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Orig i nal Article
Long-Term Ef fi cacy and Safety of
Sildenafil for Pa tients with Erec tile
Dys func tion
Back ground. To in ves ti gate the long-term ef fi cacy and safety of sildenafil for pa -
tients with erec tile dys func tion (ED).
Methods. Be tween March 1999 and Feb ru ary 2001, a to tal of 3168 pa tients vis ited
Tai pei Vet erans Gen eral Hos pi tal for pre scrip tion of sildenafil. The fol low-up pe riod was 1-3 years. A ques tion naire was de signed for eval u a tion of ef fi cacy and safety of sildenafil via tele phone sur vey.
Re sults. Of the 3168 pa tients, 1414 were in ter viewed by tele phone. Data from tele -
phone ques tion naires were suc cess fully ob tained in 1074 cases. Achieve ment of the first penile erec tion af ter sildenafil was re ported in 58.8% of our pa tients. The dis tri - bu tion of the first doses was 0.6%, 8.5%, 81.9% and 90% for 12.5 mg, 25 mg, 50 mg Di vi sion of Urol ogy, De part ment of and 100 mg, re spec tively. Af ter ad min is tra tion of sildenafil, 72.1% men had suc cess - Sur gery, Tai pei Vet erans Gen eral ful inter cours es “some times” or “al ways achiev ing vag i nal pen e tra tion”, and 72.3% Hos pi tal; and De part ment of Urol ogy, had “slight dif fi culty” or “no dif fi culty” in main tain ing of sex ual inter cours es. The “some times/most times/al ways” sat is fac tion ac counted 63.9% and 62.8%, re spec - Uro log i cal Re search Cen ter, Na tionalYang-Ming Uni ver sity, Tai pei, Tai wan, tively for pa tients and part ners. The global as sess ment of penile erec tion was im - proved in 58.6% of the pa tients. The sex ual con fi dence of the pa tients was mod er ate, high and very high in 72.4% of the pa tients. Of the 434 pa tients who failed first penile erec tions, 400 (92.2%) were re lated to im proper ad min is tra tion of sildenafil. Dis con - Key Words
tinu a tion of sildenafil in the last 3 months be fore tele phone sur vey was found in 852 pa tients (80.2%). The causes of dis con tinu a tion were loss of ef fi cacy in 51.6% of pa - tients, lack of sex ual de sire in 8.8%, and chronic dis eases in 8.2%. Spon ta ne ous erec - tion with out sildenafil was claimed in 21.5% of the pa tients (most times in 9.5% and al ways in 12.0%). The rate of ad verse events af ter tak ing sildenafil were 16.6%, and the most com mon ad verse event was fa cial flush ing (9.2%).
Con clu sions. The re sults of this study dem on strated that the ef fi cacy of sildenafil
was sim i lar to the pre vi ous clin i cal tri als. The ad verse events af ter sildenafil weremild and tol er a ble. Re cov ery of com plete or par tial spon ta ne ous erec tion was noted in some pa tients (21.5% in our study) af ter long-term us age of sildenafil.
Erec tile dys func tion (ED) is de fined as the in abil ity as high as 52% in the men aged 40-70 years.2 In the East -
to achieve and/or main tain a penile erec tion suf fi - ern, a study in ur ban ar eas of Shang hai es ti mated that the cient for sat is fac tory sex ual per for mance.1 ED is a med i - in ci dence of ED was 32.8% in men 40-49 years of age, cal con di tion with neg a tive im pact on men’s self-esteem, 36.4% in those aged 50-59 years, 74.2% in those aged qual ity of life and so cial interactivities. Ac cord ing to a 60-69 years, and 86.3% in those aged over 70 years.3 study of ED prev a lence in the West ern, the com bined Based on the website pub li ca tion from the Min is try of prev a lence of min i mal, mod er ate and com plete ED was the In te rior of the Re pub lic of China, the af flicted pop u - Cor re spon dence to: Kuang-Kuo Chen, MD, PhD, Di vi sion of Urol ogy, De part ment of Sur gery, Ta i pei Vet erans Gen eral Hos pi tal, 201, Sec. 2, Shih-Pai Road, Tai pei 112, Tai wan.
