to trigger programmed cell
death in a variety of cell
types.5 6 Increased
plasma levels of soluble Fas receptors have been reported in patients
with heart
failure.4 7
Pentoxifylline was previously found to inhibit apoptosis in different
human cell types in vitro and in
vivo.8 9 At the
time of the design of our first trial with pentoxifylline, treatment
with ß-blockers was not part of the routine therapy of patients with
heart failure in New York Heart Association (NYHA) functional class II
or III. Since then, 3 large clinical trials showed important clinical
benefits of ß-blockers in this population, including a significant
reduction in
mortality.10 11 12
Therefore, we designed the present study to establish whether in
patients with heart failure already receiving treatment with ACE
inhibitors and ß-blockers, the addition of pentoxifylline would
result in an improvement in NYHA functional class, exercise time, or
left ventricular (LV) size and function. Moreover, we again measured
TNF- and Fas/APO-1 plasma levels to explore potential mechanisms of
benefit. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Design and Patient Enrollment
The protocol was approved by the Ethics Committee of the University of the Witwatersrand and the Prescription and Therapeutic Committee of Baragwanath Hospital. All patients gave informed consent before study entry. This was a single-center, prospective, double-blind, randomized, placebo-controlled trial, with 2 parallel arms. Inclusion criteria were (1) age
18 and 
70 years, (2)
stable NYHA functional class II or III congestive heart failure of
unknown cause, (3) LV ejection fraction (LVEF) <40% by
radionuclide angiography, (4) sinus rhythm, and (5) eligible patients
in whom high-quality echocardiographic images could be obtained.
Exclusion criteria were (1) chronic obstructive pulmonary disease; (2)
significant valvular heart disease; (3) history or evidence of ischemic
heart disease; (4) systolic blood pressure >160 mm Hg and/or
diastolic blood pressure >95 mm Hg; (5) clinical conditions other
than cardiomyopathy that could increase cytokine levels (eg, rheumatoid
arthritis, sepsis); (6) pregnancy; (7) severe liver disease, defined as
enzymes >2 times the upper limit of normal; and (8) any clinical
condition that according to the investigators precluded inclusion in
the study.
After the initial screening visit, all patients received
treatment with digoxin, diuretics, ACE inhibitors, and carvedilol for 3
months. The target dose of enalapril was 10 mg BID and that of
carvedilol 25 mg BID. After 3 months of therapy, patients whose LVEF
was <40% as assessed by radionuclide angiography were randomized to
pentoxifylline 400 mg TID (n=20) or a matching placebo of similar
appearance (n=19). Monthly visits were scheduled for clinical
assessment and evaluation of compliance. Clinical examination, exercise
test, echocardiographic and radionuclide studies, plus TNF- and
Fas/APO-1 plasma level determinations were performed at baseline and
then repeated 6 months after randomization. Primary end points were
NYHA functional class, exercise tolerance, and LV systolic and
diastolic function.
TNF- and Fas/APO-1 Levels
Fifteen milliliters of blood was withdrawn from an
antecubital vein and collected into prechilled evacuated tubes
containing EDTA. Plasma was separated by centrifugation at 2500 rpm for
12 minutes within 15 minutes of collection. Aliquots were stored at
-70°C. TNF- measurements were performed with a commercially
available enzyme-linked immunoassay (Amersham, Maidstone). The average
of triplicate undiluted determinations was calculated. Fas/APO-1 was
measured with a nonisotopic quantitative immunoassay (Calbiochem)
appropriately diluted.
Functional Class and Exercise Test
The functional class of the patients during the
baseline and follow-up visits was assessed by a physician who was
unaware of the treatment assigned. The same physician evaluated all
patients. Exercise tests were performed according to a modified
Naughton protocol.13 All
tests were performed by the same cardiac
technologist.
Radionuclide and Echocardiographic
Studies
A multiple gated equilibrium cardiac blood pool
scintigraphic technique was used to measure LVEF (Elscint Apex 409).
