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ACHIEVING TREATMENT OPTIMIZATION WITH SILDENAFIL CITRATE (VIAGRA®) IN PATIENTS WITH ERECTILE DYSFUNCTION ANDREW R. MCCULLOUGH, JAMES H. BARADA, AHMED FAWZY, ANDRE T. GUAY, DIMITRIOS HATZICHRISTOU AND ABSTRACT Since its approval in 1998, sildenafil citrate (Viagra) has been shown to be efficacious in ⬎100 clinical trials involving ⬎8000 men with erectile dysfunction (ED). In clinical practice, however, many men do not continue long-term use of sildenafil for a variety of reasons; thus, 6 different aspects of optimizing treatment with sildenafil are described here. (1) Intercourse success rates, considered a reflection of real-world effectiveness, were assessed in 1276 patients with ED. Results indicated that the cumulative probability of achieving intercourse success with sildenafil increased with the number of attempts, reaching a plateau after approximately 8 attempts. (2) A comprehensive disease management approach that included a medical history, physical examination, educational material about ED, modifications of risk factors/lifestyle changes, and counseling resulted in successful intercourse in 74% of 111 patients taking sildenafil. (3) A survey conducted among primary care physicians revealed that almost 50% did not routinely question their patients about ED symptoms, although it is known that most patients would prefer their physician to take the initiative. (4) Overall, 55% of 137 men who were previously not successful with sildenafil became successful after reeducation and counseling, which included information on patient and partner expectations, how to properly take the drug, titration to maximum dose, and a minimum trial of 8 attempts for efficacy assessment. (5) Many men with ED have underlying comorbidities or take multiple medications that are risk factors for ED. Controlling these risk factors in 521 men from a multispecialty clinic led to an overall intercourse success rate of 82%; patients with multiple risk factors were less likely to have intercourse success than men with only 1 risk factor. (6) Finally, treatment satisfaction is a pivotal factor in maintaining long-term ED therapy. In an open-label trial, 82% of 443 subjects reported treatment satisfaction with sildenafil. In summary, these findings highlight how important it is for physicians to take a more comprehensive, proactive approach when treating men with ED, including control of risk factors, instructions on how to properly take the drug, partner involvement, and follow-up visits. Using these recommended measures, most men with ED, including those whose treatment was previously unsuccessful, can be treated successfully with sildenafil. UROLOGY 60 (Suppl 2B): 28–38, 2002. © 2002, Elsevier Science Inc. S ince its approval in March 1998, the efficacy and safety of sildenafil citrate (Viagra; Pfizer, Inc, New York, NY) in treating erectile dysfunction (ED) have been evaluated in clinical trials totaling ⬎11,000 patient-years.1 Overall, ⬎100 trials have been completed or are ongoing, involving ⬎8000 men.2 Efficacy of sildenafil, as evaluated using a global efficacy question (GEQ; improved ability to have erections), varies depending on the etiology and severity of ED and the comorbid conditions of the patient population. For example, in men with a broad spectrum of ED, sildenafil (50 and 100 mg) improved erections in 77% to 84% of patients.3 In specific patient populations, men with spinal cord injury4,5 had high response rates (75% and 88%, respectively), as did those with depression (90%).6 From the New York University Medical Center, New York, New York, USA; Center for Male Sexual Health, Albany, New York, USA; Urologic Institute of New Orleans, Gretna, Louisiana, USA; Center for Sexual Function/Endocrinology, Lahey Clinic, Peabody, Massachusetts, USA; and Department of Urology, School of Medicine and Centre for Sexual and Reproductive Health, Aristotle University of Thessaloniki, Thessaloniki, Greece This supplement was funded by Pfizer Inc. Andrew R. McCullough, James H. Barada, Ahmed Fawzy, Andre T. Guay, and Dimitrios Hatzichristou are paid consultants to, and study investigators funded by, Pfizer Inc. Reprint requests: Andrew R. McCullough, MD, Department of Urology, New York University Medical Center, 540 1st Avenue, Sirball Building, Suite 10U, New York, New York 10016 28 © 2002, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED 0090-4295/02/$22.00 PII S0090-4295(02)01688-6 In comparison, efficacy in men with diabetes (65%)7 or after radical prostatectomy (45%) tended to be lower.8,9 Current numbers indicate that approximately 30 million men in the United States are affected by ED, with