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Oral sildenafil therapy improves health-related quality of life and functional status in pulmonary arterial hypertension
International Journal of Cardiology 119 (2007) 400 – 402 www.elsevier.com/locate/ijcard
Letter to the Editor
Oral sildenafil therapy improves health-related quality of life and functional status in pulmonary arterial hypertension Raymond Ching-Chiew Wong, Geok Mui Koh, Poh Hoon Choong, Wei Luen James Yip ⁎ Cardiac Department, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore Received 9 May 2006; accepted 22 July 2006 Available online 24 October 2006
Abstract Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase-5 inhibitor, has shown promising results as a novel oral monotherapy in the treatment of pulmonary arterial hypertension (PAH). We conducted a cross-sectional survey of 19 consecutive PAH patients, aged 16–75 years, with WHO functional class II or worse over 3 months of oral sildenafil. Improvement in exercise capacity was achieved in 15/19 (79%) patients. 6-minute walk test distance increased from 299 ± 118 m to 360 ± 127 m, p = 0.016, and WHO functional class decreased significantly. Both PASP and CI showed a non-significant trend toward improvement. Patients also reported significant improvement in physical ( p = 0.002) and social ( p b 0.001) functioning, and general health ( p = 0.01) of Rand SF-36 questionnaire. There was improvement in domains of role limitation due to physical health ( p = 0.16), emotion ( p = 0.14), and energy level ( p = 0.4). Our study suggests that oral sildenafil monotherapy is effective in improving exercise capacity and health-related quality of life amongst PAH patients. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Pulmonary arterial hypertension; Oral sildenafil; Health-related quality of life; Functional class
Pulmonary arterial hypertension (PAH) is a serious condition that results in progressive right heart failure and death [1–3]. Patients with this condition have markedly reduced exercise tolerance and poor quality of life [4]. A selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase-5 inhibitor, sildenafil, has shown promising results as a novel oral monotherapy in the treatment of PAH. We conducted this cross-sectional survey of HR-QoL in nineteen consecutive patients (aged 41 ± 16 years) with pulmonary arterial hypertension (PAH). Nine had idiopathic PAH, two had connective tissue disease, and eight had congenital heart disease with shunts. Patients' functional capacity and symptoms of dyspnoea were assessed using WHO functional class and BORG dyspnoea index. HR-QoL changes were assessed using self-administered Rand SF-36 questionnaires at scheduled appointments at baseline and 3 months of oral sildenafil. Scores for 8 domain of SF-36 ⁎ Corresponding author. Tel.: +65 67725211; fax: +65 68722998. E-mail address: [email protected] (W.L.J. Yip). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.07.170
were calculated according to published guidelines [5]. Pulmonary artery systolic pressure (PASP) and cardiac index (CI) at both timelines were obtained in accordance to previously described Doppler ultrasound methods [6,7]. Oral sildenafil was initiated up to maximum of 25 mg TID for patients weighing less than 40 kg and 50 mg TID for those weighing above 40 kg. The mean dosage of oral sildenafil at administered was 139 ± 32 mg per day. This study was approved by the local Institutional Review Board. Improvement in exercise capacity was achieved in 15/19 (79%) patients (Table 1). WHO functional class reduced from 3 ± 1 to 2 ± 1, p = 0.001; 6-minute walk test distance increased from 299 ± 118 m to 360 ± 127 m, p = 0.016, and BORG dyspnoea index decreased from 2.3 ± 3.0 to 1.2 ± 2.0, p = 0.052. Both PASP and CI showed a non significant trend toward improvement, (104 ± 26 mmHg to 100 ± 27mmHg, p = 0.4) and (2.7 ± 1.1 to 2.9 ± 0.9 L/min/M2, p = 0.29) respectively. Our PAH cohort had significantly depressed HR-QoL scores (Fig. 1). With oral sildenafil, they reported significant improvement in physical ( p = 0.002) and social ( p b 0.001)
R.C.-C. Wong et al. / International Journal of Cardiology 119 (2007) 400–402
