Comparison of the Therapeutic and Side Effects of Tadalafil and Sildenafil in Children and Adolescents with Pulmonary Arterial Hypertension

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1 DOI /s z ORIGINAL ARTICLE Comparison of the Therapeutic and Side Effects of Tadalafil and Sildenafil in Children and Adolescents with Pulmonary Arterial Hypertension Mohammad Reza Sabri Elham Beheshtian Received: 15 August 2013 / Accepted: 6 November 2013 Ó Springer Science+Business Media New York 2013 Abstract Pulmonary arterial hypertension (PAH) is a progressive disease. In recent years, phosphodiesterase type 5 inhibitors such as sildenafil have been used to treat this disease in children. Recently, tadalafil has been used in adults with similar efficacy but it has been used less often in children. This experimental study was carried out in 18 known patients aged 4 24 years in the Emam Hossein Hospital of Isfahan, Iran. All patients had been taking sildenafil for a few months to years. Patients underwent echocardiographic study, the 6-minute walk test (6MWT), and non-invasive pulse oximetry before and after the 6MWT. These tests were repeated again after sildenafil had been switched to tadalafil for 6 weeks. After 6 weeks of tadalafil prescription, the severity of some of the patients symptoms decreased, but the New York Heart Association class of the patients did not change more. Mean ± standard deviation (SD) oxygen saturation while taking sildenafil and after 6 weeks of tadalafil were significantly different (p = 0.005). Furthermore, mean ± SD oxygen saturation after the 6MWT while taking sildenafil and after 6 weeks of tadalafil were significantly different (p = 0.036). The mean ± SD distances walked in this test while taking sildenafil and tadalafil were significantly different (p = 0.005). No significant side effects were seen; 15 patients continued tadalafil. Tadalafil may be a safe drug to treat children and young adults with PAH. We did not M. R. Sabri Department of Pediatrics, and Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran E. Beheshtian (&) School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran elham_b986@yahoo.com observe any significant side effects during usage; it improves functional capacity and oxygen saturation better than sildenafil in these patients, and requires fewer daily doses than sildenafil. Keywords Pulmonary arterial hypertension Sildenafil Tadalafil 6-minute walk test Introduction Pulmonary arterial hypertension (PAH) is a progressive disease with high mortality and morbidity. Increased pulmonary vascular resistance (PVR) leads to right sided heart dilatation and failure, low cardiac output, and death [10, 15]. Its clinical features are dyspnea, easy fatigability, weakness, peripheral edema, ascites, angina, and syncope [12]. In recent decades, prostacyclin agonists, endothelin receptor antagonists, and phosphodiesterase type 5 (PDE5) inhibitors have been used to treat PAH [5, 13, 21]. Etiologic factors, signs and symptoms, and response to treatment varies between children and adults and there are fewer studies in children than in adults with respect to treatment options [8, 14, 19]. However, children with severe PAH are treated as adults. In adults, increased functional capacity, improved quality of life, and improved survival are achieved with the above-mentioned treatment [9, 22]. Among the PDE5 inhibitors, sildenafil has been used in children and adults, and recently tadalafil has been used in adults, with similar efficacy. Sildenafil was used to treat erectile dysfunction and, in 2005, was approved by the US FDA for use in children with PAH [3, 4, 18]. However, the FDA recently warned against prescribing high doses of

2 sildenafil in children with PAH, yet the European Medicines Agency recommends its use in children [17, 20]. Materials and Methods This experimental study was carried out in the Emam Hossein hospital of Isfahan, Iran, in 2012 and The ethics committee of Isfahan University of Medical Sciences approved this study. The participants were 18 patients aged 4 24 years, with a definite diagnosis of PAH. PAH was defined as an increased mean pulmonary arterial pressure [25 mmhg at rest or [30 mmhg during exercise [18]. Owing to late diagnosis of the disease, most participants were not operable. Patient files were reviewed for demographic data, cause of PAH, disease duration, drugs taken, and duration of taking the drugs. All patients were taking sildenafil before entering the study. Thus, ethically, it was impossible to cease