Is Chronic Sildenafil Therapy Safe and Clinically Beneficial in Patients With Systolic Heart Failure?

ORIGINAL PAPER Is Chronic Sildenafil Therapy Safe and Clinically Beneficial in Patients With Systolic Heart Failure? Ahmad Amin, MD; 1 Ebrahim Mahmoudi, MD; 2 Hossein Navid, MD; 2 Mitra Chitsazan, MD 3 From the Department of Heart Failure and Transplantation, Rajaei Cardiovascular, Medical and Research Center, Tehran University of Medical Sciences; 1 the Rajaei Cardiovascular, Medical and Research Center, Tehran University of Medical Sciences; 2 and the Medical Students Cardiology Research Center, Rajaei Cardiovascular, Medical and Research Center, Tehran University of Medical Sciences, Tehran, Iran 3 Sildenafil is a selective phosphodiesterase-5 inhibitor and causes vasodilatation, particularly in pulmonary circulation. Since left heart failure may be associated with pulmonary hypertension out of proportion to left heart disease, sildenafil may have beneficial effect in such patients. The present investigation was designed as a 12-week, singlecenter, randomized, double-blind, placebo-controlled study evaluating the effects of sildenafil on mean blood pressure (primary endpoint) in patients with left systolic heart failure. Secondary endpoints included exercise capacity assessed by 6-minute walk test. A total of 106 patients were randomized 1:1 to sildenafil or placebo. Patients received sildenafil 25 mg twice a day or matching placebo for the first 2 weeks and 50 mg 3 times a week for the remainder of the trial. The placebo-corrected effect on mean blood pressure was 1.16 mm Hg (95% confidence interval, )1.6 to 5.1, P >.05), demonstrating that sildenafil did not decrease mean blood pressure. Compared with placebo, sildenafil increased the 6-minute walk test by a nonsignificant treatment effect of 14 m (P=.67). Adverse effects occurred in a comparable proportion of patients taking sildenafil and placebo, and none of the patients needed to discontinue therapy. Sildenafil is well tolerated in left heart failure patients and does not decrease blood pressure. It can be safely added to standard heart failure therapy. Ó2012 Wiley Periodicals inc. Address for correspondence: Ahmad Amin, MD, Vali-Asr Avenue, Niyayesh Boulevard, Rajaei Cardiovascular, Medical and Research Center, Tehran University of Medical Sciences, Tehran, Iran E-mail: amina33@gmail.com Manuscript received: June 20, 2012; revised: September 12, 2012; accepted: September 17, 2012 DOI: 10.1111/chf.12008 High concentration of type 5 phosphodiesterase (PDE- 5) is found in vascular smooth muscle cells of the pulmonary and peripheral arterial and venous vessels as well as in skeletal muscles, visceral and tracheobronchial muscles, brain, retina, and platelets. 1 5 This isozyme of PDEs hydrolyzes cyclic guanosine monophosphate (cgmp), which is the second messenger of nitric oxide (NO) and also a principal mediator of smooth muscle relaxation. Inhibitors of PDE-5 prolong the action of cgmp and increase NO availability to the vascular bed. 6 This results in enhanced smooth muscle relaxation and vasodilatation. 3 Sildenafil, as a selective PDE-5 inhibitor, has been in extensive clinical use for the management of primary pulmonary hypertension. However, debate exists regarding the beneficial effects of sildenafil on pulmonary hypertension out of proportion to left heart disease. It has been proposed that sildenafil might decrease the reactive part of pulmonary hypertension in a left systolic heart failure (LHF) setting. As a result, recent interest has focused on the possible beneficial effects of sildenafil in LHF patients. A growing body of experimental and clinical studies has provided evidence for beneficial effects of sildenafil on echocardiographic and hemodynamic profiles and cardiopulmonary exercise test in these patients. However, data are still far from showing real clinical benefits with sildenafil in LHF patients in terms of functional capacity measures (the distance walked in 6 minutes or New York Heart Association [NYHA] functional class), the need for frequent hospitalizations or emergency department visits, and survival measures. The present study was designed: (1) to assess the safety and tolerability of sildenafil in combination with a standard medical regimen of heart failure and (2) to investigate whether sildenafil could improve clinical outcomes and decrease the severity of symptoms in patients with LHF. PATIENTS AND METHODS Patient