Imaging was performed in the left anterior oblique projection, which
provided the best septal separation of the ventricles with a 0° to
10° caudal angulation. Calculations of LV performance were made as
previously described14 with
the automatic edge-detection algorithm for the determination of LV
borders. All studies were interpreted by a single observer. 2D targeted
M-mode echocardiography with Doppler color flow mapping was performed
with a Hewlett Packard Sonos 5500 echocardiograph attached to a 2.5- or
3.5-MHz transducer. All studies were performed and interpreted by the
same operator and recorded on videotape. End-systolic pressure was
estimated from noninvasive blood pressure measurements by use of a
Dynamap (Critikon)
monitor,15 and end-systolic
stress was calculated as previously
described.16 LV dimensions
were measured according to the American Society of Echocardiography
guidelines.17 For LV
measurements, an average of 3 beats was obtained. Diastolic mitral
flow was assessed by pulsed-wave Doppler echocardiography from the
apical 4-chamber view. The E-wave deceleration time was measured as the
interval between the peak early diastolic velocity and the point at
which the steepest deceleration slope was extrapolated to the zero
line.
The investigators who performed and interpreted the radionuclide and echocardiographic studies were blinded to treatment assigned.
Statistical Analysis
Data are presented as mean±SD. Group comparisons
were made by use of the Mann-Whitney
U test, Fisher’s exact test,
or 
2 when appropriate. The Wilcoxon
matched-pairs test was used for comparison of baseline data with the
results after 6 months within each group. Data were analyzed on a
personal computer with a commercially available statistical program
(Statistica). Significance was assumed at a 2-tailed value of
P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Of 51 patients screened, 12 were not enrolled because the LVEF was >40% after treatment with digoxin, enalapril, and carvedilol. Baseline characteristics of the remaining 39 patients at randomization are shown in Table 1
. There were no significant differences
between groups. Five patients died during the study period (3 in the
placebo group). Two patients in the treatment arm moved to remote areas
and did not complete the trial. These 7 patients who did not complete
the study were not included in the final analysis of changes in LV
function and TNF- and Fas levels. There were no significant baseline
differences between the groups after these patients had been excluded.
All patients received treatment with digoxin 0.25 mg/d and enalapril 10
mg BID. The mean dose of furosemide was 154±24 mg/d in the
pentoxifylline group versus 133±36 mg/d in the placebo group,
P=NS. The mean dose of
carvedilol was 42±13 mg in the treatment arm versus 36±16 mg in the
placebo group, P=NS. A coronary
angiogram was performed in 17 patients and revealed normal coronary
arteries in all cases. Patient compliance, estimated by pill count, was
92%.
|
Functional Class and Exercise Tolerance
The functional class was considered to have improved if
the patient’s functional status increased by 1 grade of the NYHA
classification. It was considered to have deteriorated if the
functional class decreased by 1 grade or the patient died. In the
treatment group, 66.6% of patients had an improved functional class,
16.6% remained unchanged, and 16.6% deteriorated. In the placebo
group, 10% of patients improved, 53% remained unchanged, and 37%
deteriorated (P=0.01 between
groups). Individual changes in functional class of the patients who
completed the study are shown in
Figure 1. There was a trend
(P=0.1) toward an improvement
in exercise tolerance in the pentoxifylline group
(Table 2). Of the 20 patients treated with pentoxifylline,
11 were in functional class I at the end of the study. In this
subgroup, exercise time improved from 10.9±4.8 to 15.7±6.2 minutes,
P=0.04.
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|
LV Dimensions and Function
There was a trend toward, but not a significant,
decrease in end-diastolic diameter in the pentoxifylline group. This
was associated with a significant decline in end-systolic diameter. The
net result was an increment in LVEF
(P=0.03)
(Table 2
). End-systolic diameter decreased significantly,
even though there was no decrease in the afterload, estimated as
end-systolic stress, that would be suggestive of a direct improvement
in contractility. No significant changes in LV dimensions or parameters
of LV systolic or diastolic function were observed in the placebo
group. The mean change in LVEF from baseline to 6 months was 7.8±8%
in the pentoxifylline group versus 0.9±6% in the placebo group,
P=0.04. Individual changes of
LVEF of the patients who completed the study are depicted in
Figure 2. Eleven patients in the pentoxifylline group
improved the LVEF after 6 months of therapy. These patients had higher
baseline Fas/APO-1 plasma levels than the 5 patients whose LVEF
deteriorated despite therapy (11.3±3.7 versus 5.4±2.2 U/mL,
respectively, P=0.005). There
were no other baseline differences between these 2 groups. There was no
significant difference in the absolute change in the E/A ratio between
groups (0.5±0.9 versus 0.3±0.6 for the treatment and control groups,
respectively,
P=0.4).
|
TNF- and Fas/APO-1 Levels
Baseline plasma levels of TNF- and Fas/APO-1 were
similar in the treatment and placebo groups. TNF- plasma levels were
significantly higher in the study population than in a group of 20
healthy volunteers (2.40±1.8 versus 1.44±1.3 pg/mL, respectively,
P=0.02). The baseline TNF-
plasma level was lower than the one we previously documented in a
similar population by the same diagnostic
technique.1 The only obvious
difference between the 2 groups is that in the present study, patients
received treatment with carvedilol for 3 months before the cytokine
determination. There was no significant change in the TNF- level
after treatment with pentoxifylline.
