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a University of Copenhagen, Division of Sexual Physiology, Denmark
b Divisione di Urologia, Istituto San Raffaele, Italy
c Newport Beach, California
d Pfizer Ltd., Sandwich, Kent, United Kingdom
Gorm Wagner, Division of Sexual Physiology, University of Copenhagen, RIGSHOSPITALET, Suite 7121, 9, Blegdamsvej, DK-2100 Copenhagen, Denmark.
Decision Editor: William B. Ersler, MD
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Abstract |
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65 years or older) were assessed. Methods. We analyzed data obtained from five double-blind, placebo-controlled studies of the efficacy and tolerability of oral sildenafil taken as required (but not more than once daily) over a 12-week to 6-month period. Two subgroups were evaluated: (i) elderly patients with ED of broad-spectrum etiology (n = 411), and (ii) elderly patients with ED and diabetes (n = 71). Efficacy was assessed using a global efficacy question, questions 3 and 4 of the International Index of Erectile Function (IIEF), and the five sexual function domains of the IIEF.
Results. All efficacy assessments indicated that sildenafil significantly improved erectile function both in elderly patients with ED of broad-spectrum etiology and in elderly patients with ED and diabetes. The most common adverse events were mild-to-moderate headache, flushing, and dyspepsia. The rates of discontinuation due to adverse events were low and were comparable to the rates with placebo.
Conclusions. Sildenafil is an efficacious and well-tolerated treatment for ED in elderly men.
ERECTILE dysfunction (ED), the persistent inability to achieve and/or maintain an erection sufficient for satisfactory sexual activity (1)(2), is a common medical disorder affecting elderly men. The Massachusetts Male Aging Study estimated that in the United States, approximately 45% of men aged 65 to 69 years have moderate or complete ED (3). Although ED is associated with age, it is not a direct consequence of aging. It is more directly associated with the pathological processes of diseases that often occur with aging and with some medications used to treat these diseases (3)(4). The Massachusetts Male Aging Study, a large epidemiological study, showed that ED is associated with heart disease, diabetes, and hypertension, and with medications used to treat these diseases (3). In that study, the probability of severe ED in patients aged 40 to 70 years was 39% for patients being treated for heart disease, 15% for patients being treated for hypertension, and 28% for patients being treated for diabetes. Several other studies have found that the prevalence of ED in men with diabetes is particularly high, ranging from 28% to 59% (3)(5)(6)(7)(8)(9)(10). Furthermore, the prevalence of ED also was significantly correlated with treatment with cardiac, antihypertensive, and hypoglycemic medications (3).
Sexual function continues to be important to men as they age, and ED has a negative impact on partner relationships and overall quality of life for elderly men (11)(12). However, effective treatment for ED can improve the emotional well being of the patient and the quality of life for both the patient and his partner (13)(14)(15)(16). The development of effective ED therapies has benefited from a rapidly developing understanding of the mechanism of penile erection. Penile erection depends on the relaxation of corpus cavernosum smooth muscle, which occurs when locally released nitric oxide (NO) induces an increase in cyclic guanosine monophosphate (cGMP) levels (17)(18). NO-induced increases in cGMP levels in the corpus cavernosum are attenuated by phosphodiesterase type 5 (PDE5), which metabolizes cGMP (19). Sildenafil citrate (VIAGRA®), a selective inhibitor of PDE5, has been shown to be an effective and well-tolerated oral agent for treating ED in the general population of adult men with ED of broad-spectrum etiology (20). However, compared with the general population of patients with ED, elderly patients are more likely to have other concomitant medical problems, including diabetes, and are more likely to be taking one or more medications for the treatment of these conditions. Thus, there is a need for specific data on the efficacy and tolerability of sildenafil treatment in elderly patients with ED and in elderly patients with ED and diabetes.
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Methods |
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18 years of age or older with a primary clinical diagnosis of ED of at least 6 months' duration. Of the five studies, two fixed-dose and two flexible-dose studies enrolled patients with ED of broad-spectrum etiology, including a few patients with diabetes under stable medical management (see below). Data for the elderly (aged 65 years or older) patients enrolled in these four studies (broad-spectrum ED subgroup) were pooled for the analyses presented in this report. The fifth study only enrolled men with ED and a concurrent clinical diagnosis of diabetes (as defined by the National Diabetes Data Group) (21) of >5 years' duration for type 1 diabetes and >2 years' duration for type 2 diabetes. These patients, as well as the patients enrolled in the broad-spectrum ED studies who had diabetes, were required to have been under stable medical management (diet, oral hypoglycemic agents, or insulin) for their diabetes for at least 3 months before entry into the study. Laboratory test results (i.e., glycosylated hemoglobin of <12% and fasting plasma glucose levels of <300 mg/dl) obtained at entry into the study were used to confirm that each patient's diabetes was adequately controlled. Data from the elderly patients enrolled in the fifth study were analyzed in a second subgroup analysis (ED and diabetes subgroup). Patients were ineligible for inclusion in these studies if they were being treated with nitrates or NO donors. Additional exclusion criteria included a significant history of cardiovascular disease (cardiac failure, unstable angina, ST-segment depression, or life-threatening arrhythmia), the occurrence of a cardiovascular event or stroke within the previous 6 months, or uncontrolled hypertension or hypotension. Patients also were excluded if they had ED due to spinal cord injury; penile anatomical defects; primary sexual disorders other than ED or hormonal imbalances (elevated prolactin or low free testosterone); major hematological, renal, or hepatic abnormalities; a major psychiatric disorder; or a history of alcohol or substance abuse.
All studies consisted of a screening visit (Week -4), a 4-week run-in period without treatment, and a 12-week to 6-month double-blind treatment period. For the 12-week broad-spectrum ED studies, clinic visits took place at Weeks -4, 0, 4, 8, and 12 for both the fixed-dose and flexible-dose studies, and also at Week 2 for the flexible-dose studies. For the 6-month, fixed-dose, broad-spectrum ED study, visits occurred at Weeks –4, 0, 2, 4, 8, 12, 16, 20, and 24; for the 6-month, flexible-dose, broad-spectrum ED study, visits occurred at Weeks –4, 0, 2, 4, 8, 12, 18, and 26. Patients in the flexible-dose ED and diabetes study had clinic visits at Weeks -4, 0, 2, 4, 8, and 12.
A total of 411 elderly patients with ED of broad-spectrum etiology and 71 elderly patients with ED and diabetes were randomized to treatment in these studies. The patients in the broad-spectrum ED studies were randomized to receive either fixed- or flexible-dose sildenafil (n = 253) or placebo (n = 158). Patients in the fixed-dose studies received either 25-mg, 50-mg, or 100-mg doses of sildenafil; patients in the flexible-dose studies received a starting dose of 25 mg or 50 mg, with an option to increase the dose to 100 mg or to decrease it to 25 mg depending on efficacy and tolerability. The patients in the flexible-dose diabetes study were randomized to receive either sildenafil (n = 40) or placebo (n = 31); the starting dose was 50 mg, which could be increased to 100 mg or decreased to 25 mg depending on efficacy and tolerability. In all five studies, patients were instructed to take the study drug 1 hour before sexual activity but not more than once daily.
Efficacy Assessments
Primary efficacy assessments were performed at Week 12 and included responses to a yes/no global efficacy question (GEQ) ("Did treatment improve your erections?") and responses to question 3 (Q3) and question 4 (Q4) of the International Index of Erectile Function (IIEF) (22), which evaluated the ability to achieve and maintain an erection, respectively. Responses to Q3 and Q4 of the IIEF were scored on a 5-point categorical scale; a score of 1 indicated "almost never/never" and a score of 5 indicated "almost always/always." A score of 0 indicated "did not attempt sexual intercourse." Secondary efficacy assessments included scores for the five sexual function domains of the IIEF (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), derived by subgrouping scores for all 15 questions of the IIEF (22). Partner responses to an optional questionnaire that asked about the partner's perception of the patient's ability to achieve and maintain an erection were also evaluated.
Safety Assessments
All adverse events were recorded at each visit. Reports of adverse events were compiled from investigators' observations, patient reports in response to nonleading questions, and volunteered reports. Serious adverse events were those that (i) resulted in death; (ii) were considered to be life threatening; (iii) resulted in permanent disability; (iv) required hospitalization or prolongation of a hospital stay; (v) involved cancer, a congenital abnormality, or were the result of a drug overdose; or (vi) were considered serious enough by the investigator to warrant being immediately reported to the study sponsor. Standard laboratory tests and sitting blood pressure and pulse rate measurements were conducted at each visit. Physical examinations and 12-lead ECG monitoring were performed at Weeks -4 and 12.
Data Analysis
Efficacy analyses included data obtained from the intention-to-treat population, which included any patient who received at least one dose of the study drug and had at least one efficacy assessment after receiving the study drug. All patients who received at least one dose of the study drug were included in the safety assessments.
The GEQ data were evaluated by logistic regression analysis (20). Responses to the IIEF questions were analyzed using analysis of covariance (20). All analyses of significance were two-sided and tested at the 5% level.
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Results |
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Efficacy
At the end of treatment, 69% of the patients in the broad-spectrum ED subgroup who received sildenafil reported that treatment had improved their erections compared with 18% who had received placebo (p < .001) (Fig. 1). Similarly, a significant treatment effect was observed for patients in the ED and diabetes subgroup who received sildenafil. Of these patients, 50% reported improvements in their erections, compared with 10% of those who received placebo ( p < .001).
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The number of partners who completed the optional partner questionnaire was small (26%). However, the baseline scores and the end-of-treatment scores for partner responses to questions related to the ability to achieve (Q1) and maintain (Q2) erections corroborated the results reported by the elderly patients in both subgroups. For patients in the broad-spectrum ED subgroup receiving sildenafil, the mean score for partner Q1 increased from the mean baseline score of 2.4 to 3.3, and the mean score for partner Q2 increased from a mean baseline score of 1.7 to 3.0. For patients in the ED and diabetes subgroup receiving sildenafil, the mean score for partner Q1 increased from a mean baseline of 2.3 to 3.8, and the mean score for partner Q2 increased from 1.2 to 3.0. For partners of patients receiving placebo in both subgroups, end-of-treatment scores for Q1 and Q2 were similar to those obtained at baseline.
Safety Assessments
Sildenafil treatment was well tolerated by the elderly patients with ED (with or without concomitant diabetes) who were enrolled in these five studies. The most commonly (5%) experienced adverse events in the two subgroups were headache, flushing, and dyspepsia, which occurred in 17%, 13%, and 8%, respectively, of patients receiving sildenafil (Table 2 ). Most of these adverse events were mild or moderate in nature. Altered vision was experienced by a small number of patients who received sildenafil (4%) and was usually described as a transient and mild color tinge to vision, increased sensitivity to light, or blurred vision. Flushing was the most common cardiovascular adverse event to occur in patients receiving sildenafil. The overall incidence of cardiovascular adverse events other than flushing for patients in the sildenafil group was 7% (21 out of 293 patients), which was comparable to that for patients in the placebo group (7%; 13 out of 189 patients). Of the elderly patients enrolled in these studies, 22 experienced serious adverse events; 11 were receiving placebo, and 11 were receiving sildenafil. None of these serious adverse events was considered to be related to treatment. One 66-year-old patient had a cardiac arrest approximately 1 month after his last dose of sildenafil and died 3 days later. This subject was suffering from hypertension and hypercholesterolemia and had a previous history of alcohol abuse. The investigator considered the event to be due to a probable myocardial infarction (MI) and not related to the study drug. In addition, two other deaths were reported among the patients with serious adverse events, one among patients randomized to sildenafil and one among patients randomized to placebo. The former was secondary to an accident and the latter to a suicide. Both occurred approximately 1 month after the last dose of the study drug was taken, and neither were felt by the investigators to be treatment related. There were no clinically significant, treatment-related laboratory test abnormalities among elderly patients receiving placebo or sildenafil.
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Discussion |
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The efficacy of sildenafil in elderly patients with ED of broad-spectrum etiology was comparable to that observed in a patient group representative of the general population of patients with ED (aged 18 years) (20). Patients in that combined analysis had a similar mean duration of ED (3.2–5 years), and the mean age was about 10 years younger than that of the elderly patients reported here. After treatment with sildenafil, 69% of elderly patients in the broad-spectrum ED subgroup studied here reported improved erections, whereas 74% of patients with ED in the general population reported improved erections after receiving sildenafil (flexible dosing; 25 mg to 100 mg) (20). The improvements in Q3 and Q4 scores over baseline values for elderly patients in the broad-spectrum ED subgroup who took sildenafil were also similar to those for the nonelderly patients in these studies (unpublished data) and also to those reported for the general population of patients with ED who took sildenafil (20). The mean Q3 score for elderly patients in the broad-spectrum ED subgroup who received sildenafil was 1.8 times greater than the baseline score (20), whereas the mean Q3 score for nonelderly patients receiving sildenafil was 1.7 times greater than baseline, and the mean score for Q3 among the general population of patients with ED receiving sildenafil was 2.0 times greater (20). Mean scores for Q4 for both the elderly and nonelderly patients in the broad-spectrum ED subgroup receiving sildenafil were 2.1 times greater than baseline scores, and the mean Q4 score for the general population of patients with ED who took sildenafil was 2.4 times greater than baseline (20).
Although sildenafil was less efficacious in patients in the ED and diabetes subgroup than in elderly patients in the broad-spectrum ED subgroup, the results were not entirely unexpected, and the efficacy of sildenafil in the ED and diabetes subgroup is of particular interest. In addition to the added burden of diabetes, these patients had a longer mean duration of ED and a greater incidence rate of other comorbid medical conditions, as indicated by the higher percentage of patients taking medications (in addition to diabetes medications) for other medical conditions. The high percentage of elderly patients in the ED and diabetes subgroup who were receiving antihypertensive agents (68%) is particularly noteworthy because male sexual dysfunction (and ED in particular) is commonly associated with the use of virtually all antihypertensive agents (3)(23)(24). Because sildenafil was as effective in elderly patients in the broad-spectrum ED subgroup as it was in the general population as reported previously (20), the results of our study suggest that, regardless of age, patients being treated for diabetes and hypertension (both significant risk factors for ED) might not respond to treatment for ED as well as patients who do not have to contend with these additional medical problems.
Sildenafil was well tolerated, and the safety profile was similar to that reported for the general population of patients with ED (20)(25). The incidence rates for the most common adverse events for the 293 elderly patients with ED who received sildenafil (headache, 17%; flushing, 13%; and dyspepsia, 8%) were comparable to those reported for 734 patients with ED, representing the general population of men with ED, enrolled in flexible-dose studies of sildenafil (headache, 16%; flushing, 10%; and dyspepsia, 7%) (25). Flushing was the most common cardiovascular adverse event. The overall incidences of cardiovascular adverse events other than flushing for patients treated with sildenafil were similar for the sildenafil- and placebo-treatment groups. The incidence of visual adverse events (4%) was low in elderly patients, and these events were predominantly transient and mild or moderate in nature. As with the general population of patients with ED, the rates of discontinuation of sildenafil treatment due to adverse events, both causality and treatment related, were low and comparable to those of patients receiving placebo (25).
Adverse drug interactions are of concern in elderly men who, as a group, are more likely than younger men to be under medical treatment for other conditions. It should be noted that patients using NO donors or nitrates, such as nitroglycerin, were not permitted to enroll in the studies reported here. Sildenafil potentiates the hypotensive effects of nitrates, and its administration to patients who use NO donors or nitrates in any form is contraindicated (26). However, a substantial proportion of the elderly patients included in our analyses were receiving other concomitant medications, such as diabetes and antihypertensive medications, hypolipidemic agents, and drugs for the treatment of rheumatic diseases and gout. As discussed above, the safety profile of sildenafil in the elderly was similar to that reported for the general population of patients with ED (20)(25), and there was no indication in the analyses of safety data for elderly patients of significant untoward drug-drug interactions with sildenafil.
An additional concern when considering treatment of ED in elderly men is the potential for precipitating adverse cardiac events, especially in patients with pre-existing cardiovascular disease. In a study of 858 sexually active patients (male and female, elderly and nonelderly) who experienced a nonfatal MI, Muller and colleagues noted that 9% reported having had sexual activity in the 24 hours before the MI, and 3% reported having had sexual activity within 2 hours of the MI (27). Furthermore, the authors reported that sexual activity was a likely contributor to the onset of MI in about 1% of cases. Morales and colleagues (25) reported that the incidence of serious cardiovascular adverse events in more than 3700 patients receiving sildenafil was 3.5–4.1/100 man-years of treatment compared with 5.7/100 man-years in patients receiving placebo. Furthermore, the incidence of MI was 1.0–1.7/100 man-years in patients receiving sildenafil versus 1.4/100 man-years in patients receiving placebo. The five studies reported here were included in that analysis. A further examination of the data for just the elderly patients included in these five studies indicates that there were no confirmed reports of MI, although one elderly patient experienced cardiac arrest (resulting in death), for which an MI was suspected. Of all the nonelderly patients in these studies, there were three incidents of MI among those receiving sildenafil and two among those receiving placebo. The number of events is too small to permit comment on the statistical or clinical significance of these findings. Although it does not appear that there is an excess risk for MI in elderly men who receive sildenafil, physicians may wish to consider the cardiovascular status of their patients before initiating any treatment for ED.
The efficacy and tolerability profiles demonstrated in this subgroup analysis and the ease of use and mode of action of sildenafil (i.e., sildenafil has no effect in the absence of sexual stimulation) are of significance both to prescribing general physicians and gerontologists. The number of elderly men is expected to increase significantly over the next decade, and as many as 50% to 70% of these men will develop some degree of ED (3). