European Journal of Heart Failure

European Journal of Heart Failure 2002 4(3):305-309; doi:10.1016/S1388-9842(02)00008-9

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© 2002 European Society of Cardiology

The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy

Karen Sliwa^*, Daniel Skudicky, Geoffrey Candy, Anette Bergemann, Mark Hopley and Pinhas Sareli

Department of Cardiology, Baragwanath Hospital University of the Witwatersrand, PO Bertsham 2013, Johannesburg, South Africa

^* Corresponding author. Tel.: +27-11-933-8197; fax: +27-11-938-8945. E-mail address: hahnle{at}netactive.co.za

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Acknowledgments References

 
We have reported previously that despite treatment with angiotensin-converting enzyme inhibitors and β blockers, the outcome of patients with peripartum cardiomyopathy (PPC) remains unfavorable. Similar to other etiologies of left ventricular dysfunction, we found elevated levels of tumor necrosis factor- (TNF-) in this group of patients. In the present study we sought to evaluate the effects of pentoxifylline, a drug known to inhibit the production of TNF-, on clinical status, left ventricular function, and circulating plasma levels of TNF-, in patients with PPC. We followed prospectively 59 consecutive women with PPC. The first 29 patients (group 1) were treated with diuretics, digoxin, enalapril and carvedilol. The next 30 consecutive patients (group 2) received pentoxifylline 400 mg TID in addition to the previous therapy. Clinical evaluation, echocardiograms and TNF- determinations were performed at baseline and after 6 months of treatment. Patients in the pentoxifylline group were older and had a higher E/A ratio. Nine patients died (eight in group 1, P=0.009 between groups). A combined end-point of poor outcome defined as either death, failure to improve the left ventricular ejection fraction >10 absolute points or functional class III or IV at latest follow-up, occurred in 52% of patients in group 1 and 27% of patients in group 2 (P=0.03). Treatment with pentoxifylline (P=0.04) was the only independent predictor of outcome. In conclusion, the results of this study suggest that the addition of pentoxifylline to conventional treatment, improves outcome in patients with peripartum cardiomyopathy.

Key Words: Cardiomyopathy • Cytokines • Heart failure

Received June 29, 2001; Revised August 3, 2001; Accepted October 23, 2001

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Acknowledgments References

 
Peripartum cardiomyopathy (PPC) is a disorder of unknown etiology in which left ventricular dysfunction and symptoms of heart failure occur between the last trimester of pregnancy and up to the first 6 months postpartum. A high mortality rate and overall poor clinical outcome has been reported in a high percentage of these patients [1–4]. We have reported previously the clinical outcome of patients with PPC receiving current optimal treatment for heart failure, including diuretics, digoxin, angiotensin-converting enzyme inhibitors and carvedilol [4]. Despite this treatment, mortality at 6 months remained very high (28%).

Treatment with pentoxifylline, a xanthine derived agent known to inhibit the production of tumor necrosis factor- (TNF-), has been shown to improve functional class and left ventricular function in patients with idiopathic dilated cardiomyopathy [5,6]. However, whether similar results can be achieved in patients with other etiologies of left ventricular dysfunction remains to be established. Therefore, we designed the present study to evaluate the effects of pentoxifylline, on clinical status, left ventricular function, and circulating plasma levels of TNF-, in patients with PPC.

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Acknowledgments References

 
2.1. 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. The investigation conforms with the principles outlined in the Declaration of Helsinki. We enrolled prospectively 59 consecutive black patients with newly diagnosed PPC attending Baragwanath Hospital cardiac clinic. This study population fulfilled the following inclusion criteria: (1) age >16 years; (2) New York Heart Association functional class II–IV; (3) symptoms of congestive heart failure that developed in the last trimester of pregnancy or in the first 6 months postpartum; (4) no other identifiable cause of heart failure; (5) left ventricular ejection fraction <40% by transthoracic echocardiography; (6) sinus rhythm; and (7) eligible patients in whom high quality echocardiographic images could be obtained. Exclusion criteria were: (1) chronic obstructive pulmonary disease; (2) significant organic valvular heart disease; (3) systolic blood pressure >170 mmHg and/or diastolic blood pressure >105 mmHg; (4) clinical conditions other than cardiomyopathy that could increase the cytokine levels, (i.e. rheumatoid arthritis, sepsis, acquired immuno-deficiency syndrome; (7) significant liver disease (defined as enzymes >two times the upper limit of normal); and (8) severe anemia (hemoglobin concentration <9.0 g/dl).

The first 29 patients (group 1) were treated with conventional therapy including diuretics, digoxin, enalapril and carvedilol. The 6-month outcome of these patients has been reported previously [4]. The following 30 consecutive patients that were entered into the study, received pentoxifylline 400 mg TID for 6 months in addition to conventional therapy (group 2). One month after enrolment the dose of drugs were evaluated. The dose of enalapril and carvedilol remained unchanged until the end of the trial. All patients were entered into the trial at first presentation to the hospital. Patients attended the cardiac clinic for clinical evaluation at least once a month. The same physicians were in charge of the evaluation and treatment of the 59 patients. Echocardiograms and TNF- determinations were performed at baseline and after 6 months of treatment (Fig. 1).

View larger version (17K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Flow diagram.

 
2.2. TNF- plasma levels
Fifteen ml of blood were withdrawn from an antecubital vein and collected into prechilled evacuated tubes containing ethylenediaminetetraacetic acid. Plasma was separated by centrifugation at 2500 rpm for 12 min within 15 min of collection and aliquots frozen at –70 °C. TNF- measurements were performed using a commercially available enzyme-linked immunoassay (Amersham, Maidstone). The average of triplicate undiluted determinations was calculated.

2.3. Echocardiographic studies
Two-dimensional targeted M-mode echocardiography with Doppler color flow mapping was performed using a Hewlett Packard Sonos 5500 echocardiograph attached to a 2.5 or 3.5 Mhz transducer. All studies were recorded on videotape and were done by the same operator. Left ventricular dimensions were measured according to the American Society of Echocardiography guidelines [7]. For left ventricular measurements the average of >3 beats was obtained. The Left ventricular ejection fraction was determined as previously described [8]. None of the patients had paradoxical septal motion (no patient had left bundle branch block). Diastolic mitral flow was assessed by pulsed-wave Doppler echocardiography from the apical four-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.

2.4. Analysis of outcome
A pre-specified combined end-point of poor outcome was defined as either death, functional class III or IV at latest follow-up class, or failure to improve left ventricular ejection fraction by 10 absolute units.

2.5. Statistical analysis
Data are presented as mean±standard deviation. Group comparisons were made by use of Mann–Whitney U test or binomial test as appropriate. Wilcoxon matched pairs test was used for comparison of baseline data and the results after 6 months. Multivariate analysis of baseline characteristics was done using logistic regression analysis to establish predictors of outcome. Data were analyzed on a personal computer by use of a commercially available statistical program (Statistica). Significance was assumed at a two-tailed value of P<0.05.

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Acknowledgments References

 
Baseline characteristics of the study population are shown in Table 1. Patients treated with pentoxifylline were older and had a higher E/A ratio. There were no other significant baseline differences between the two groups. Only one patient had twin pregnancy. All patients started with symptoms in the postpartum period. There were eight deaths in the first group and only one death among patients treated with pentoxifylline (P=0.009 between groups). Four patients were lost to follow-up (two in each group), and two patients in the first group relocated to remote areas and did not complete the study. One month after inclusion into the trial all patients received digoxin 0.25 mg daily, enalapril 20 mg BID and carvedilol. Mean dose of Carvedilol was 27±8 mg daily in group 1 and 26±12 mg daily in the pentoxifylline group (P=NS). The mean daily dose of furosemide was also similar (156±27 mg vs. 153±18 mg for groups 1 and 2, respectively, P=NS).

View this table: [in this window] [in a new window]   Table 1 Baseline characteristics of patients treated without (group 1) or with pentoxifylline (group 2)

 
3.1. Functional class and left ventricular function
The functional class was considered to improve, if the patient increased the functional status by at least 1 grade of the New York Heart Association classification. It was considered to deteriorate, if the patient decreased the functional class by at least 1 grade or died. In group 1, 60% of patients improved the functional class, and in 40% it remained unchanged or deteriorated. In patients treated with pentoxifylline, functional class improved in 93% and remained unchanged or deteriorated in 7% (P=0.006 between groups). Patients in group 1 that survived and completed the 6 months follow up (n=17), showed a non-significant reduction in left ventricular end-diastolic (61±9 to 54±9 mm, P=0.26) and end-systolic diameter (53±9 to 43±11 mm, P=0.54), with a significant improvement in left ventricular ejection fraction (27±10% to 43±16%, P=0.00003). In the pentoxifylline group, 27 patients completed the follow up period. In this group there was a significant reduction in left ventricular end-diastolic (63±6 to 58±8 mm, P=0.0005) and end-systolic diameter (56±6 to 45±10 mm, P<0.000001) resulting in an increment in ejection fraction from 23±7 to 44±13%, P<0.000001.