administration of this drug. Patients were evaluated once, when they were taking sildenafil, and once after switching to tadalafil (Phama Chemie Co. LTD, Tehran, Iran) with no overlap period (they started receiving tadalafil the day after they stopped receiving sildenafil). Most patients also received captopril (66.6 %) and aspirin (55.5 %). Two patients had ceased taking aspirin 1 year ago because of epistaxis. Of the patients, 33.3 % were receiving digoxin and one patient was receiving warfarin. The inclusion criteria for the study were as follows: definite diagnosis of PAH, aged[4 years, willingness of patients and their parents to participate in the study, and no other diseases. The exclusion criteria were as follows: intolerance of, or hypersensitivity to, tadalafil; development of severe adverse effects that made the continuation of tadalafil impossible; and unwillingness of the patient or their family to continue the study. Patients were telephoned and asked to meet the researcher if they were willing to participate in the study. During the medical visit, patients were asked about the drugs and the dosage they took. They were also categorized according to New York Heart Association (NYHA) classification. The objectives of the study were explained to patients and their families. They then signed an informed written consent. Before prescription of tadalafil (at 1 mg/ kg/day and a maximum dose of 40 mg/day), patients underwent an echocardiographic study by a pediatric cardiologist, and were evaluated for right ventricular size and function. Moreover, pulmonary artery pressure was estimated according to the tricuspid regurgitation (TR) gradient, and PVR was estimated based upon TR velocity (TRV) and velocity time interval (VTI) of the right ventricular outflow tract (RVOT) to the formula [PVR (Woods unit) = TRV/VTI of RVOT 9 10? 0.16]. The 6-minute walk test (6MWT) was carried out in a relaxed atmosphere with a moderate temperature of 22 C in one of the roofed and unobstructed corridors of the Emam Hossein Hospital, which was 40 m long and had interval markings every 1 m. Before performing the 6MWT, the test was explained to the patient and the family, and a non-invasive pulse oximetry was conducted for the patient. Patients were then asked to walk back and forth along the walkway as far as possible at their own pace for 6 min. The time was recorded with a chronometer. Three chairs were provided along the walkway to be used by the patient if needed. However, none of the patients needed to use the chair and stop the test. After 6 min, the patients were asked to stop walking, and the pulse oximetry test was repeated. The distance walked was recorded by one of the researchers. The day after sildenafil was discontinued, tadalafil was initiated at the specified doses for the patients. Other drugs taken by the patients were continued at the previous doses. The families were asked to call the researchers and report any observed adverse effects. Patients were asked to return to the hospital 6 weeks after administration of tadalafil. During the return visit, the functional performance of participants according to NYHA classification, experience of probable adverse effects, and their personal satisfaction with tadalafil were evaluated. Patients also underwent an echocardiography and repeated the 6MWT, undergoing pulse oximetry before and after that. The data collected were analyzed using SPSS, version 20. Analysis of quantitative data and comparison with the ratios were done using the t test, and frequency of distribution between the two groups was compared using the v 2 test. p values \ 0.05 were considered statistically significant. Results A total of 21 patients participated in the study, three of whom were omitted from the study as they did not return for the second visit. In total, 18 patients with PAH continued to the end of the investigation, two of whom had Down syndrome. The mean age of the participants was 14.4 ± 6.4 years; 13 (72.2 %) were aged\18 years. Seven participants were male. The mean ages of the male and female patients were 16.4 ± 4.3 and 13 ± 7.3 years, respectively. According to the results obtained by the t-test, the mean age of male and female patients was not significantly different (p = 0.29). Mean body mass index (BMI) was 15.9 ± 1.65 kg/m 2. In terms of NYHA classification, seven, seven, and four patients were in class I, II, and III, respectively. Table 1 shows the frequency of the underlying causes of PAH in the study group. Figure 1 presents the frequency of the major complaints of patients. Among the physical examination findings, systolic murmur with variable intensity and loud P2 with a