401
Table 1 Changes in functional class, symptoms, exercise capacity and PASP after at least 3 months of follow-up
WHO functional class 6-minute walk test (meters) Borg score PASP (mmHg) Cardiac Index (L/min/M 2)
Baseline (mean ± SD)
3 months post-sildenafil (mean ± SD)
Change in parameter (mean ± SD)
p
3±1 287 ± 127 2.4 ± 2.9 101 ± 26 2.7 ± 1.1
2±1 345 ± 141 m 1.4 ± 2.2 98 ± 27 2.9 ± 0.9
− 0.5 ± 0.6 49 ± 96 −1 ± 2 −2 ± 15 0.2 ± 0.8
0.001 0.015 0.052 0.4 0.29
functioning, and general health ( p = 0.01). There was trend to improvement in role limitation due to physical health ( p = 0.16), emotion ( p = 0.14), and energy level ( p = 0.4). Six-minute walk test interval improvement was significantly correlated with physical functioning domain ( p = 0.04). There were no significant differences in domain improvement according to diagnosis of IPH versus congenital heart disease ( p values all N0.1, except domain of emotional change where p value = 0.52), and baseline WHO functional class II versus III ( p = 0.297). This is the first study that evaluates HR-QoL score in patients with PAH on sildenafil. Our study showed that 3 months of oral sildenafil monotherapy is effective in improving 6-minute walk test, symptom of dyspnoea and health-related quality of life scores in PAH patients. While combination therapy of intravenous prostacyclin or inhaled iloprost and oral sildenafil were reported to be beneficial [8–10], monotherapy of oral sildenafil in PAH patients was only recently reported to effect significant improvement in six-minute walk test in a randomized, placebocontrolled study. Galie et al. randomized 278 patients with symptomatic PAH to placebo or sildenafil orally for 12 weeks. There was an increase in 6-minute walk test
Fig. 1. Quality of life changes expressed in categories specified in Rand SF36 Questionnaire. Grey bars indicated scores at baseline, dark bars indicate scores after 3 months of oral sildenafil. ⁎ Indicates p values N 0.2.
distance (placebo-corrected) of 45 m, 46 m and 50 m for 20, 40, and 80 mg of sildenafil, respectively ( p b 0.001) and significantly improved the WHO functional class [11]. The benefit was maintained through the 6-month study period. Sastry et al. compared the efficacy of sildenafil with placebo in 22 patients with PAH in a randomized crossover design and reported significant increase of 44% in treadmill exercise time from 475+/−168 s at the end of placebo phase to 686+/ −224 s at the end of sildenafil phase ( p b 0.0001) [12]. Michelakis compared oral sildenafil to inhaled NO and reported comparable results in achieving pulmonary vasodilation and exercise capacity improvement [13]. Our study confirms preferential effects of sildenafil on PASP. Kothari and Duggal similarly reported clinical improvement in a subject with secondary PAH even when no decrease in pulmonary artery pressure was demonstrated [14]. Our cohort of PAH patients reported markedly depressed SF-36 scores across all domains. Taichman et al. similarly reported significantly impaired HR-QoL in physical, social and emotional characteristics based on SF-36 survey and respiratory-specific assessment tools [15]. Our subjects reported improvement in QOL post-oral sildenafil in 5 out of 8 domains of Rand SF-36, of which physical functioning, social functioning and general health categories reached statistical significance. Additionally, role limitation due to physical health and energy level showed strong trend toward improvement. Pain score predictably remained the same, as it was not a dominant symptom of PAH. Compared with population norms, participants in a study of 53 patients with PAH (53% received epoprostenol, and 72% reported moderate-to-severe functional limitations with a New York Heart Association class 3 or 4 at enrollment) reported moderate-to-severe impairment in multiple domains of HRQOL, including physical mobility, emotional reaction, pain, energy, sleep, and social isolation. They have substantial functional and emotional limitations that adversely affect their HRQOL [4]. In another study, by Taichman et al, HR-QoL was evaluated in a cross-sectional study of 155 outpatients with PAH (Class II and III WHO functional class) using generic and respiratory-disease specific measurement tools. Patients with PAH suffered severe impairments in both physical and emotional domains of HR-QoL. Greater sixminute walk distance correlated with better health-related quality of life scores, as did functional Class II versus Class III symptoms. We do not find significant SF-36 components difference between idiopathic PAH and congenital heart disease. One study reported scleroderma patients having