3.2. Analysis of outcome
Composite end-point of poor outcome (either death, functional class III or IV at latest follow-up class, and or failure to improve left ventricular ejection fraction by 10 absolute units) occurred in 15 patients (52%) in group 1, and in eight patients (27%) in group 2 (P=0.03 between groups). From all baseline characteristics analyzed, treatment with pentoxifylline (P=0.04) was the only independent predictor of outcome using logistic regression analysis.

3.3. TNF- plasma levels
Baseline plasma levels of TNF- were not different between groups (6.3±4.7 pg/ml (n=29) vs. 4.4+3.3 pg/ml (n=30), P=0.08). There was a significant reduction in TNF- concentration in the 27 patients treated with pentoxifylline that completed the study (from 4.5±3.5 to 3.0±1.1 pg/ml, P=0.03), with a non-significant decline in the 17 patients in group 1 that finished the trial (6.9±4.7 to 4.6±4.4 pg/ml, P=0.13).

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Acknowledgments References

 
Treatment with angiotensin-converting enzyme inhibitors and β blockers have significantly improved the outcome of patients with heart failure due to left ventricular systolic dysfunction. However, despite the addition of these drugs, the outcome of patients with PPC remains unfavorable. We have documented previously a mortality rate of 28% after 6 months of treatment with diuretics, digoxin, enalapril and carvedilol [4] in patients with PPC. Similar to other etiologies of left ventricular dysfunction, we found elevated levels of TNF- in these patients. Therefore, and based on our previous observation that pentoxifylline improves functional class and left ventricular performance in patients with idiopathic dilated cardiomyopathy [5,6], we decided to evaluate whether the addition of pentoxifylline to conventional treatment for heart failure would improve outcome in patients with PPC. Due to the fact that PPC is a relatively uncommon entity, and the consequent difficulties in recruiting an adequate number of patients to conduct a randomized trial, we decided to treat the next 30 consecutive patients with PPC that presented to our clinic and fulfilled the inclusion-exclusion criteria with pentoxifylline and compared the results with the first 29 patients. Pentoxifylline has been shown to suppress or reduce the production of TNF- [9–11]. It was also found to inhibit apoptosis in different human cell types in vitro and in vivo [12,13]. In this registry of consecutive patients diagnosed with PPC, we observed a lower mortality rate and better functional class in patients treated with pentoxifylline in addition to conventional therapy. Both groups of patients showed a significant improvement in ejection fraction. However, only patients treated with pentoxifylline had a concomitant significant reduction of the left ventricular diameters. Furthermore, due to the high mortality rate, only 17 patients treated with conventional therapy completed the study and therefore had a second echocardiogram to evaluate changes in left ventricular diameters and function from baseline. Another interesting finding in this study was a non-significant reduction in TNF- levels among the 17 patients in group 1 that completed the trial. Therapy with β blockers has been previously shown to reduce the levels of circulating cytokines. Ontsuka et al. [14] showed a significant decline in the TNF- plasma levels following 12 weeks of treatment with metoprolol or bisoprolol in patients with dilated cardiomyopathy. Moreover, Prabhu et al. [15] showed a significant decline in the myocardial expression and protein production of TNF- with metoprolol. Therefore, it is possible that treatment with carvedilol resulted in a decrease in TNF- levels in the group of patients not treated with pentoxifylline.

In conclusion, the results of this non-randomized study suggest that treatment with pentoxifylline improves outcome of patients with PPC. These results must be confirmed in a randomized trial.

4.1. Potential study limitations
The study included consecutive patients but was not randomized. Thus, one cannot exclude an unintended selection bias in the patients. Therefore erroneous conclusions may be drawn when comparing one population group to another. The patients with peri-partum cardiomyopathy have poor prognosis [4] and are referred infrequently to our clinic. Given the favorable outcome in patients with idiopathic dilated cardiomyopathy treated with pentoxifylline [5,6], we treated the consecutive peri-partum patients with pentoxifylline. The baseline characteristics were similar between groups. Moreover, the only two different parameters at baseline (older age and worse diastolic function in the pentoxifylline group) should have adversely affected the outcome of these patients. A larger prospective randomized trial is required to confirm these results.

	Acknowledgments

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Acknowledgments References

 
This study was partially funded by the Helen Griffin Trust and Iris and Ellen Hodges Trust, University of the Witwatersrand, Johannesburg.

	References

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Acknowledgments References

 

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