Fas/APO-1 plasma concentration was also significantly higher
in the study population than in the healthy volunteers (9.1±4.2 versus
0.84±0.2 U/mL, respectively,
P<0.0001). There was a
significant decline in the Fas/APO-1 levels after 6 months of treatment
with pentoxifylline, with no significant changes in the placebo group
(Table 2). The mean change in the Fas/APO-1 levels in the
pentoxifylline group was -3.2±5 U/mL, versus 0.3±4 U/mL in the
placebo group,
P=0.05.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There has been increasing interest in the past few years in the role of proinflammatory cytokines, particularly that of TNF-
, in the pathogenesis and progression of heart
failure.18 19 20 21 22
This observation led different investigators to evaluate the question
of whether the manipulation of the cytokine levels could have a
salutary effect in patients with heart failure. Deswal et
al23 reported an improvement
in quality-of-life score, 6-minute walking test, and LVEF with the use
of a soluble p75 TNF receptor fusion protein (etanercept) in patients
with advanced heart failure. Although both the study performed with
etanercept and ours are small, the improvement of LV function appears
to be greater with pentoxifylline. Furthermore, other advantages of
pentoxifylline over etanercept could be that it inhibits the production
of TNF- rather than neutralizing this cytokine, its easier form of
administration, and its lower cost. Cohn et
al24 showed a dose-dependant
increase in mortality with vesnarinone, a quinolinone derivative that
can inhibit the production of
TNF-.25 Although we are
not aware of any large-scale study that evaluated the safety of
pentoxifylline in patients with heart failure, this drug has been used
for >25 years in patients with peripheral vascular disease, with a
very low incidence of side
effects.26 The results of
our 2 randomized trials did not show any increment in mortality in
patients treated with pentoxifylline, but these results still need to
be confirmed in larger-scale studies. Another potentially important
difference between pentoxifylline and both etanercept and vesnarinone
is the inhibition of apoptosis shown with pentoxifylline.
Pentoxifylline as an Adjunct to Therapy
With ß-Blockers
We previously reported beneficial effects of
pentoxifylline in patients with idiopathic dilated cardiomyopathy
treated with diuretics, digoxin, and ACE
inhibitors.1 Since then, 3
large clinical trials showed important clinical benefits of
ß-blockers in this population, including a significant reduction in
mortality.10 11 12
In the present study, we show that the addition of pentoxifylline to
treatment with digoxin, ACE inhibitors, and carvedilol results in a
significant improvement in functional class and LV function in patients
with idiopathic dilated cardiomyopathy. Because ß-blockers are
currently indicated for the treatment of patients with NYHA functional
class II or III heart failure due to LV systolic dysfunction, the
results of this study are clinically relevant. Although both studies
conducted with pentoxifylline had a positive outcome, there are some
important differences in the results of these 2 trials. First, the
degree of improvement in LVEF was higher in the first study (from
22.3±9% to 38.7±15%, versus 24±9% to 31±13% in the present one,
P=0.05). One possible
explanation is that in the present study, we selected a population that
had a more severe form of cardiomyopathy, because they remained with
severe LV systolic dysfunction despite the addition of carvedilol.
Twelve patients initially screened were not randomized because the LVEF
was >40% after treatment with carvedilol. Furthermore, mean baseline
LV end-diastolic diameter was larger in the present study group than in
the previous report (69±8 versus 65±6 mm, respectively,
P=0.04).
Interestingly, patients enrolled in this study had
relatively low baseline plasma levels of TNF- compared with our
previous study group (2.40±1.76 versus 9.45±8.7 pg/mL,
P<0.0001), even though they
appeared to be "sicker" as assessed by the larger baseline LV
end-diastolic diameter. Conceivably, treatment with carvedilol may have
suppressed TNF- production in this patient cohort. Prabhu et
al27 showed a significant
decline in the myocardial expression and protein production of TNF-
with metoprolol in the context of experimental myocardial infarction.