Population Patients older than 18 years with NYHA class II or III systolic heart failure (echocardiography-derived left ventricular ejection fraction <35%) who had been receiving optimal anti heart failure therapy (adequate doses of diuretics and neurohormonal blockades including b- blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and aldosterone antagonists according to latest guidelines on heart failure 7 ) and were followed at the Heart Failure and Transplant Clinic of Rajaei Cardiovascular, Medical and Research Center, a tertiary center for cardiovascular diseases in Tehran, Iran, from 2008 to 2011 were included in this randomized, double-blind, placebo-controlled trial. Patients were excluded if they were receiving long-term nitrate therapy; had uncontrolled arrhythmia, significant valvular disease, moderate or severe mitral valvular disease, Congest Heart Fail. 2013;19:99 103 Vol. 19 No. 2 March. April 2013 99

peripheral vascular disease, obstructive sleep apnea, severe chronic obstructive pulmonary disease, collagen vascular disease, optic neuropathy, or unexplained visual impairment; and primary pulmonary hypertension. Patients who had experienced myocardial infarction or had undergone revascularization or coronary angioplasty within the past 6 months were also excluded from the study. Patients taking nitrates, antifungals, certain antidepressants, or other drugs that can interfere with sildenafil plasma concentrations were also excluded. None of the patients had been hospitalized or changed medical therapy during the past 3 months. The study was conducted according to the most recent amendments to the Declaration of Helsinki and in adherence to good clinical practice guidelines. Institutional review boards at Tehran University of Medical Science and other ethics committees approved the study protocol, and written informed consent was obtained from all patients. Study Design Our study was a 12-week, double-blinded, randomized, placebo-controlled trial conducted in Rajaei Cardiovascular, Medical and Research Center. Eligible patients were randomized 1:1 to receive double-blinded sildenafil or placebo. Randomization was controlled by study medication packaging (Marham Daru Pharmaceutical Company, Tehran, Iran). Patients were randomized in a consecutive order, starting with the lowest provided medication number. The investigators, patients, monitors, and sponsor personnel remained blinded to the treatment until closure of the clinical database. In addition to their background therapy for heart failure, patients received sildenafil 25 mg twice a day or matching placebo for the first 2 weeks and 50 mg 3 times a day for the remainder of the trial. Patients who did not tolerate the target dose were downtitrated to the starting dose. Clinical examination and NYHA functional class were assessed periodically. A 6-minute walk test was performed at baseline and at week 12. Statistical Analysis Primary Endpoints. The first primary endpoint of this study was a safety endpoint, ie, the change in mean blood pressure (BP) from baseline to week 12. For this endpoint, a noninferiority test was conducted comparing sildenafil with placebo. The null hypothesis was that the mean difference between the sildenafil and placebo groups was negative and >5%. Hypothesis testing was based on 2-sided 95% confidence intervals (using Student t distribution). If the null hypothesis concerning the systemic BP was rejected, a second test was to be performed concerning the second primary endpoint of the study, ie, the change in 6-minute walk distance from baseline to week 12. For this endpoint, the superiority of sildenafil compared with placebo was to be tested. The null hypothesis was that the mean change in 6-minute walk distance from baseline to week 12 in the placebo group equals that in the sildenafil group. Hypothesis testing was based on 2-sided 95% confidence intervals (using Student t distribution). Secondary Endpoints. Secondary endpoints included the changes from baseline to week 12 in need for frequent hospitalizations or emergency department visits and survival measures. Demographics baseline data are presented as numbers (percentages) and meanstandard deviation. RESULTS Of the 106 patients included in the study, 53 received sildenafil and 53 received placebo. During the study period, 2 patients died due to multiple organ failure. Both of them were in the placebo arm. Baseline Characteristics Treatment groups were well matched with respect to age, sex, body mass index, clinical, and functional characteristics (Table I). All patients were in NYHA functional class II or III (56 [52.8%] and 50 [47.2%], respectively). Baseline 6-minute walk test was considerably reduced as compared with the predicted normal values. 