half of all men ⬎40 years of age experiencing some degree of ED.10 Unfortunately, most men with ED (90%) remain undiagnosed because they do not seek treatment for a condition from which the overwhelming majority would benefit.11 ED can potentially be the first indication for other underlying, serious diseases, and can have a significant effect on a patient’s quality of life. Because ED and cardiovascular disease share many common risk factors, men seeing a primary care physician (PCP) for their ED should be screened for underlying cardiovascular disease. Conversely, men seeking treatment and/or at high risk for hypertension, diabetes, depression, or other comorbidities known to be associated with ED should be screened for ED using, for example, the Sexual Health Inventory for Men (SHIM).12 Many men are reluctant to discuss ED with their physician. In fact, a study in France involving ⬎7000 patients with diabetes, hypertension, or both, demonstrated that, despite a high prevalence of ED, ⬎50% the patients had not been treated; however, a large proportion of these patients wished to be treated and wanted their physician to initiate a discussion on this topic.13 Since its approval in 1998, ⬎100 million prescriptions written by ⬎500,000 physicians have been filled, with ⬎1 million new and/or refill prescriptions dispensed each month for the past year.2 PCPs comprise the biggest group (64%) of prescribers, with urologists, second (15%). However, urologists as a specialty group wrote the most prescriptions per month per physician (9.0), compared with PCPs, who dispensed an average of 3.9 prescriptions per month. Despite this high number of first-time prescriptions, patient behavior with respect to continued drug use varies widely. Of patients tracked for 1 year (March 2000 to February 2001) 52% filled a second prescription during the 12-month period and 31% filled ⬎7 prescriptions. The age group with the most prescriptions (new and refill) was 50 to 59 years of age (33%), followed by 60 to 69 (25%) and 40 to 49 years of age (21%).2 Ideally, a prescription refill rate similar to the clinical efficacy rate of 70% might be expected. However, clinical trials are designed to demonstrate efficacy and do not necessarily reflect real-world considerations. For example, in clinical trials, (1) patients are more motivated, (2) patients and partners are better educated because both have to sign an informed consent form, (3) medication is free of cost, and (4) follow-up/reeducation are provided by physicians and research staff who are highly knowledgeable in treatUROLOGY 60 (Supplement 2B), August 30, 2002 ing ED. On the other hand, failure to continue using the drug on a long-term basis could be caused by numerous reasons including: (1) disappointment with the initial results, (2) concern about safety issues, (3) being bothered by or misunderstanding side effects, (4) relationship problems (their partner may not be interested in resuming sexual activity), (5) the cost of the medication, or (6) gradual loss of efficacy caused by worsening underlying medical conditions. Proper instructions by physicians prescribing sildenafil to their patients on how to use the drug appear to play an important role in treatment satisfaction, outcome, and continued use. The level of understanding the treating physician has of ED, how comfortable they are in initiating treatment for ED, how much time is spent educating a patient, how much, if any, follow-up treatment is provided, and whether patients are referred to a specialist (immediately, or only after sildenafil fails) are all vital for treatment success. Moreover, the involvement and/or education of the patient’s partner is paramount to success because patients seeking treatment for ED may not have been sexually active for long periods of time, and their partners may not be immediately receptive to resuming sexual activity. The data presented in this article show the benefit of proper patient education and follow-up treatment by the physician, and the success that can result with persistent use of sildenafil, even if the initial attempts fail. METHODS Many different approaches have been taken to assess and improve success of sildenafil treatment for ED, including 6 studies described below. ASSESSMENT OF INTERCOURSE SUCCESS RATES Measurement of intercourse success is considered representative of real-world effectiveness. Thus, intercourse success rates were assessed by examining data obtained from event logs of 1276 patients with ED who were enrolled in 6 prospective, double-blind, placebo-controlled, flexible-dose studies from 1996 to 1998. Men taking sildenafil (n ⫽ 654) or placebo (n ⫽ 622) were stratified by ED