When TNF- is expressed or given at sufficiently high concentrations,
it can induce LV dilation and systolic
dysfunction.2 3 19
Given that pentoxifylline reduces TNF-
production,28 29
we hypothesized that this might be one of the mechanisms by which this
drug improves LV size and function in patients with dilated
cardiomyopathy. The inability of pentoxifylline to reduce circulating
levels of TNF- in this study does not exclude the possibility that
it may be operating via suppression of myocardial TNF- expression.
This will require further investigation.
Apoptosis
Apoptosis has been increasingly recognized as one of
the factors that may contribute to progressive LV
dysfunction.30 31
Cytokines,32 33
hypoxia,34 myocardial
ischemia,35 overstretching
of the myocytes,36 and other
insults can induce apoptosis. Although current evidence supports the
possibility that apoptosis occurs in heart failure, it is still unclear
to what extent it contributes to the progression of myocardial
dysfunction. Hirota et al,37
using a gene-knockout mouse model, recently demonstrated that apoptosis
plays a critical role in the transition between compensatory cardiac
hypertrophy and heart failure during aortic pressure overload.
Therefore, the use of therapies that can block apoptotic pathways could
be a useful strategy in the treatment of patients with heart failure.
Pentoxifylline has been shown to inhibit apoptosis in different human
cell types in vitro and in
vivo.8 9 Belloc et
al8 reported a 20% to 60%
reduction in apoptosis after the ingestion of 400 mg of pentoxifylline.
This reduction was greater than the one they observed in vitro and was
not related to phosphodiesterase inhibition, suggesting that different
mechanisms other than direct inhibition of apoptosis could be involved
in vivo. Fas is an apoptosis-signaling surface receptor known to
trigger programmed cell death in a variety of cell
types.5 6 Increased
plasma levels of soluble Fas receptors have been reported in patients
with heart
failure.4 7 The
reduction in the soluble Fas levels observed in this study suggests a
possible inhibition of apoptosis by pentoxifylline and may represent
another important mechanism of action of this drug that can have a
beneficial effect on the outcome of patients with heart
failure.
Conclusions
In patients with idiopathic dilated cardiomyopathy, the
addition of pentoxifylline to treatment with digoxin, ACE inhibitors,
and carvedilol is associated with a significant improvement in symptoms
and LV function.
Received August 10, 2000; revision received October 19, 2000; accepted November 11, 2000.
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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K. Sliwa, A. Woodiwiss, E. Libhaber, F. Zhanje, C. Libhaber, R. Motara, and R. Essop C-reactive protein predicts response to pentoxifylline in patients with idiopathic dilated cardiomyopathy Eur J Heart Fail, October 1, 2004; 6(6): 731 - 734. [Full Text] [PDF]
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J. Francis, Y. Chu, A. K. Johnson, R. M. Weiss, and R. B. Felder Acute myocardial infarction induces hypothalamic cytokine synthesis Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2264 - H2271. [Abstract] [Full Text] [PDF]
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P. Bahrmann, U. M. Hengst, B. M. Richartz, and H. R. Figulla Pentoxifylline in ischemic, hypertensive and idiopathic-dilated cardiomyopathy: effects on left-ventricular function, inflammatory cytokines and symptoms Eur J Heart Fail, March 1, 2004; 6(2): 195 - 201. [Abstract] [Full Text] [PDF]
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K. Sliwa, A. Woodiwiss, V. N. Kone, G. Candy, D. Badenhorst, G. Norton, C. Zambakides, F. Peters, and R. Essop Therapy of Ischemic Cardiomyopathy With the Immunomodulating Agent Pentoxifylline: Results of a Randomized Study Circulation, February 17, 2004; 109(6): 750 - 755. [Abstract] [Full Text] [PDF]
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J J V McMurray Heart failure in 10 years time: focus on pharmacological treatment Heart, October 1, 2002; 88(90002): ii40 - 46. [Full Text] [PDF]
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K. Sliwa, D. Skudicky, G. Candy, A. Bergemann, M. Hopley, and P. Sareli The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy Eur J Heart Fail, June 1, 2002; 4(3): 305 - 309. [Abstract] [Full Text] [PDF]
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J. McMurray and M. A. Pfeffer New Therapeutic Options in Congestive Heart Failure: Part II Circulation, May 7, 2002; 105(18): 2223 - 2228. [Full Text] [PDF]
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