8 Mean BP Mean BP at the end of the study was similar in both groups (85.196.80 mm Hg vs 84.038.75 mm Hg in the placebo and sildenafil groups, respectively) (Table II). The placebo-corrected effect was )1.16 mm Hg (95% confidence interval, )1.6 to 5.1, P>.05). The results showed noninferiority; hence, the primary endpoint was met. These results confirm that sildenafil treatment does not reduce systolic BP. None of our patients had a decrease in systolic BP >10% from baseline to the end of the study (maximum decreases, )6.4% in the placebo group and )8.7% in the sildenafil group). Hospitalizations and Emergency Department Visits The frequency of hospitalizations and emergency department visits during the study period were lower in the sildenafil group compared with the placebo group, but these differences did not reach statistical significance (P=.33 and.07 for hospitalizations and emergency department visits, respectively). Exercise and Functional Capacity The 6-minute walk test increased in the placebo group by 7170 m and in the sildenafil group by 8513 m, resulting in a nonsignificant treatment effect of 14 m (P=.67) (Table II). Sixteen patients in the placebo group (15%) improved from NYHA class III to NYHA class II compared with 23 patients in the sildenafil group (22%). Seven patients in the placebo group (7%) improved from NYHA class III to NYHA class I compared with 2 patients in the sildenafil group (2%). Twenty-four patients in the placebo group (23%) and 24 patients 100 Congest Heart Fail Vol. 19 No. 2 March. April 2013

TABLE I. Baseline Characteristics of Study Population Variable Sildenafil Age, y 51.2914.80 50.6114.18 Sex (male female) 38 (72) 15 (28) 40 (75) 13 (25) Weight, kg 73.2410.72 75.0321.75 Body mass index, kg m 2 273 264 NYHA class II 27 (51) 29 (55) III 26 (49) 24 (45) Etiology of heart failure Ischemic 19 (36) 20 (38) Valvular 1 (2) 2 (4) Cardiomyopathy 33 (62) 31 (58) Heart failure pharmacotherapy Diuretic 53 (100) 52 (98) ACE inhibitor or ARB 51 (96) 49 (92) b-adrenergic receptor antagonist 50 (94) 51 (96) Spironolactone 35 (66) 51 (62) Digoxin 16 (30) 13 (25) Cardiac resynchronization therapy 3 (6) 4 (8) Implantable cardiac-defibrillator 6 (11) 4 (8) Ventricular assist device 0 0 Comorbid conditions Hypertension 12 (23) 10 (19) Diabetes 14 (26) 13 (25) Dyslipidemia 10 (19) 9 (17) Chronic renal failure 2 (4) 1 (2) Chronic liver disease 1 (2) 3 (6) Current smoking 9 (17) 10 (19) Heart rate, bpm 8212.66 7811 Blood pressure, mm Hg Systolic 115.4214.82 113.8317.77 Diastolic 75.5110.15 73.9710.89 Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; bpm, beats per minute; NYHA, New York Heart Association. Data are presented as meanstandard deviation or number (percentage). in the sildenafil group (23%) improved from NYHA class II to NYHA class I. All other patients remained in their previous NYHA class. Safety Adverse events considered by the investigator to be related to treatment were seen in 23 (43.39%) patients in the sildenafil group and in 27 (50.94%) patients in the placebo group. The most common adverse effects occurred in a comparable proportion of patients taking sildenafil and placebo (Table III) and included headache (13% vs 11%), flushing (13% vs 15%), and dizziness (15% vs 11%). The observed adverse events were mild in all cases and did not result in the need for discontinuation of the therapy. DISCUSSION In this single-center, randomized, double-blind, placebo-controlled trial for adults with advanced heart failure, sildenafil proved to be safe in terms of mean BP and other safety measures; however, it failed to show any more improvement in 6-minute walk distance or NYHA functional class over placebo. Patients in the sildenafil arm were less likely to be rehospitalized or have any other emergency medical visits, but the differences did not reach statistical significance. Short-term effects of sildenafil on hemodynamic parameters of heart failure are well-described in the previous studies. Numerous short-term effects have been assumed for sildenafil therapy including increase of myocardial contractility, 8 blunting of adrenergic stimulation, 9 reduction of left ventricular afterload, 8 improvement of lung diffusion capacity 10 and pulmonary hemodynamics at rest 10 and on exertion, 11 and increase of exercise ventilation efficiency and aerobic performance. 10,11 Small trials have also assessed the effects of longterm sildenafil treatment in LHF patients. Lewis and his associates 12 examined the effects of sildenafil in TABLE II. Responses on the Clinical Outcomes After 12 Weeks of Double-Blind Treatment With Sildenafil or Sildenafil Sildenafil vs Variable Baseline Change P Value Baseline Change P Value P Value SBP 115.4214.82 )2.1015.96.98 113.8317.77 )2.2716.35.97.87 DBP 75.5110.15 )4.3711.27.04 75.9710.89 )2.2716.35.83.95 Mean BP 88.8111.00 )3.6211.96.06 87.2612.34 )3.2312.38.08.92 NYHA I 0 24 (45) 0 27 (51) II 27 (51) )1 (2) <.001 29 (55) )7 (13) <.001.58 III 26 (49) )23 (43) 24 (45) )20 (38) 6MWT 320114 8513 m <.001 36076 7170 <.001.67 Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; NYHA, New York Heart Association; SBP, systolic blood pressure; 6MWT, 6-minute walk test. Data are presented as meanstandard deviation or number (percentage). Congest Heart Fail Vol. 19 No. 2 March. April 2013 101

TABLE III. Incidence of Adverse Events Following Treatment With Sildenafil or Adverse event Sildenafil P Value Headache 7 (13.20) 6 (11.32).82 Insomnia 2 (3.77) 4 (7.54).58 Gastritis 3 (5.66) 7 (13.20).33 Paresthesia 3 (5.66) 4 (7.54).80 Dyspepsia 4 (7.54) 6 (11.32).16 Rash 2 (3.77) 5 (9.43).54 Epistaxis 1 (1.88) 2 (3.77).13 Flushing 7 (13.20) 8 (15.09).58 Dizziness 8 (15.09) 6 (11.32).55 Diarrhea 3 (5.66) 5 (9.43).33 Myalgia 5 (9.43) 7 (13.20).44 Nasal congestion 4 (7.54) 6 (11.32).51 Disturbance of color vision 0 0 1 Blurred vision 3 (5.66) 4 (7.54).82 Light hypersensitivity 3 (5.66) 2 (3.77).79 Blood shot eyes 3 (5.66) 2 (3.77).72 Eye pain 2 (3.77) 1 (1.88).69 Priapism 4 (7.54) 6 (11.32).86 Data are presented as number (percentage). LHF patients with secondary pulmonary hypertension. The authors showed that sildenafil improved exercise capacity as measured by peak oxygen uptake and 6- minute walk distance. Sildenafil also significantly increased the peak exercise cardiac output and stroke volume and significantly decreased resting and exercise peripheral vascular resistance as well as right ventricular ejection fraction. Such changes were observed without a significant change in heart rate, arterial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Moreover, a significant improvement was seen in Minnesota Living With Heart Failure Questionnaire in patients who received sildenafil as compared with placebo. In contrast to our results, the aforementioned study 12 demonstrated that sildenafil treatment was associated with lesser hospitalization as compared with the control group. Guazzi and colleagues 13 evaluated the long-term effects of sildenafil on brachial artery flow-mediated dilatation (FMD), cardiopulmonary exercise testing, and ergoreflex response in 46 men with LHF. Patients underwent cardiopulmonary exercise testing and measurements of flow-mediated vasodilation and at baseline and 3 and 6 months. Patients who received sildenafil had significant reduction of systolic pulmonary artery pressure, ergoreflex effect on ventilation, ventilation to CO 2 production slope (VE VCO 2 ) and breathlessness score, and significant increases in FMD, peak VO 2, and ratio of VO 2 to work rate changes when compared with the placebo arm. Behling and his coworkers 14 in a double-blind, placebo-controlled trial of 19 LHF patients showed that a protocol of 4 weeks of treatment with oral sildenafil (50 mg 3 times a day) is associated with significant improvement in oxygen consumption, ventilatory efficacy, and oxygen uptake kinetics, assessed by cardiopulmonary exercise test as well as a remarkable decrease in the echocardiography-derived systolic pulmonary artery pressure. The authors concluded that chronic sildenafil therapy improved exercise capacity and pulmonary hypertension of LHF patients. According to the beneficial effects of sildenafil shown in previous studies, we aimed to investigate the benefits of sildenafil in systolic heart failure. According to our results, sildenafil resulted in no better outcome than placebo in terms of functional capacity and, more specifically, a very reliable and feasible clinical test: 6-minute walk distance. It should be emphasized that 6-minute walk distance is a predictor of death in patients with systolic heart failure and has been used as the primary efficacy end point in many clinical trials involving such patients. This could have been due to the patients characteristics in our study; in other words, we had patients with acceptable rightsided hemodynamics along with those with variable degrees of left failure induced pulmonary hypertension and right ventricular dysfunction who might be assumed to benefit more from sildenafil as a pulmonary vasodilator. The reason is that in the first place we aimed to investigate the well-known side effect with chronic sildenafil therapy in heart failure patients: drop in BP. It turned out that none of the patients in the sildenafil group developed any significant drop in BP compared with the placebo group, and this result was notably true even for the patients with relative resting hypotension (systolic BP <90 mm Hg) and in combination with all anti-failure medications, many of which would profoundly lower systemic BP. Accordingly, sildenafil is safe in patients with systolic heart failure receiving other anti-failure therapies. We did not show any obvious clinical benefits with sildenafil in heart failure, and further studies to address whether heart failure patients actually benefit from this pulmonary vasodilator agent are necessary. STUDY LIMITATIONS Although our study had a larger study population compared with most of the previous investigations, the observed discrepancy may be a result from our relatively small sample size. Furthermore, the fact that we did not assess pulmonary hemodynamics before and after treatment with sildenafil or placebo is another limitation. It is important to evaluate the effects of such treatment on either noninvasively or invasively measured hemodynamic parameters. Future investigations with larger study populations that address pulmonary hemodynamic data before and after treatment deserve high priority and may provide more conclusive results. 102 Congest Heart Fail Vol. 19 No. 2 March. April 2013

CONCLUSIONS Effects of chronic sildenafil therapy on clinical outcomes of heart failure were sparse. However, sildenafil dosing up to 50 mg 3 times daily is well tolerated in LHF patients and can be safely added to standard heart failure therapy. Given the clinical importance of the drug s safety and the evidence presented here, the use of this finding to assess the role of sildenafil in HF treatment should be considered. With regard to the previously shown beneficial effects of sildenafil and the results of our study, further clinical studies are needed to clarify the role of sildenafil treatment in LHF patients. References 1 Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effect of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile response of trabeculaecarneae and aortic rings. Am J Cardiol. 1999;83:3C 12C. 2 Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995;75:725 748. 3 Reffelmann T, Kloner RA. Therapeutic potential of phosphodiesterase5 inhibition for cardiovascular disease. Circulation. 2003; 108:239 244. 4 Senzaki H, Smith CJ, Juang GJ, et al. Cardiac phosphodiesterase 5 (cgmp-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. FASEB J. 2001;15:1718 1726. 5 Gresser U, Gleiter CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil: review of the literature. Eur J Med Res. 2002;7:435 446. 6 Burnett AL. Phosphodiesterase 5 mechanisms and therapeutic applications. Am J Cardiol. 2005;96:29Me31M. 7 Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388 2442. 8 Hirata K, Adji A, Vlachopoulos C, O Rourke MF. Effect of sildenafil on cardiac performance in patients with heart failure. Am J Cardiol. 2005;96:1436 1440. 9 Borlaug BA, Melenovsky V, Marhin T, et al. Sildenafil inhibits betaadrenergic-stimulated cardiac contractility in humans. Circulation. 2005;112:2642 2649. 10 Guazzi M, Tumminello G, Di Marco F, et al. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol. 2004;44:2339 2348. 11 Lewis GD, Lachmann J, Camuso J, et al. Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation. 2007;115:59 66. 12 Lewis GD, Shah R, Shahzad K, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007;116:1555 1562. 13 Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol. 2007;50:2136 2144. 14 Behling A, Rohde LE, Colombo FC, et al. Effects of 5 0 -phosphodiesterase four-week long inhibition with sildenafil in patients with chronic heart failure: a double-blind, placebo-controlled clinical trial. J Card Fail. 2008;14:189 197. Congest Heart Fail Vol. 19 No. 2 March. April 2013 103