And Late-Hemodynamic Coronary Effects of Tadalafil in Men with Erectile Dysfunction and Coronary Artery Disease

ORIGINAL ARTICLE Immediate- and late-hemodynamic coronary effects of tadalafil in men with erectile dysfunction and coronary artery disease

F Bellotto1, M Ruscazio1, G Bonanni1,2, R Montisci1, A Cutolo1, C Sarais1, T Setzu1, A Borrini1 and S Iliceto1

1Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova, Padova, Italy and 2Department of Surgical and Medical Sciences, University of Padova, Padova, Italy

We investigated whether coronary flow reserve (CFR) can be modified by tadalafil, a long-acting phosphodiesterase 5 (PDE5) inhibitor, in patients with documented coronary artery disease (CAD). CFR was non-invasively evaluated in 12 men with a positive history for erectile dysfunction (ED) and angiographically documented CAD, in the distal portion of the left anterior descending coronary artery, free from critical stenosis, with contrast enhanced echocardiography at time zero (T0). Then, after 20 mg tadalafil was orally administered CFR measurement was repeated after 2 h (T1) and after 24 h (T2). Doppler curves suitable for the analysis were obtained in all patients (CFR feasibility: 100%). The peak diastolic velocity after adenosine infusion increased from 71.3714.3 cm/s at T0 to 82.5724.0 at T1 (P ¼ NS) and to 89.5721.1 at T2 (P ¼ 0.0010). CFR after tadalafil increased significantly from 2.670.3 at T0 to 3.170.7 at T1 (P ¼ 0.0078) and a further increment was found at T2 (3.570.9; P ¼ 0.0010 vs T0). Our study shows that oral administration of tadalafil exerts a long standing, potentially beneficial effect on coronary microvasculature in patients with ED. International Journal of Impotence Research (2008) 20, 168–172; doi:10.1038/sj.ijir.3901592; published online 16 August 2007;