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R.C.-C. Wong et al. / International Journal of Cardiology 119 (2007) 400–402
worst HR-QoL scores, though the exact mechanism is unclear [15]. A larger prospective study with longer period of follow up is needed to determine long-term safety profile and the impact of oral sildenafil on survival. References [1] Brenot F. Primary pulmonary hypertension. Case series from France. Chest 1994;105:33S–6S. [2] Oakley CW. Primary pulmonary hypertension. Case series from the United Kingdom. Chest 1994;105:29S–32S. [3] D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–9. [4] Shafazand S, Goldstein MK, Doyle RL, Hlatky MA, Gould MK. Health-related quality of life in patients with pulmonary arterial hypertension. Chest 2004;126:1452–9. [5] Ware JE, Kosinski M. Interpreting SF-36 summary health measures: a response. Qual Life Res 2001;10:405–13 [discussion 415–20]. [6] Hatle L, Angelsen BA, Tromsdal A. Non-invasive estimation of pulmonary artery systolic pressure with Doppler ultrasound. Br Heart J 1981;45:157–65. [7] Zoghbi WA, Quinones MA. Determination of cardiac output by Doppler echocardiography: a critical appraisal. Herz 1986;11:258–68.
[8] Garcia Hernandez FJ, Ocana Medina C, Mateos Romero L, et al. Combined treatment with intravenous prostacyclin and sildenafil in patients with pulmonary hypertension: report of 4 cases. Med Clin (Barc) 2004;122:64–6. [9] Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001;104:1218–22. [10] Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515–22. [11] Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57. [12] Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004;43:1149–53. [13] Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105:2398–403. [14] Kothari SS, Duggal B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J 2002;54:404–9. [15] Taichman DB, Shin J, Hud L, et al. Health-related quality of life in patients with pulmonary arterial hypertension. Respir Res 2005;6:92.
Letter to the Editor
Oral sildenafil therapy improves health-related quality of life and functional status in pulmonary arterial hypertension Raymond Ching-Chiew Wong, Geok Mui Koh, Poh Hoon Choong, Wei Luen James Yip ⁎ Cardiac Department, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074, Singapore Received 9 May 2006; accepted 22 July 2006 Available online 24 October 2006
Abstract Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase-5 inhibitor, has shown promising results as a novel oral monotherapy in the treatment of pulmonary arterial hypertension (PAH). We conducted a cross-sectional survey of 19 consecutive PAH patients, aged 16–75 years, with WHO functional class II or worse over 3 months of oral sildenafil. Improvement in exercise capacity was achieved in 15/19 (79%) patients. 6-minute walk test distance increased from 299 ± 118 m to 360 ± 127 m, p = 0.016, and WHO functional class decreased significantly. Both PASP and CI showed a non-significant trend toward improvement. Patients also reported significant improvement in physical ( p = 0.002) and social ( p b 0.001) functioning, and general health ( p = 0.01) of Rand SF-36 questionnaire. There was improvement in domains of role limitation due to physical health ( p = 0.16), emotion ( p = 0.14), and energy level ( p = 0.4). Our study suggests that oral sildenafil monotherapy is effective in improving exercise capacity and health-related quality of life amongst PAH patients. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Pulmonary arterial hypertension; Oral sildenafil; Health-related quality of life; Functional class
Pulmonary arterial hypertension (PAH) is a serious condition that results in progressive right heart failure and death [1–3]. Patients with this condition have markedly reduced exercise tolerance and poor quality of life [4]. A selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase-5 inhibitor, sildenafil, has shown promising results as a novel oral monotherapy in the treatment of PAH. We conducted this cross-sectional survey of HR-QoL in nineteen consecutive patients (aged 41 ± 16 years) with pulmonary arterial hypertension (PAH). Nine had idiopathic PAH, two had connective tissue disease, and eight had congenital heart disease with shunts. Patients' functional capacity and symptoms of dyspnoea were assessed using WHO functional class and BORG dyspnoea index. HR-QoL changes were assessed using self-administered Rand SF-36 questionnaires at scheduled appointments at baseline and 3 months of oral sildenafil. Scores for 8 domain of SF-36 ⁎ Corresponding author. Tel.: +65 67725211; fax: +65 68722998. E-mail address: [email protected] (W.L.J. Yip). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.07.170
were calculated according to published guidelines [5]. Pulmonary artery systolic pressure (PASP) and cardiac index (CI) at both timelines were obtained in accordance to previously described Doppler ultrasound methods [6,7]. Oral sildenafil was initiated up to maximum of 25 mg TID for patients weighing less than 40 kg and 50 mg TID for those weighing above 40 kg. The mean dosage of oral sildenafil at administered was 139 ± 32 mg per day. This study was approved by the local Institutional Review Board. Improvement in exercise capacity was achieved in 15/19 (79%) patients (Table 1). WHO functional class reduced from 3 ± 1 to 2 ± 1, p = 0.001; 6-minute walk test distance increased from 299 ± 118 m to 360 ± 127 m, p = 0.016, and BORG dyspnoea index decreased from 2.3 ± 3.0 to 1.2 ± 2.0, p = 0.052. Both PASP and CI showed a non significant trend toward improvement, (104 ± 26 mmHg to 100 ± 27mmHg, p = 0.4) and (2.7 ± 1.1 to 2.9 ± 0.9 L/min/M2, p = 0.29) respectively. Our PAH cohort had significantly depressed HR-QoL scores (Fig. 1). With oral sildenafil, they reported significant improvement in physical ( p = 0.002) and social ( p b 0.001)
R.C.-C. Wong et al. / International Journal of Cardiology 119 (2007) 400–402
401
Table 1 Changes in functional class, symptoms, exercise capacity and PASP after at least 3 months of follow-up
WHO functional class 6-minute walk test (meters) Borg score PASP (mmHg) Cardiac Index (L/min/M 2)
Baseline (mean ± SD)
3 months post-sildenafil (mean ± SD)
Change in parameter (mean ± SD)
p
3±1 287 ± 127 2.4 ± 2.9 101 ± 26 2.7 ± 1.1
2±1 345 ± 141 m 1.4 ± 2.2 98 ± 27 2.9 ± 0.9
− 0.5 ± 0.6 49 ± 96 −1 ± 2 −2 ± 15 0.2 ± 0.8
0.001 0.015 0.052 0.4 0.29
functioning, and general health ( p = 0.01). There was trend to improvement in role limitation due to physical health ( p = 0.16), emotion ( p = 0.14), and energy level ( p = 0.4). Six-minute walk test interval improvement was significantly correlated with physical functioning domain ( p = 0.04). There were no significant differences in domain improvement according to diagnosis of IPH versus congenital heart disease ( p values all N0.1, except domain of emotional change where p value = 0.52), and baseline WHO functional class II versus III ( p = 0.297). This is the first study that evaluates HR-QoL score in patients with PAH on sildenafil. Our study showed that 3 months of oral sildenafil monotherapy is effective in improving 6-minute walk test, symptom of dyspnoea and health-related quality of life scores in PAH patients. While combination therapy of intravenous prostacyclin or inhaled iloprost and oral sildenafil were reported to be beneficial [8–10], monotherapy of oral sildenafil in PAH patients was only recently reported to effect significant improvement in six-minute walk test in a randomized, placebocontrolled study. Galie et al. randomized 278 patients with symptomatic PAH to placebo or sildenafil orally for 12 weeks. There was an increase in 6-minute walk test
Fig. 1. Quality of life changes expressed in categories specified in Rand SF36 Questionnaire. Grey bars indicated scores at baseline, dark bars indicate scores after 3 months of oral sildenafil. ⁎ Indicates p values N 0.2.