severity based on scores from the erectile function (EF) domain of the International Index of Erectile Function (IIEF)14,15: no ED, EF domain score 26 to 30; mild ED, 22 to 25; mild-to-moderate ED, 17 to 21; moderate ED, 11 to 16; severe ED, 1 to 10. Event log questions included: (1) Was the study medication taken? (2) Did you have any sexual stimulation? (3) Did you have successful intercourse? Unlike many studies using the IIEF, which relies on 4-week patient recall, this study used immediate recall of every sexual experience with sildenafil. DISEASE MANAGEMENT APPROACH This was a comprehensive disease management program that included several different elements, such as a complete medical history and physical examination, educational material on ED and on all available treatment options, modifications or risk factors/lifestyle changes as appropriate, and initiation of sexual counseling when clinically appropriate. 29 PCPs have taken on an increasingly important role in the management of ED, and how well that task is handled is vital for treatment success. A 9-question survey was distributed to PCPs attending scientific meetings between April and December 1998. Overall, 1634 physicians (46% family physicians, 32% internists, and 22% in other specialties) were surveyed on how they treated their patients with ED.16 using nitrates, or who had failed a cardiac stress test were excluded from this study. Medication and Lifestyle Modification. Medical and drug-use histories were retrieved from the clinical database. Patients using medications believed to interfere with sexual functioning were switched to an alternative drug. For example, -blockers (eg, metoprolol or propanolol) believed to aggravate sexual dysfunction were replaced with atenolol. Similarly, patients with hypertension were considered for a switch to an angiotensin-converting enzyme inhibitor or an angiotensin-receptor antagonist, and patients with hyperlipidemia who were taking gemfibrozil were switched to a statin.18 Smokers were encouraged to stop smoking or to reduce their cigarette intake. Patients were encouraged to limit alcohol intake to 1 drink per day on those days that sildenafil was used and to ⱕ2 drinks per day on other days. Hormonal Assessment. Because hypogonadism may be a contributing factor in causing ED, patients whose profiles indicated a possibility of hypogonadism were evaluated for serum testosterone levels; if found to be below age-appropriate levels, patients were given a testosterone supplement or had their endogenous testosterone levels increased using the fertility drug clomiphene citrate. Men with known hypogonadism were treated with testosterone replacement therapy for 3 months; if their ED did not resolve, sildenafil treatment was initiated. A small group of patients (n ⫽ 44) received sildenafil treatment before a diagnosis of hypogonadism was made. Sildenafil efficacy in these men was compared with those men with hypogonadism who had the benefit of a 3-month testosterone therapy. Patients received an initial 50-mg dose of sildenafil, which could be adjusted to 25 mg or 100 mg based on efficacy and tolerability, and recorded the number of successful intercourse attempts for a period of 6 to 8 weeks. Success was defined as an erection rigid enough for vaginal penetration and of long enough duration to reach ejaculation. Adverse events were also noted throughout this time. REEDUCATION OF MEN WHO WERE INITIALLY SILDENAFIL NONRESPONDERS ASSESSMENT OF TREATMENT SATISFACTION WITH SILDENAFIL Consecutive patients who visited a urology clinic were enrolled in a goal-oriented disease management program for up to 18 months. At the initial visit, a complete medical history was taken and a physical examination was performed. When clinically indicated, a male hormone panel, sequential multiple analyzer–7, and penile Doppler examination were also performed. Major inclusion criteria were: male patients ⬎18 years of age with a clinical diagnosis of ED of any etiology, who visited the clinic between April 1998 and December 1998. Patients with contraindications for the use of sildenafil were not eligible. A starting dose of 50-mg sildenafil was prescribed, and patients with a partial response or no response to sildenafil at the 1-month follow-up visit were given the 100-mg dose. At subsequent follow-up visits (3, 6, and 12 months), those patients who failed to respond to the 100-mg dose were switched to other treatment options, based on patient and partner preference. EF was assessed using question (Q)3 (achieving an erection) and Q4 (maintaining an erection) from the IIEF, which were rated on a 5-point scale ranging from 1 (almost never/never) to 5 (almost always/always), with a score of 0 corresponding to no sexual activity. Responders were classified based on the treating physician’s clinical assessment and the patient’s responses to questions Q3 and Q4 of the IIEF. Responses were classified as successful (an erection sufficient for penetration), partial (an erection not sufficient for penetration), and failure (no erection). PRACTICE PATTERNS OF PRIMARY CARE PHYSICIANS IN ERECTILE DYSFUNCTION MANAGEMENT A retrospective chart review of men exposed to sildenafil therapy by their PCP for the treatment of ED over a 22-month period was used to identify 137 men who had been unsuccessful with sildenafil. Patients received a review of their referral chart; a physician interview; a patient recall questionnaire; the IIEF questionnaire before and after therapy; and education on ED, sildenafil, patient expectations, and other therapy options. Patient recall of the evaluation and education was assessed, and dose titration was obtained from the referring PCP. Patients without contraindications were offered a second trial of sildenafil after intensive education, including titration to the 100-mg dose for those who had not previously done so. Therapy outcome was measured using Q3/Q4 from the IIEF and a GEQ. A minimum trial of 8 attempts at the final dose was used for efficacy assessment.17 CONTROL OF ASSOCIATED RISK FACTORS Many men with ED have underlying comorbidities that are risk factors for ED. Controlling these risk factors with medication and/or lifestyle changes can improve the chance of success with sildenafil treatment. This was an open-label study of 521 patients with ED (based on self-assessment) in a multispecialty clinic.9 Associated risk factors, such as hypertension, hypogonadism, and/or use of multiple medications were managed by lifestyle modification/medication before ED treatment with sildenafil. Patients with ED for ⱖ6 months and an intercourse failure rate of ⱖ50% were eligible for inclusion. Patients who had previously used sildenafil, were concurrently 30 Treatment satisfaction by both patient and partner can play a critical role in maintaining long-term therapy for ED. To assess this, a multicenter, open-label, single-treatment study with flexible dosing was performed. There were 2 phases: an 8-week primary phase, followed by a 28-week extension phase. Only data from the 8-week phase are reported here. Overall, 443 subjects were enrolled at 77 sites: 235 who had not been receiving treatment for their ED before this study (n ⫽ 125 aged ⱕ60 years; n ⫽ 110 ⬎60 years) and 208 who had received ED treatment other than sildenafil (yohimbine, intracavernosal [IC] alprostadil, IC phentolamine, and/or papaverine, vacuum device) before entering the study (n ⫽ 107 aged ⱕ60 years; n ⫽ 101 ⬎60 years). Primary efficacy was analyzed after 8 weeks using the 11-item Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS).19 Answers are scored from a range of 0 to 5; subsequently, for each patient, the average of scores from questions 1 to 11 was multiplied by 25 to give a total score ranging from 0 to 100. This EDITS index score was used as the primary efficacy variable, and treatment satisfaction was defined as a score ⱖ50. Secondary efficacy assessments included 3 GEQs (GEQ1, improved erections; GEQ2, improved ability for sexual intercourse; GEQ3, frequency of erection that allowed satisfactory intercourse) and 2 questions from the SHIM, a shortened, 5-item version of the IIEF (Q4, achieving an erection; Q5, maintaining an erection). Responses to GEQs 1 and 2 were yes/no; responses to GEQ3, Q4, and Q5 were rated on a 5-point scale: 1 ⫽ almost never/never to 5 ⫽ almost always/ always, 0 ⫽ did not attempt intercourse. UROLOGY 60 (Supplement 2B), August 30, 2002 FIGURE 1. Distribution of patients by erectile dysfunction severity. ED ⫽ erectile dysfunction; EF ⫽ erectile function. RESULTS ASSESSMENT OF INTERCOURSE SUCCESS RATES Distribution of patients by ED severity is shown in Figure 1. The cumulative probability of achieving intercourse success with sildenafil increased with the number of attempts (54% and 64% for the first and second attempt, respectively) and reached a plateau of 86% (Figure 2). A similar pattern was seen in men with mild-to-moderate (n ⫽ 372) or severe ED (n ⫽ 248) on sildenafil who reached a cumulative probability of 85% and 65%, respectively (Figure 2). In most patients, success occurred with the 50-mg dose. In all, 46% of attempts with sildenafil (vs 12% with placebo) resulted in successful intercourse 90% of the time, whereas 80% of attempts with sildenafil (vs 41% with placebo) resulted in successful intercourse ⱖ50% of the time. Thus, the therapeutic success rate of sildenafil was sustained. DISEASE MANAGEMENT APPROACH A total of 200 patients were screened, 111 patients were enrolled, and 96 patients completed the study. Overall, 60 of 111 (54%) patients reported a “successful response” to a 50-mg dose of sildenafil at the 1-month visit (patients had been instructed to have 4 to 6 attempts; Figure 3). Of those patients who reported a “partial response” at the 1-month visit (n ⫽ 32), ⬎50% (n ⫽ 19) became successful with a higher dose of sildenafil, and 2 patients reported success after switching to intraurethral alprostadil suppositories. By the end of the study, 74% (82 of 111) of patients who received 50 mg or 100 mg of sildenafil reported successful intercourse (Figure 3). Of those patients who did not respond to an increased dose of sildenafil (n ⫽ 29), 17% (5 of 29) became UROLOGY 60 (Supplement 2B), August 30, 2002 successful after switching to a different treatment modality (intraurethral alprostadil suppositories, n ⫽ 2; IC injection, n ⫽ 2; vacuum pump, n ⫽ 1), and 52% (15 of 29) opted not to switch treatments and discontinued. Responses to Q3 and Q4 from the IIEF are shown in Figure 4. PRACTICE PATTERNS OF PRIMARY CARE PHYSICIANS IN ERECTILE DYSFUNCTION MANAGEMENT This survey showed that less than half (45%) of physicians routinely questioned their patients about ED-related symptoms. Most PCPs relied on a detailed sexual history (71%) and a complete medical history and physical examination (74%) to make an ED diagnosis, whereas 53% and 36% used routine laboratory analysis and serum testosterone/luteinizing hormone/prolactin determinations, respectively, as the initial diagnostic tests. For treatment of ED, most physicians relied on lifestyle changes (70%), sexual counseling (57%), sildenafil prescriptions (60%), and hormone therapy (25%). To a lesser degree, PCPs prescribed vacuum devices (17%), intraurethral alprostadil suppositories (15%), and IC injection therapy (9%).16 REEDUCATION OF MEN WHO WERE INITIALLY SILDENAFIL NONRESPONDERS Data from 137 consecutive men exposed to sildenafil, referred by 27 different PCPs, were analyzed between August 1998 and July 2000 (22 months). Complete follow-up data were available for 114 of 137 men (83%). Overall, 36% of men recalled PCP discussion of side effects, food/alcohol effects (34%), and patient-partner expectation of therapy (21%). More than half (55%) were referred after a maximal dose of 50 mg and/or a trial of ⬍5 attempts. In all, 23% then elected no further therapy or therapy 31 FIGURE 2. Intercourse success rates, as determined from event log data, in men with erectile dysfunction taking sildenafil (top). Intercourse success rates in men stratified by erectile dysfunction severity (bottom). change, and 3 patients had a nitrate-use contraindication. The remaining 85 men were reeducated in sildenafil use and expectations, and 89% of those initiated therapy at the 100-mg dose. Adverse events or partner discord caused 9 patients not to complete the rechallenge (Figure 5). Altogether, 41 of 76 (54%) of those completing the trial were responders as judged from Q3/Q4 of the IIEF and the GEQ. Patients with diabetes, taking multiple hypertensive agents, and active smokers were more likely to be nonresponders. A total of 13 of 35 (37%) nonresponders went on to successful therapy with other treatment modalities that included IC injections and penile prostheses (Table I). CONTROL OF ASSOCIATED RISK FACTORS Patients (median age, 59 years) who had modified their associated risk factors had an overall suc32 cess rate of 82% (defined as an erection rigid enough for vaginal penetration and of long enough duration to reach ejaculation); success at every intercourse attempt occurred in 77% of patients. The success rate for those men with concomitant medical conditions ranged from 43% in patients having undergone nerve-sparing prostatectomy, to 85% in hypogonadal patients receiving testosterone treatment, patients with neurologic disease, and those abusing alcohol (Figure 6). The success rate was second highest in patients with hypertension (83%), followed by smokers (80%), those taking multiple medications (77%), and those with asymptomatic coronary artery disease (71%). Patients with multiple risk factors, such as those with hypertension and diabetes (n ⫽ 43), had a higher percentage of intercourse failures (35%) compared with men who had only 1 risk factor. Efficacy in the subgroup of patients with hypoUROLOGY 60 (Supplement 2B), August 30, 2002 FIGURE 3. Patient disposition in a disease management program. gonadism and known low levels of free testosterone (n ⫽ 44) was compared with a control group of 44 men with normal levels of free testosterone (ⱖ11 pg/mL) and