3 Table 1 Frequency of the underlying cause of pulmonary arterial hypertension in the study group Diseases N (%) VSD?PH 3 (16.7) VSD?PDA?PH 1 (5.6) AVSD?PH 2 (11) SP AVSD 1 (5.6) SP VSD 2 (11) PA?VSD?MAPCA?PH 3 (16.7) DORV?VSD?PH 1 (5.6) DORV?multiple VSD?PH 1 (5.6) SV?MGA?PH 2 (11) Ebstein anomaly?vsd?ph 1 (5.6) PH secondary to radiotherapy 1 (5.6) Total 18 (100) AVSD atrioventricular septal defect, DORV double outlet right ventricle, MAPCA major aortopulmonary collateral artery, MGA malposition of the great arteries, PA pulmonary atresia, PDA patent ductus arteriosus, PH pulmonary hypertension, SP status postoperative, SV single ventricle, VSD ventricular septal defect Fig. 1 Frequency of patients major complaints prevalence of 88.8 and 83.3 % were the most frequent findings, respectively. The prevalence rates of other common findings, RV tap, cyanosis and clubbing, and hepatomegaly, were 55.5, 11.1, and 5.5 %, respectively. A permanent pacemaker had been implanted in one patient 2 years before the study. Among the echocardiographic findings, all patients (except the one with a pacemaker) had normal sinus rhythm. The changes observed in echocardiographic results were right axis deviation (RAD) of the QRS (64.6 %), right ventricular hypertrophy (RVH) (72.2 %), right atrial hypertrophy (RAH) (16.6 %), and left atrial hypertrophy (LAH) (5.5 %). The mean ± standard deviation (SD) dose of sildenafil was 54.5 ± 29.3 mg/day (lowest 20 mg/day, highest 100 mg/day). On average, patients had received sildenafil for 4.5 years. The mean ± SD dose of tadalafil was 31.6 ± 10.3 mg/day (lowest 15 mg/day, highest 40 mg/ day). With respect to drug-induced adverse effects and considering that the study patients had no overlap between taking sildenafil and then tadalafil, seven patients experienced adverse effects while they were on sildenafil and 11 patients had no significant problems. Three patients experienced side effects with both sildenafil and tadalafil, while five patients did not experience any side effects on either drug. Six patients showed side effects with tadalafil but did not have any with sildenafil. According to the results obtained from the McNemar test, the frequency of occurrence of adverse effects following administration of sildenafil and tadalafil was not significantly different (p = 0.75). The frequency of adverse effects observed following taking sildenafil and tadalafil is shown in Fig. 2. During the study, one patient was excluded because of dyspnea, cough, and cyanosis after 4 weeks of taking tadalafil. When the symptoms occurred, the patient had the symptoms of a common cold and coryza. This patient was excluded from the study by parental request and was again treated with sildenafil. The symptoms improved gradually when the common cold was resolved. After starting tadalafil, orthopnea decreased in all four patients who had this symptom. Furthermore, some of the other complaints decreased in severity: cyanosis in five patients, palpitation in four patients, chest pain in three patients, and exercise-induced fatigue in nine patients. After 6 weeks of treatment with tadalafil, seven, nine, and two patients were in NYHA class I, II, and III, respectively. Although NYHA class changed in two patients from class III to II, it was not statistically significant. Percentage of blood oxygen saturation was determined by non-invasive pulse oximetry. While the patients were on sildenafil, the values obtained were ± 9.19 and ± 9.34 % before and after the 6MWT, respectively. According to the paired t-test results, the values were not significantly different. The results obtained after 6 weeks administration of tadalafil before and after the 6MWT were 93.2 ± 6.6 and 92.6 ± 7.1 %, respectively; they were not significantly different (p = 0.18). The mean ± SD oxygen saturation while taking sildenafil and after 6 weeks of tadalafil and before the 6MWT were ± 9.7 and ± 6.6, respectively. It was a statistically significant difference, according to the results of the paired t-test (p = 0.005). The mean ± SD of oxygen saturation after the 6MWT while taking sildenafil and after 6 weeks of tadalafil were 90.5 ± 9.8 and 92.6 ± 7.1, respectively, which were statistically significant differences with regard to the paired t-test results (p = 0.036). Mean (confidence interval) oxygen saturation before and after the 6MWT for the two drugs is demonstrated in Fig. 3.