distance (placebo-corrected) of 45 m, 46 m and 50 m for 20, 40, and 80 mg of sildenafil, respectively ( p b 0.001) and significantly improved the WHO functional class [11]. The benefit was maintained through the 6-month study period. Sastry et al. compared the efficacy of sildenafil with placebo in 22 patients with PAH in a randomized crossover design and reported significant increase of 44% in treadmill exercise time from 475+/−168 s at the end of placebo phase to 686+/ −224 s at the end of sildenafil phase ( p b 0.0001) [12]. Michelakis compared oral sildenafil to inhaled NO and reported comparable results in achieving pulmonary vasodilation and exercise capacity improvement [13]. Our study confirms preferential effects of sildenafil on PASP. Kothari and Duggal similarly reported clinical improvement in a subject with secondary PAH even when no decrease in pulmonary artery pressure was demonstrated [14]. Our cohort of PAH patients reported markedly depressed SF-36 scores across all domains. Taichman et al. similarly reported significantly impaired HR-QoL in physical, social and emotional characteristics based on SF-36 survey and respiratory-specific assessment tools [15]. Our subjects reported improvement in QOL post-oral sildenafil in 5 out of 8 domains of Rand SF-36, of which physical functioning, social functioning and general health categories reached statistical significance. Additionally, role limitation due to physical health and energy level showed strong trend toward improvement. Pain score predictably remained the same, as it was not a dominant symptom of PAH. Compared with population norms, participants in a study of 53 patients with PAH (53% received epoprostenol, and 72% reported moderate-to-severe functional limitations with a New York Heart Association class 3 or 4 at enrollment) reported moderate-to-severe impairment in multiple domains of HRQOL, including physical mobility, emotional reaction, pain, energy, sleep, and social isolation. They have substantial functional and emotional limitations that adversely affect their HRQOL [4]. In another study, by Taichman et al, HR-QoL was evaluated in a cross-sectional study of 155 outpatients with PAH (Class II and III WHO functional class) using generic and respiratory-disease specific measurement tools. Patients with PAH suffered severe impairments in both physical and emotional domains of HR-QoL. Greater sixminute walk distance correlated with better health-related quality of life scores, as did functional Class II versus Class III symptoms. We do not find significant SF-36 components difference between idiopathic PAH and congenital heart disease. One study reported scleroderma patients having
402
R.C.-C. Wong et al. / International Journal of Cardiology 119 (2007) 400–402
worst HR-QoL scores, though the exact mechanism is unclear [15]. A larger prospective study with longer period of follow up is needed to determine long-term safety profile and the impact of oral sildenafil on survival. References [1] Brenot F. Primary pulmonary hypertension. Case series from France. Chest 1994;105:33S–6S. [2] Oakley CW. Primary pulmonary hypertension. Case series from the United Kingdom. Chest 1994;105:29S–32S. [3] D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–9. [4] Shafazand S, Goldstein MK, Doyle RL, Hlatky MA, Gould MK. Health-related quality of life in patients with pulmonary arterial hypertension. Chest 2004;126:1452–9. [5] Ware JE, Kosinski M. Interpreting SF-36 summary health measures: a response. Qual Life Res 2001;10:405–13 [discussion 415–20]. [6] Hatle L, Angelsen BA, Tromsdal A. Non-invasive estimation of pulmonary artery systolic pressure with Doppler ultrasound. Br Heart J 1981;45:157–65. [7] Zoghbi WA, Quinones MA. Determination of cardiac output by Doppler echocardiography: a critical appraisal. Herz 1986;11:258–68.
[8] Garcia Hernandez FJ, Ocana Medina C, Mateos Romero L, et al. Combined treatment with intravenous prostacyclin and sildenafil in patients with pulmonary hypertension: report of 4 cases. Med Clin (Barc) 2004;122:64–6. [9] Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001;104:1218–22. [10] Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515–22. [11] Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57. [12] Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004;43:1149–53. [13] Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105:2398–403. [14] Kothari SS, Duggal B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J 2002;54:404–9. [15] Taichman DB, Shin J, Hud L, et al. Health-related quality of life in patients with pulmonary arterial hypertension. Respir Res 2005;6:92.