Keywords: coronary flow reserve; erectile dysfunction; tadalafil

Introduction Phosphodiesterase 5 (PDE5) inhibitors work to improve ED by preventing the breakdown of cyclic Erectile dysfunction (ED), defined as the inability to guanosine monophosphate (cGMP), resulting in achieve and maintain an erection sufficient for increased cellular content and consequent relaxa- satisfactory sexual performance, is a frequent con- tion of smooth muscle cells in the arteries and dition.1 Coronary artery disease (CAD) and ED of arterioles of the corpus cavernosum of the penis. vascular origin are frequently concomitant,2–6 since Sildenafil, vardenafil and tadalafil have been shown they share the same risk factors, in particular to be effective and safe in a broad population of men smoking habits, diabetes, obesity, hypertension and with ED, including patients with CAD. Since the low-serum high-density lipoproteins. Microvascular enzyme PDE5 that they inhibit is present in smooth dysfunction due to endothelial damage lies at the muscle cells of all systemic arteries and veins, these basis of both conditions;7 resulting in altered agents have the potential to impact the cardiovas- bioavailability of nitric oxide (NO), prostaglandins, cular system.8 As a whole, they are mild vasodila- angiotensin and endothelin, with consequent lim- tors with no effect on heart rate, minimal ited capacity for vasodilation and increase in hemodynamic effects and only small additive intimal medial thickness, which leads to athero- decreases in blood pressure, even when they are sclerotic degeneration of the arteries involved. combined with other antihypertensive medicines. For these reasons, PDE5 inhibitors have a substan- tial potential for utilization in the cardiovascular field not only with the aim of safely improving sexual capacity but also of modulating the vaso- Correspondence: Dr F Bellotto, Department of Cardiologic, reactivity of the entire arterial bed. Thoracic and Vascular Sciences, University of Padova, Cardiologia-Via Giustiniani 2, Padova, Italy. Sildenafil was the first drug to be used, and E-mail: [email protected] therefore its cardiovascular effects have been the Received 5 March 2007; revised 19 June 2007; accepted 21 most frequently studied: this PDE5 inhibitor has June 2007; published online 16 August 2007; been demonstrated to cause a slight reduction in Effects of tadalafil in men with ED and CAD F Bellotto et al 169 arterial and pulmonary pressure,9 in addition to echocontrast infusion, on an Acuson Sequoia ultra- small effects on systolic stroke volume and cardiac sound unit (C256 chocardiography System, Acuson frequency, both in healthy subjects and CAD Siemens) using a broad-band transducer with patients.10–13 Tadalafil, the latest PDE5 inhibitor second-harmonic capability (3V2c). Once the rou- released on the market, has a structure which differs tine echo Doppler examination was completed, CFR substantially from its precursors, and confers a was evaluated using contrast-enhanced transthor- uniquely long half-life of 17.5 h making it suitable acic Doppler before and after adenosine infusion. for long-term use.14 As a matter of fact, it has been We evaluated CFR in the LAD with transthoracic recently demonstrated that the use of this drug over Doppler (CE-TTE) during a 5-min adenosine infu- a 4-week period, improves endothelial function in sion (140 mg/kg/min; Adenoscan, Sanofi-Synthelabo, subjects with increased cardiovascular risk with a Berlin, Germany). When the PW Doppler pattern benefit that is sustained 2 weeks after discontinuing was not clearly detectable, we used a Doppler signal treatment.15 The aim of this study was to evaluate contrast enhancer Levovist (Schering AG, Berlin), the early and late effects of tadalafil on coronary infused with a controlled-infusion pump (IVAC flow reserve (CFR), measured by a non-invasive P4000 Anaesthesia Syringe pump) at a concentra- method—transthoracic echocardiography—in sub- tion of 300 mg/ml, and an infusion rate of 1 mg/min. jects with ED and angiographically documented Blood pressure and electrocardiogram were re- CAD. corded at rest and every minute during adenosine infusion. Cardiac medications were not interrupted before adenosine infusion, although methyl- Materials and methods xanthine-containing medications were withheld 48 h before the study. Beverages containing methyl- xanthine substances (cola, tea, coffee and so on) Study subjects were prohibited for 24 h before the study. The effects of tadalafil were studied in 12 men with 7 CFR in the LAD was calculated by one experi- CAD, aged 44–71 (mean age 60.8 9.4) years. All enced echocardiographer—who was blind to the had demonstrated critical coronary artery stenosis in scope of the study and to the presence or absence of at least one vessel, but no lesions on the left anterior a control group, but not to the sequence of the descending (LAD) artery; angiography preceded the measurements—as the ratio of peak diastolic velo- evaluation by no more than 2 months. All subjects city during hyperemia over peak diastolic velocity at were considered to be in a clinically stable condi- baseline. For each parameter, the three highest tion (chronic cardiac ischemia or previous myocar- values were averaged. M-mode and two-dimen- dial infarction at least 2 months before evaluation), sional echocardiography and pulsed wave Doppler with a positive history of ED (difficulty in reaching were used to evaluate cardiac chamber and valve and/or maintaining an erection, with a IIEF-5 morphology and function. questionnaire score p21). Patients requiring nitrate therapy were excluded, as were those with evidence of marked myocardial hypertrophy or diabetes. All the enrolled subjects, were taken statins, indepen- Statistical methods dently with the lipid status, and continued their Statistical analyses were performed by StatXact-5 normal therapy (ASA, b-blockers, ACE-inhibitors (Cytel Software Corporation). Data are presented as and so on), were appropriately informed as to the the means7s.d. The Friedman test was used to nature of the study and gave their informed consent compare the three time points for each variable for the study procedures. considered separately. The two-sided Wilcoxon The procedures followed are in accordance with signed rank test was performed to compare each the ethical standards of the Institutional Responsi- pair of times if significance was found. A value of ble Committee on human experimentation. Po0.05 was accepted as statistically significant for the Friedman test. To control for multiplicity, the Bonferroni correction was applied. Study protocol CFR was evaluated non-invasively in all patients in the distal portion of the LAD by contrast enhanced Results echocardiography (CE-TTE) at time zero and then 20 mg of tadalafil were administered per os. CFR Hemodynamics measurements are shown in Table 1 measurement was repeated 2 h (T1) and 24 h (T2) systolic and diastolic blood pressures as long as after drug administration. heart rates did not change significantly, 2 and 24 h As previously described in detail,16,17 to assess after oral administration of tadalafil, compared to CFR a complete two-dimensional M-mode echo baseline. Doppler (spectral and color) study was performed Doppler curves suitable for analysis were obtained in all patients both before and after intravenous in all patients (CFR feasibility: 100%): as expected,

International Journal of Impotence Research Effects of tadalafil in men with ED and CAD F Bellotto et al 170 Table 1 Hemodynamic measurements

Baseline (T0) 2 h (T1) 24 h (T2)

SBP (mm Hg) Rest 123.379.6 116.3710.7 118.878.6 Adenosine 109.679.6 108.3714.7 110.4712.0

DBP (mm Hg) Rest 74.279.0 72.579.2 71.577.5 Adenosine 67.579.2 66.1712.5 66.779.8

HR (beats/min) Rest 62.2710.8 64.9710.0 63.579.6 Adenosine 70.8715.2 74.7716.0 74.7716.2 CFR (ratio of maximal hyperemic/baseline coronary blood flow) 2.670.3 3.170.71 3.570.9*

Abbreviations: CFR, coronary flow reserve; DBP, diastolic blood pressure; SBP, systolic blood pressure. 1Po0.01 T1 vs T0. *Po0.01 T2 vs T0.

6 no differences in hemodynamics after tadalafil administration, with the same slight reduction of 5 basal coronary flow velocities, followed by a significant increase after adenosine infusion. The 4 increase of CFR after tadalafil in our patients cannot be attributed to hemodynamic variations, since heart 3 rate and mean aortic pressure were not significantly different before or after tadalafil, either in basal 2 condition or after adenosine infusion (Table 1); moreover, in previous studies we demonstrated the 1 T0 T1 T2 capacity of non-invasive CFR detected by Doppler echocardiography to be a reliable marker of coronary Figure 1 CFR in each subject (ratio of maximal hyperemic/ baseline coronary blood flow). CFR, coronary flow reserve. microvascular impairment in CAD and other cardiac diseases.19–21 This suggests that tadalafil can induce significant coronary microcirculatory vasodilata- tion, by the observation of nonsignificant changes baseline CFR measurements revealed a normal in basal coronary flow velocity in the absence of pattern in all study subjects. Peak diastolic velocity flow limiting stenosis of the epicardial vessels. Our after adenosine infusion increased from 71.37 study did not attempt to assess the side effects of the 14.3 cm/s at T0 to 82.5724.0 at T1 (P ¼ 0.082) and drug, but to reveal a potentially long-acting, bene- to 89.5721.1 at T2 (P ¼ 0.0010). CFR after tadalafil ficial effect on coronary microcirculation in patients increased significantly from 2.670.3 at T0 to with known CAD. Herrmann et al.12 demonstrated 3.170.7 at T1 (P ¼ 0.0078) and a further increment the effect of a PDE5 inhibitor on CFR, assessed with was found at T2 (3.570.9; P ¼ 0.0010 vs T0) an intracoronary Doppler guidewire in 25 coronary (Figure 1). arteries—most of them with significant stenosis— and 12 arteries without stenosis as controls, after 100 mg sildenafil administered orally (mean time between measurements, approximately 60 min). Discussion They found a global increase of 13% in CFR after sildenafil, although it was lower in the severely The potential to increase CFR by PDF5 inhibitors is stenosed arteries than in the reference arteries extremely interesting not only because coronary (1.2670.26 vs 2.1970.44, Po0.05). To exclude the patients can use the drug safely, but also with a effect of coronary stenosis, which may affect CFR therapeutic purpose beyond that of simply treating due to increased epicardial resistance, we studied ED, as suggested by Rosano et al.18 in combination only patients without critical stenosis on LAD, as with trimetazidine, sildenafil was superior to ni- determined by coronary angiography and confirmed trates in controlling episodes of myocardial ische- by normal CFR values at time zero. In addition, the mia during sexual activity in CAD patients. further improvement after tadalafil cannot be attrib- Our study shows that oral administration of uted to individual variations in CFR, because tadalafil exerts a long acting, potentially beneficial reproducibility in assessing CFR had previously effect on coronary microvasculature in patients with been assessed in our laboratory and only revealed a ED. In agreement with Herrmann et al.,12 we found small range of inter-test variability (70.3).17

International Journal of Impotence Research Effects of tadalafil in men with ED and CAD F Bellotto et al

22 171 Halcox et al. measured the acute effect of erectile dysfunction: prospective results from the Massachus- sildenafil on resting coronary vascular tone in 24 sets Male Aging Study. Am J Epidemiol 2000; 152: 533–541. patients 45 min after 100 mg oral sildenafil, and 2 Solomon H, Man JW, Wierzbicki AS, Jackson G. Relation of erectile dysfunction to angiographic coronary artery disease. observed an epicardial coronary artery vasodilata- Am J Cardiol 2003; 91: 230–231. tion induced by the drug. In our study, the increase 3 Bortolotti A, Parazzini F, Colli E, Landoni M. The epidemiol- in CFR induced by tadalafil represents the first ogy of erectile dysfunction and its risk factors. Int J Androl direct demonstration of the capacity of this PDE5 1997; 20: 323–334. 4 Montorsi P, Montorsi F, Schulman C. Is erectile dysfunction inhibitor to modulate coronary arteriolar resistance the tip of the iceberg of a systemic vascular disorder? Eur Urol in patients with known CAD, with an effect that 2003; 44: 352–354. persists over time. In fact, in our patients, a mean 5 Gazzarusso C, Giordanetti S, De Amici E, Bertone G, Falcone increase in CFR 2 h after tadalafil administration C, Geroldi D et al. Relationship between erectile dysfunction was confirmed ( þ 20.8% with respect to CFR at and silent myocardial ischemia in apparently uncomplicated type 2 diabetic patients. Circulation 2004; 110: 22–26. baseline) which reached statistical significance 6 Montorsi P, Ravagnani PM, Galli S, Rotatori F, Veglia F, (P ¼ 0.0078); at 24 h, the effect on CFR not only Briganti A et al. Association between erectile dysfunction and persisted but was further increased ( þ 35.6% with coronary artery disease. Role of coronary clinical presentation respect to baseline; P ¼ 0.0010) confirming the long and extent of coronary vessels involvement: the COBRA trial. half-life of this drug. Eur Heart J 2006; 27: 2632–2639. 23 7 Solomon H, Man JW, Jackson G. Erectile dysfunction and the Dietz et al. assessed CFR in the left LAD in 21 cardiovascular patient: endothelial dysfunction is the com- diabetics with ED at baseline and 1 h after 50 mg mon denominator. Heart 2003; 89: 251–253. sildenafil: baseline CFR was at the lower level of the 8 Kloner RA. Cardiovascular effects of the 3 phosphodiesterase- normal range and decreased insignificantly after 5 inhibitors approved for the treatment of erectile dysfunction. Circulation 2004; 110: 3149–3155. sildenafil administration, probably due to the severe 9 Galie` N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesh D microvascular and endothelial dysfunction known et al. Sildenafil citrate therapy for pulmonary arterial to occur in diabetic patients.24 Instead, our patients hypertension. N Engl J Med 2005; 353: 2148–2157. were not affected by insulin-dependent diabetes 10 Jackson G, Benjamin N, Jackson N, Allen MJ. Effects of sildenafil citrate on human hemodynamics. Am J Cardiol mellitus and had a normal baseline CFR, which 1999; 83: 13C–20C. increased after administration of the drug, demon- 11 Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, Russel strating not only the absence of coronary critical Jr RO et al. ACC/AHA expert consensus document. Use of stenosis but also a normal coronary microvascula- sildenafil (Viagra) in patients with cardiovascular disease. ture response to hyperemia-stimulated expression of American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999; 33: 273–282. a preserved endothelial function. 