similar concomitant risk factors. Men with slightly low testosterone levels (n ⫽ 33; 10.6 pg/mL) reported that 75% of all intercourse attempts with sildenafil were successful. Men with moderately low testosterone levels (n ⫽ 7; 8.1 pg/mL) reported a success rate of ⬍75%, whereas men with severely low testosterone levels (n ⫽ 4; 7.4 pg/mL) did not respond to sildenafil at all. Overall, 18% of all patients were sildenafil nonresponders (defined as ⬎75% of intercourse attempts failing), despite attempts to control associated risk factors. ASSESSMENT OF TREATMENT SATISFACTION WITH SILDENAFIL After 8 weeks of dosing with 25-, 50-, or 100-mg doses of sildenafil, 82% of patients responding to the EDITS questionnaire were satisfied with their treatment, as defined by a combined EDITS score of ⱖ50. Estimated satisfaction rates were similar in men preUROLOGY 60 (Supplement 2B), August 30, 2002 viously untreated (83%) and previously treated (84%) for ED, and were slightly higher in younger than in older men, regardless of the kind of treatment received before this study (86% vs 80%). Responses to the SHIM indicated an improvement in the ability to achieve and maintain an erection and in overall satisfaction with sexual intercourse during the previous 8 weeks (Figure 7). Similarly, efficacy as measured using 3 GEQs demonstrated that sildenafil was efficacious, regardless of the age of the patient or whether they had received prior treatment for their ED (Table II). COMMENT Because more men are seeking treatment for their ED, physicians, especially PCPs, are increasingly more involved in the decision-making process about evaluation and treatment of these patients.16 Surveys have shown that overall treatment success and long-term use of sildenafil are lower when prescribed by PCPs compared with specialists.20 Likely reasons include differing patient populations and expectations, and insufficient PCP 33 FIGURE 4. Efficacy results in a disease management program. Baseline and end-of-treatment (EOT) scores for International Index of Erectile Function question (Q)3 and Q4. EOT scores are patient responses to Q3 and Q4 at the stage they reached “success” (ie, 50 mg sildenafil, 100 mg sildenafil, switch to another treatment modality). knowledge to be able to diagnose, educate, and treat patients with ED. Considering that PCPs comprise the biggest group of prescribers, it is clear that better education on sexual health is needed for this group of healthcare providers. In general, PCPs and other healthcare providers dealing with the increasing incidence of ED face 4 major issues: (1) realizing the importance of identifying and treating patients with ED, (2) increasing the effectiveness of this process, (3) providing adequate patient education on the use of sildenafil, and (4) providing proper patient follow-up. THE IMPORTANCE OF IDENTIFICATION AND TREATMENT OF PATIENTS WITH ERECTILE DYSFUNCTION Because ED shares a number of risk factors with cardiovascular disease, and may be the first indication and possibly a surrogate marker for underlying cardiovascular disease, screening for ED will likely identify high-risk patients and allow earlier detection and treatment of serious diseases, such as hypertension, diabetes, and dyslipidemia (eg, cardiovascular disease, peripheral vascular disease). By modifying these risk factors, subsequent treatment of ED has a better chance of success. In addition, ED can have a major negative impact on selfesteem and quality of life of both the patient and his partner. ED can lead to depression, and the use 34 of antidepressant drugs can in turn aggravate ED. ED that may develop as a result of medications used to treat chronic conditions, such as hypertension, diabetes, dyslipidemia, and depression, can be treated successfully with sildenafil, which may result in improved treatment compliance for chronic, yet potentially life-threatening diseases. EFFECTIVENESS OF IDENTIFICATION AND TREATMENT OF PATIENTS WITH ERECTILE DYSFUNCTION With approximately 90% of men with ED remaining undiagnosed and untreated, changes in the way healthcare providers deal with this issue are needed. Perceptions of ED therapy appear to be different between PCPs and specialists/urologists, with treatment outcomes less favorable in the former group. PCPs are less likely to screen at-risk patients and to identify and refer for treatment failures.16 Although surveys have shown that patients clearly wish their physician to bring up the subject of sexual health,13 embarrassment of both parties (patient and physician) often prevents an open discussion on this topic. PCPs might also be hampered by time constraints, and typically, they may not educate