Fax: +886-2-2875-7540; E-mail:[email protected] Long-Term Ef fi cacy and Safety of Sildenafil la tion over 40 years of age made 4,221,448 at the end of never/never/ex tremely dif fi cult) to 5 (al most al ways/al - 2001. By re fer ring the above data, the es ti mated prev a - ways/not dif fi cult) with 0 in di cat ing “no at tempt for in - lent pop u la tion of ED was 1.83 to 1.88 mil lion in Tai wan ter course”, or from 1 (very dis sat is fied/very low) to 5 (very sat is fied/very high). The other ques tions in cluded Sildenafil (Viagra®) was the first Food and Drug Ad - the rate of achiev ing penile erec tion and the causes of min is tra tion (FDA, USA) ap proved ef fec tive oral med i - fail ing erec tion af ter the first ad min is tra tion of sildenafil, ca tion for pa tients with ED, which is a se lec tive in hib i tor and the ef fi cacy of sub se quent tak ing of sildenafil.
of cy clic guanosine monophosphate (cGMP)-spe cific Global as sess ment of im prove ment of erec tion was also phosphodiesterase type 5, the pre dom i nant isoenzyme used to eval u ate the ef fi cacy of sildenafil. The con di tions catabolizing cGMP in cor pora cavernosa. The pres er va - of tak ing sildenafil in the last 3 months be fore tele phone tion of cGMP de vel oped sub se quently, which re stored sur vey were checked, in clud ing spon ta ne ous erec tion re lax ation of cavernosal smooth mus cles af ter sex ual with out sildenafil and causes of dis con tinu a tion. Finally, The ef fi cacy and safety of sildenafil was well doc u - The pa tient de mo graph ics and tele phone avail able mented af ter se rial clin i cal tri als all over the world.4-8 num bers were ex tracted from our out pa tient reg is ter sys - The in ter course suc cess rate or suc cess ful at tempts at in - tem in dom i nant com puter. Part time med i cal stu dents ter course were 62% to 77.6%; the ad verse events were con ducted the tele phone in ter view af ter a planned train - 6% to 43.7%. The global as sess ment of im prove ment re - ing course. The fi nal doc u ments were checked up and pa - gard ing erec tion was sta tis ti cally sig nif i cant in the above tients were ex cluded if the cases in volved mis taken tele - stud ies. Rizk et al. have con ducted a study on long-term phone num bers, prob lems of tele com mu ni ca tions, poor ef fi cacy of pa tients within 1, then 2 years af ter re ceiv ing com mu ni ca tion in tele phone con ver sa tion, in ad e quate sildenafil.4 Be yond that lit tle was re ported for any lon ger sit u a tion at phone call, re fusal, cur rent se ri ous dis ease, pe riod of fol low-up study. Herein, we stud ied the ef fi - cacy and safety of sildenafil af ter long-term post-marketing Sta tis ti cal anal y sis was done with com mer cial soft - us age in the pa tients with ED uti liz ing a self-designed ware for de scrip tive sta tis tics. Chi-Square test, Fisher’s Ex act test and McNemar’s test were used. A p value less than 0.05 was con sid ered sig nif i cant.
Be tween March 1999 and Feb ru ary 2001, a to tal of 3168 pa tients vis ited the out pa tient de part ment of Tai pei Tele phone sur veys were suc cess fully con ducted on Vet erans Gen eral Hos pi tal with broad-spectrum eti ol o - 1414 pa tients, and 340 pa tients (24.0%) de nied the his - gies of ED and re ceived pre scrip tions of sildenafil. The tory of tak ing sildenafil. There fore 1074 pa tients were clin i cal phy si cians of vari ant spe cial ties ad justed the en rolled in the sta tis ti cal anal y sis. The mean age was dos ages ac cord ing to its ef fi cacy and tolerability. The 69.1 years (range: 26-92). Totally 632 pa tients (58.8%) com mon con tra in di ca tions were his tory of tak ing or - ex pe ri enced penile erec tion af ter the first tak ing of ganic ni trate-containing drug and se verely com pli cated sildenafil, while the other 442 pa tients (41.2%) failed penile erec tion, mostly due to im proper ad min is trat ing of The ques tion naire was de signed in March 2002 con - sildenafil (90.5%, 400/442). Heavy diet be fore med i ca - tain ing the items 3, 4, 7, 14, 15 of the in ter na tional in dex tion ac counted the most for that im proper ad min is tra tion of erec tile func tion (IIEF) re gard ing the abil ity of achiev - (Fig. 1). The ad min is tra tion of sildenafil made no dif fer - ing and main tain ing, sat is fac tion and con fi dence of ence in the rate be tween the cases who ex pe ri enced the penile erec tion.12 They were scored from 1 (al most first erec tion with sub se quent fail ure of erec tion (6.2%), Jour nal of the Chi nese Med i cal As so ci a tion Vol. 66, No. 8 sex ual ac tiv ity af ter tak ing sidenafil, and were ex cluded Table. 1. The condition of erections after first taking sildenafil
and subsequent taking sildenafil (n = 623)
from anal y sis. The re main ing 855 pa tients were an a lyzed for ef fi cacy of sidenafil. Of the 855 pa tients with as sess - ment of IIEF Q 3 and Q5, 72.1% had more than 50% of achiev ing pen e tra tion at sex ual in ter course (Fig. 2).
Mean while, 73.4% of pa tients rated their penile erec tions be ing able to main tain dur ing vag i nal pen e tra tion with slight or lit tle dif fi culty (Fig. 3). Be cause the Ori en tal and the first fail ure of erec tion with sub se quent penile peo ple are usu ally un der ex pres sive of their feel ings, erec tion (17.8%) (p = 0.89) (Ta ble 1).
drug sat is fac tion was de fined if the pa tients an swered Of the 1074 pa tients en rolled, 219 pa tients de nied that they “al ways/al most ev ery time/of ten/some times” Fig. 1. Types of im proper ad min is tra tion of sildenafil (n = 400); * = Not within 1 hour be fore meal or 2 hours af ter meal.
Fig. 2. Dis tri bu tion of fre quency of be ing able to pen e trate sex ual part ner af ter tak ing sildenafil (n = 855).
Long-Term Ef fi cacy and Safety of Sildenafil Fig. 3. Dis tri bu tion of var i ous dif fi cul ties to main tain erec tion af ter tak ing sildenafil (n = 855).
Fig. 4. Sat is fac tion with sex ual life. Left panel showed the rate of pa tients sat is fied with the treat ment. Right panel re vealed the
rate of pa tients sat is fied with the sex ual re la tion ship with their part ners. A = Al most never/never; B = A few times; C = Some -
times; D = Most times; E: Al most al ways/al ways. p = 0.95a, the rate of pa tients sat is fied with the treat ment vs. the rate of pa tients
sat is fied with the sex ual re la tion ship with their part ners.
achieved and main tained penile erec tion, and dis sat is fac - con tinu a tion was dis closed in 80.2% of the pa tients.
tion was de fined if the fre quency of sat is fac tion was Only 19.8% of the pa tients claimed con tin u ing use of lower than that. Ac cord ingly, 572 pa tients (66.9%) got sildenafil. The causes of dis con tinu a tion were loss of ef - sat is fied with the treat ment, and 560 pa tients (66.1%) fi cacy in 437 pa tients (51.6%), chronic dis eases in 9.6%, were sat is fied with the sex ual re la tion ship with their ab sence of sex ual de sire in 8.8%, and part ner-related rea - part ners (Fig. 4). The both rates were not sig nif i cantly sons in 2.5%. There was a sig nif i cantly higher rate of pa - dif fer ent (p = 0.95). Sim i larly, the con fi dence in achiev - tients tak ing 100 mg at the sub se quent dose of sildenafil ing and main tain ing erec tion was “mod er ate/high/very (p < 0.001) (Fig. 6). 70.6% of the men tak ing 50 mg high” in most pa tients (N = 623, 73.0%) (Fig. 5). Over all, sildenafil as the first dose main tained this dos age, but the global as sess ment showed im prove ment of erec tion 28.5% pa tients shifted to 100 mg as the sub se quent dos - af ter med i ca tion in 517 pa tients (60.7%).
age (data not shown). Of 1074 pa tients un der sur vey, 30 In the near est 3 months be fore tele phone sur vey, dis - pa tients did not an swer. Of the other 1044, 125 (12.0%) Jour nal of the Chi nese Med i cal As so ci a tion Vol. 66, No. 8 Fig. 5. Dis tri bu tion of var i ous rates of con fi dence of get ting and keep ing erec tion af ter tak ing sildenafil (n = 855).
Fig. 6. Dis tri bu tion of first and sub se quent dos ages (n = 577); c: Fisher’s Ex act Test.
had al ways spon ta ne ous erec tion in no need of drug in med i ca tion due to ad verse events in our study.
the last 3 months, and the other 100 pa tients (9.5%) had spon ta ne ous erec tion with out drug in most times. An - other, 225 (21.50%) said that they could have spon ta ne - DIS CUS SION
ous penile erec tion in more than 50% sex ual at tempts With the wide use of sildenafil for the treat ment of Ad verse events were re ported in 175 pa tients ED, phy si cians find it very dif fi cult to re fuse the de mand (16.3%), which in cluded fa cial flush ing in 99 pa tients from pa tients for pre scrip tion.4 The is sue that pre scrip - (9.2%), diz zi ness in 45 (4.2%), tachy car dia or pal pi ta tion tion of sildenafil changes the clin i cal di ag no sis and treat - in 20 (1.9%), gas tro in tes ti nal dis tur bance in 19 (1.8%), ment of erec tile dys func tion is still con tro ver sial.9,10 blu ish vi sion in 11 (1.0%), and hypotension in 5 pa tients There is no pub lished re port re lated to post-marketing (0.5%). How ever, most events were mild or mod er ate sur veil lance about the ef fi cacy and safety of sildenafil.11 and were tol er a ble. Only 4 pa tients dis con tin ued the The pos si bil ity of many un con trolled fac tors and bias in Long-Term Ef fi cacy and Safety of Sildenafil the sur vey of post-marketing pa tients makes it hard to a peu tic level af ter a long-term treat ment. In our study, 467 have pre cise sta tis ti cal anal y sis in this study. Nev er the - pa tients re ceived 50 mg as the first dose. Finally, 28.5% of less, this study still pro vides some over view data of them in creased the dos age by 50 mg (to tal 100 mg) as the long-term fol low-up of men with ED treated with fi nal dose, while 70.6% of pa tients main tained the treat - ment dose of 50 mg. The low rate (17.8%) as so ci ated with Re gard ing the as sess ment of ef fi cacy, our re sult cor rect man ners of tak ing sildenafil and the high dis con - showed that 72.1% pa tients tak ing sildenafil had tinu a tion rate (80.2%) in our ED pa tients may con trib ute achieved suf fi cient penile erec tion for vag i nal pen e tra - to re cov ery of spon ta ne ous erec tion, im proper man ner of tion, and that 73.4% pa tients main tained the penile erec - tak ing med i cine and old age (av er age: 69.1 years). The tion through out sex ual in ter course. Goldstein et al. re - sex ual de sire of the el derly may not be high, which may ported in a con trolled study that 69% of pa tients had suc - as so ci ate with high dis con tinu a tion rate. There fore, we cess ful sex ual in ter course tak ing sildenafil.5 In the Asian em pha sized the im por tance of pa tient in struc tion, dose ti - stud ies, Chen et al. re ported a pla cebo-controlled trial tra tion, ed u ca tion of pri mary care phy si cian and sched uled and elu ci dated that 62% of the pa tients tak ing sildenafil fol low-up of pa tients in an at tempt to de crease the dis con - had suc cess ful sex ual in ter course while 88.2% of men tinu a tion rate. How ever, we noted that 125 of 1044 pa - had im prove ment in penile erec tion.7 An other study tients (12.0%) al ways had spon ta ne ous erec tion with out through South east Asia re vealed 87% rate of suc cess ful the need for drug in the last 3 months, and the other 100 at tempts at in ter course.8 Ron ald et al. as sessed the ef fi - pa tients (9.5%) had spon ta ne ous erec tion with out drug in cacy of sildenafil with erec tile dys func tion in ven tory of most times. Rizk et al. re ported that 82 of 200 pa tients fin - treat ment sat is fac tion (EDITS) ques tion naire and 75% of ished the sec ond sur vey, and 43 of 82 (52%) had con tin - the pa tients were sat is fied with the treat ment, whereas ued the treat ment. Of the 43 pa tients who still used 88.2% pa tients had pos i tive an swers of abil ity to have sildenafil, 16 (37%) had to in crease the dos age by 50 mg inter cours es in the global as sess ment of ques tion.6 There to achieve ad e quate penile erec tion. Of the 28 pa tients seems to be no ma jor dif fer ence of ef fi cacy of sildenafil with good ini tial re sponse to sildenafil, 14 pa tients (50%) stopped the med i ca tion due to loss of ef fi cacy. He sug - The rate of fail ing the first trial of sildenafil in our gested the pos si bil ity of “tachyphylaxis” be cause only pa tients was 41.2%, but only 17.8% of them had cor rec - 52% of pa tients con tin ued the med i ca tion and the ma jor tion of the ad min is tra tion man ner. The o retically, the cause of dis con tinu a tion was loss of ef fi cacy (50%). Also, prob a bil ity of erec tion in duced by the first tak ing of there were 6 of 28 pa tients (21.4%) with spon ta ne ous sildenafil and the sub se quent same med i ca tion will not erec tion with out treat ment of drug,4 which was quite sim i - be dif fer ent. In our study, there was no sta tis ti cal dif fer - lar to our re sult (21.5%). Mar shall et al. re ported the tran - ence in erec tion prob a bil ity be tween the first tak ing and sient, par tial or com plete res to ra tion of spon ta ne ous erec - the sub se quent tak ing of the same med i ca tion (Ta ble 1).
tions in 35% to 73% of men with ED af ter long-term intra - A high dis con tinu a tion rate (80.2%) in the lat est 3 cavernosal self-injection of alprostadil. They ev i denced months was noted in our pa tients. There fore, there should im prove ment of the penile cir cu la tion af ter long-term be much space to im prove the ef fi cacy of sildenafil by treat ment in men with arteriogenic ED.13,14 Fur ther more, way of, for ex am ple, pa tient in struc tion, dose ti tra tion, con sid er ing psy chi at ric fac tors, we sup posed that the pa - ed u ca tion of pri mary care phy si cian and sched uled fol - tients’ sub se quent self-confidence would en hance even with out sildenafil. How ever, the mech a nism of com plete Loss or ab sence of ef fi cacy is the pre dom i nant fac tor or par tial re turn of erec tile func tion in our pa tients tak ing of dis con tinu a tion of tak ing sildenafil. In this sur vey, sildenafil awaits fur ther pro spec tive, ran dom ized and dou - 80.2% of pa tients dis con tin ued sildenafil in the last 3 ble-blind con trol stud ies. Re gard ing to the is sue of months and 51.6% of them claimed the loss of ef fi cacy.
tachyphylaxis, our data were sim i lar to the re port by Rizk The dos age of sildenafil has to in crease for keep ing a ther - Jour nal of the Chi nese Med i cal As so ci a tion Vol. 66, No. 8 The rate of ad verse events in our pa tients was 16.3%, Viagra (sildenafil ci trate) treat ment as de ter mined by the erec - which is sim i lar to the study (6-18%) by Goldstein and tile dys func tion in ven tory of treat ment sat is fac tion ques tion - co work ers,5 but lower than the re ports by Ron ald et al. naire. Urol ogy 2001;57:960-5.
(42%),6 by Chen et al. (43.7%)7 and by Tan et al. (22.8%).8 7. Chen KK, Hsieh JT, Huang ST, Jiaan DB-P, Lin JS-N, Wang CJ. AS SESS-3: A ran dom ized, dou ble-blind, flex i ble-dose The re sults of this study dem on strated that the ef fi - clin i cal trial of the ef fi cacy and safety of oral sildenafil in the cacy of sildenafil af ter mar ket ing was sim i lar to the pre - treat ment of men with erec tile dys func tion in Tai wan. Int J vi ous clin i cal tri als. The ad verse events af ter sildenafil were mild and tol er a ble. Re cov ery of com plete or par tial 8. Tan HM, Moh CL, Mendoza JB, Gana T, Albano GJ, Cruz D, spon ta ne ous erec tion was noted in some pa tients (21.5% et al. Asian Sildenafil Ef fi cacy and Safety Study (AS SESS-1): in our study) af ter long-term us age of sildenafil.
A dou ble-blind, pla cebo-controlled, flex i ble-dose study of oral sildenafil in Ma lay sian, Singaporean, and Fil i pino men with erec tile dys func tion. Urol ogy 2000;56:635-40.
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9. Kim YC. Al go rithm for di ag no sis and treat ment of erec tile dys func tion in the era of sildenafil ci trate. Int J Androl 2000; 1. NIH con sen sus de vel op ment panel on im po tence. JAMA 10. Garg RK, Khaishgi A, Dandona P. Is man age ment of im po - 2. Feldman HA, Goldstein I, Hatzichchristou DG, Krane RJ, Mc - tence with sildenafil chang ing clin i cal prac tice? Lan cet 1999; Kin lay JB. Im po tence and its med i cal and psychosocial cor re - lates: re sults of the Mas sa chu setts male ag ing study. J Urol 11. Willem M, Rene’ FK, Pieter V. Com par a tive tolerability and ef fi cacy of treat ments for im po tence. Drug Safety 1999;20: 3. Wang YX, Leng J, Chen B, Huang XY. The prev a lence of erec tile dys func tion in el der adults in Shang hai: an anal y sis of 12. Rosen RC, Riley A, Wangner G, Osterloh IH, Kirkpatrick J, 1582 cases. Int J Impot Res 1997;9(suppl 1):S45.
Mishra A. The in ter na tional in dex of erec tile func tion (IIEF): a 4. Rizk EG, Harry R, Riydh T, Thomas K, Harry C. Long-term mul ti di men sional scale for as sess ment of erec tile dys func tion. ef fi cacy of sildenafil and tachyphylaxis ef fect. J Urol 2001; 13. Mar shall GA, Breza J, Lue TF. Im proved hemodynamic re - 5. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD.
sponse af ter long-term intracavernous in jec tion for im po tence. Oral sildenafil in the treat ment of erec tile dys func tion. N Engl 14. Brock G, Tu LM, Linet OI. Re turn of spon ta ne ous erec tion 6. Ron ald L, Carol JB, Wil liam DB, Wil liam HB, Stan ley EA, dur ing long-term intracavernosal alprostadil (Caverject) treat - Vera JS, Rich ard LS. Pa tient and part ner sat is fac tion with ment. Urol ogy 2001;57:536-41.

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