4 Fig. 2 Frequency and type of adverse effects observed following administration of sildenafil and tadalafil in the study group Fig. 3 Mean and confidence interval of oxygen saturation before and after 6MWT. CI confidence interval, 6MWT 6-minute walk test Fig. 4 Median, range, and 25th and 75th percentile of the distance passed with regard to the drug used (Y axis is in meter) The mean ± SD distances walked in the 6MWT while taking sildenafil and tadalafil were ± 89.4 and ± 77 meters, respectively. The values were significantly different according to the paired t-test results (p = 0.005). The distribution of the distances walked is shown in Fig. 4. We compared the distance walked in the 6MWT before and after tadalafil in patients who were aged B18 years or [18 years. It should be noted that the mean ± SD difference in the distances walked in the 6MWT after tadalafil for the two age groups were ± 10.9 and 13 ± 13.8 meters, respectively. In both age groups, patients walked further after tadalafil administration, and, although it was more in the younger age group, according to the results obtained from the analysis of variance, the two age groups were not significantly different in this respect (p = 0.23). Although the echocardiographic indices measured were in agreement on the PAH findings, precise analysis of the findings was impossible owing to the heterogeneity and the wide range of underlying cardiac problems. Of the 18 patients studied, 15 were willing to continue tadalafil owing to an improvement in their symptoms, increased functional capacity, and less frequent administration (once a day). Two patients did not continue tadalafil because of its higher daily costs compared with sildenafil (almost 2.5 times higher in our country). It should be noted that the higher cost was a major concern for most of the parents. One patient returned to sildenafil as her parents believed that her cyanosis was aggravated. For this patient, no significant change was observed in the results of the 6MWT and oxygen saturation tests, or echocardiographic findings before and after switching the drug. An incidental finding was that two patients observed a change in menstrual cycle: one had menstrual irregularity and one had a more regular menstrual cycle after tadalafil administration.

5 Discussion The main objective of the study was to compare the therapeutic and adverse effects of tadalafil and sildenafil in children, adolescents, and young adults with PAH. According to the results obtained, the echocardiographic changes while taking the two drugs were not significantly different. In the study by Garg et al. [11], who investigated the therapeutic effect of sildenafil on patients with PAH, the drug led to improvement in the patients symptoms and echocardiographic indices, including the PVR/systemic vascular resistance (SVR) ratio and cardiac index, the distance walked in the 6MWT, and NYHA class [11]. In the current study, all patients were treated with sildenafil before the beginning of the study, and this drug could not be stopped. We changed it to tadalafil and after 6 weeks, although no statistically significant changes were observed in NYHA class, decreases in chest pain, cyanosis, and exercise-induced fatigue were observed. In the current study, the mean ± SD distance walked in the 6MWT after taking tadalafil increased significantly, and was consistent with results obtained for adults in previous studies [1, 2, 11]. While taking tadalafil, oxygen saturation significantly increased before and after 6MWT compared with while taking sildenafil. Since this was not investigated in previous studies, it might be concluded that tadalafil, in comparison with sildenafil, may increase pulmonary blood flow and systemic oxygenation more. The frequency of development of adverse effects after taking sildenafil and tadalafil did not significantly differ, which is consistent with results reported in previous studies [14, 16]. Most adverse effects were spontaneously resolved within 2 3 days after taking tadalafil, including pain in extremities and headache. However, none of the adverse effects led to discontinuation of tadalafil except for one patient who quit the study after a common cold. An incidental finding was that two patients observed a change in menstrual cycle. Previous studies have proposed a relationship between the nitric oxide pathway and pulmonary circulation. Moreover, nitric oxide affects the endometrium. These details and also the mechanism of action of the drug can justify the finding [6, 7]. In the study performed by Takatsuki et al. [16] the incidence rate of adverse effects while taking sildenafil or tadalafil was not significant. Results obtained in our study indicate that parents and patients were satisfied with the effect of tadalafil in terms of improvement of symptoms, results of 6MWT and pulse oximetry, absence of significant adverse effects, and once-daily administration of tadalafil (vs. sildenafil three to four times daily). Therefore, it can be concluded that tadalafil can be considered an alternative to sildenafil in some cases without a large change in side-effect profile, with similar efficacy. Acknowledgments The Isfahan University of Medical Sciences financially supported this study. We thank the University authorities who offered critical administrative support and managerial services in carrying out the study, and also all the researchers for their help and support. Conflict of interest interest. All authors state that they have no conflicts of Ethical Standards The authors assert that all procedures contributing to this work complied with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committees of Isfahan University of Medical Sciences. References 1. Affuso F, Palmieri EA, Di Conza P et al (2006) Tadalafil improves quality of life and exercise tolerance in idiopathic pulmonary arterial hypertension. 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