patients on all available treatment options. Specialists, on the other hand, often perform a more detailed diagnostic evaluation, take a more goal-oriented disease management approach, and UROLOGY 60 (Supplement 2B), August 30, 2002 FIGURE 5. Patient disposition of initial sildenafil nonresponders. AE ⫽ adverse event; GEQ ⫽ global efficacy question; IIEF ⫽ International Index of Erectile Function. TABLE I. Initial sildenafil nonresponders: efficacy after patient reeducation GEQ1, % GEQ2, % Mean number of attempts before first success (range) IIEF Q3, mean score IIEF Q4, mean score Yes No 59 52 41 48 3.1 (1–9) Baseline 12 Weeks 1.6 1.4 3.4 3.1 GEQ ⫽ global efficacy question; IIEF ⫽ International Index of Erectile Function; Q ⫽ question. tend to recognize and address treatment failures early. The use of the SHIM, a brief, validated instrument, can be very helpful in identifying patients with ED and can be used to document EF before prescribing agents that may contribute to ED (eg, antihypertensives, lipid-lowering agents, antidepressants) and should be used routinely in all men UROLOGY 60 (Supplement 2B), August 30, 2002 with cardiovascular, metabolic, or psychiatric disease.12 PROPER EDUCATION ON THE USE OF SILDENAFIL Physicians should better educate their patients on the use of sildenafil. Increasingly, sildenafil is the treatment of choice that will be offered to a patient, 35 FIGURE 6. Sildenafil efficacy in patients with risk factors or concomitant conditions (percent success). Partial success was determined only in the HYP⫺T group. Proportions of successful versus unsuccessful patients for each condition were compared using binomial tests of independent proportions. Significant difference at P ⱕ0.05. A-CAD ⫽ asymptomatic coronary artery disease; ALC ⫽ alcohol abuse; ASMA ⫽ asthma; DM ⫽ diabetes mellitus; DM⫹NP ⫽ diabetes mellitus plus neuropathy; HYP⫹T ⫽ hypogonadism plus testosterone treatment; HYP⫺T ⫽ hypogonadism without testosterone treatment; HTN ⫽ hypertension; HTN⫹DM ⫽ hypertension plus diabetes mellitus; MM ⫽ multiple medications; ND ⫽ neurological disease; PRO ⫽ nerve-sparing prostatectomy; PFIB ⫽ penile fibrosis; PVD ⫽ peripheral vascular disease; TOB ⫽ tobacco abuse; TURP ⫽ transurethral resection of the prostate. and if proper instructions are not given and immediate intercourse success is not achieved, men are less likely to continue their trial with sildenafil and may potentially give up on ED treatments entirely. Thus, when educating patients, the physician should emphasize the following: (1) the need for sexual stimulation, (2) the proper timing of when to take the drug (including its relation to meals and the types of food eaten), (3) the importance of dose titration when lower doses are not effective, and (4) the need for patience (eg, taking the drug on several occasions to provide adequate opportunity for success). In addition, patients should understand that although sildenafil is to be taken approximately 30 to 60 minutes before intercourse, its effect can last approximately 4 hours, allowing more spontaneous use. However, the therapeutic effect can be delayed and/or compromised by a high-fat meal, smoking, and/or excessive alcohol intake during the hours preceding sexual activity. THE IMPORTANCE OF FOLLOW-UP VISITS If men are unsuccessful with sildenafil, the physician should carefully evaluate the following: (1) 36 has the patient had sufficient exposure to the drug (eg, were there more than a couple of attempts at intercourse, was there adequate dose titration), (2) has the drug been taken appropriately (eg, was there sexual stimulation), and (3) have risk factors been modified and underlying diseases been treated. Men who have previously failed with sildenafil can become successful with reeducation and/or dose escalation. Finally, whether or not men have the support of their partners can be the deciding factor for treatment success. A study by Lewis et al.21 has shown that involvement of the partner when making treatment decisions is associated with higher treatment satisfaction in men and their partners. After ED diagnosis with the SHIM, treatment progress can be monitored during regular follow-up visits to the treating physician.19 If all of the above issues have been addressed and sildenafil treatment still fails, the patient may have a more severe underlying associated condition, such as peripheral vascular disease or hypogonadism. Therefore, inappropriate follow-up treatment/assessment by the physician can lead not only to UROLOGY 60 (Supplement 2B), August 30, 2002 FIGURE 7. Responses to question 4 (Q4; ability to maintain an erection) and Q5 (ability to have satisfactory sexual intercourse) from the