12 Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemo- The possibility of increasing CFR in subjects with dynamic effects of sildenafil in men with severe coronary CAD, even if only in vessels free of critical lesions, artery disease. N Engl J Med 2000; 342: 1622–1626. with drugs used for the treatment of ED, makes it 13 Gillies HC, Roblin D, Jackson G. Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science possible to imagine their use outside the realm of to clinical studies in patients with cardiovascular disease. Int J sexual impotence. The regional increase in CFR, Cardiol 2002; 86: 131–141. induced by tadalafil and prolonged over time, may 14 Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of increase coronary microvasculature blood supply, tadalafil. Am J Cardiol 2003; 92(9A): 37M–46M. possibly improving myocardial ischemia in CAD. 15 Rosano GMC, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. Chronic treatment with tadalafil improves endothelial func- These preliminary data suggest the usefulness of tion in men with increased cardiovascular risk. Eur Urol 2005; further longitudinal studies, to evaluate the real 47: 214–222. impact of improved CFR exerted by tadalafil on 16 Caiati C, Montaldo C, Zedda N, Bina A, Iliceto S. New myocardial metabolism and contractile function and noninvasive method for coronary flow reserve assessment. Contrast-enhanced transthoracic second harmonic echo Dop- on clinical outcomes in patients with CAD. pler. Circulation 1999; 99: 771–778. 17 Caiati C, Montaldo C, Zedda N, Montisci R, Ruscazio M, Lai G et al. Validation of a new noninvasive method (contrast- Acknowledgments enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with We thank Ellen Murphy for her collaboration in the intracoronary Doppler flow wire. J Am Coll Cardiol 1999; 34: drafting of this work and Luigi Salmaso for statis- 1193–1200. tical analysis. 18 Rosano GMC, Marazzi G, Patrizi R, Cerquetani E, Vitale C, Volterrani M et al. Comparison of trimetazidine plus sildenafil to chronic nitrates in the control of myocardial ischemia during sexual activity in patients with coronary artery disease. Conflicts of interest Am J Cardiol 2005; 95: 327–331. 19 Montisci R, Chen L, Ruscazio M, Colonna P, Cadeddu C, Caiati None. C et al. Non-invasive coronary flow reserve is correlated with microvascular integrity and myocardial viability after primary angioplasty in acute myocardial infarction. Heart 2006; 92: References 1113–1118. 20 Tona F, Caforio AL, Montisci R, Angelini A, Ruscazio M, 1 Araujo AB, Johannes CB, Feldman HA, Derby CA, McKinlay Gambino A et al. Coronary flow reserve by contrast-enhanced JB. Relation between psychosocial risk factors and incident echocardiography: a new noninvasive diagnostic tool for

International Journal of Impotence Research Effects of tadalafil in men with ED and CAD F Bellotto et al 172 cardiac allograft vasculopathy. Am J Transplant 2006; 6: function, platelet activation, and myocardial ischemia. JACC 998–1003. 2002; 40: 1232–1240. 21 Tona F, Caforio AL, Montisci R, Gambino A, Angelini A, 23 Dietz U, Tries HP, Merkle W, Jaursch-Hancke C, Lambertz H. Ruscazio M et al. Coronary flow velocity pattern and coronary Coronary artery flow reserve in diabetics with erectile flow reserve by contrast-enhanced transthoracic echocardio- dysfunction using sildenafil. Cardiovasc Diabetol 2003; 2:8. graphy predict long-term outcome in heart transplantation. 24 Avogaro A, Toffolo G, Kiwanuka E, de Kreutzenberg SV, Circulation 2006; 114: I49–I55. Tessari P, Cobelli C. -arginine-nitric oxide kinetics in normal 22 Halcox JPJ, Nour KRA, Zalos G, Mincemoyer RA, Waclawiw and type 2 diabetic subjects: a stable-labelled 15N arginine M, Rivera CE et al. The effects of sildenafil on human vascular approach. Diabetes 2003; 52: 795–802.

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