Sexual Health Inventory for Men questionnaire. Responses were rated from 1 (most positive) to 5 (most negative). Thus, a decrease in score represents an improvement in response. EOT ⫽ end of treatment. TABLE II. Treatment satisfaction study: efficacy after 8 weeks Previously Untreated for ED GEQ1, % yes GEQ2, % yes GEQ3, mean Previously Treated for ED <60 yr (n ⴝ 122) >60 yr (n ⴝ 108) Total (n ⴝ 230) <60 yr (n ⴝ 105) >60 yr (n ⴝ 98) Total (n ⴝ 203) 91.0 90.0 4.2 85.2 82.4 3.7 88.3 86.4 3.9 91.4 85.7 4.0 83.7 83.3 3.6 87.7 84.6 3.8 ED ⫽ erectile dysfunction; GEQ ⫽ global efficacy question. inadequate treatment for ED, but also to potentially serious comorbidities being undiagnosed and/or untreated. RECOMMENDATIONS FOR SILDENAFIL TREATMENT OPTIMIZATION The treatment guidelines below should aid physicians in better identifying and treating patients with ED and help ensure continued treatment success. EVALUATION AND TREATMENT CONSIDERATIONS ● PCPs should screen their patients for ED because ED may be the first indication and a possible surrogate marker of more generalized peripheral vascular, cardiovascular, or metabolic disease. A medical history (including a sexual history) should be taken, and a focused physical examination should be performed. ● Control medical risk factors, either before or at the time of issuing a sildenafil prescription: (1) encourage discontinuation of smoking and moderation in alcohol consumption (ie, no smoking or drinking in the hours preceding sildenafil use); (2) control hyperlipidemia, hypertension, and diabeUROLOGY 60 (Supplement 2B), August 30, 2002 tes; (3) when medically appropriate, consider switching patients from existing medications that may aggravate ED to others known to have less of an effect on EF; and (4) treat hypogonadism as appropriate. ● Include the patient’s partner in the treatment decision-making process whenever possible, especially if ED has been present for a long time. ● Refer to sexual counseling and/or specialist care whenever appropriate. PHYSICIAN INSTRUCTIONS AND PATIENT EDUCATION ● Emphasize the need for sexual stimulation. ● Instruct the patient about titrating appropriately. For example, counsel patients to try a 100-mg dose of sildenafil if the 50-mg dose is well tolerated but does not provide adequate efficacy, or decrease to 25 mg if appropriate. ● Instruct the patient about timing—take the drug anytime before or after a meal, approximately 30 to 60 minutes before sexual activity and no more than once a day; however, if a faster onset is desired, it should be taken on an empty stomach (or at least not after a high-fat meal); however, the therapeutic window for effectiveness covers ap37 proximately a 4-hour period. Even if intercourse does not occur within the first hour after taking sildenafil, many patients do not realize that they can still have successful intercourse for several hours thereafter, allowing more spontaneity. ● Explain that excessive use of alcohol should be avoided, as it can have a negative effect on EF; however, there are no safety concerns about the concomitant use of alcohol and sildenafil. ● Inform patients that although most responses occur within the first 1 to 2 doses, it may take up to 7 to 8 attempts (including titration to the correct dose) for some patients before they achieve intercourse success; patients need to be encouraged not to give up before an adequate number of attempts have been tried, using the maximum tolerated dose along with adequate sexual stimulation. The first few attempts at intercourse may be very emotionally charged and anxiety-producing for both patient and partner, especially if patients have not been sexually active for a long time. FOLLOW-UP ASSESSMENT, EFFICACY, AND SIDE EFFECTS ● Schedule follow-up visits at regular intervals to assess treatment progress. This is essential for the best possible treatment outcome, especially if concomitant diseases are present that could worsen over time, possibly affecting treatment efficacy. Lack of follow-up assessment/treatment may deprive the patient of an effective therapy and may fail to uncover more serious comorbid conditions. ● Discuss side effects with the patient. The most common side effects of sildenafil are headache, facial flushing, and dyspepsia. Less commonly, nasal congestion, bluish vision, blurred vision, or sensitivity to light may occur. Most of these side effects have been mild to moderate and transient. In clinical trials, treatment discontinuation because of side effects has been low.1,22 ● Understand that the most important consideration for patients taking sildenafil seems to be efficacy, not side effects. 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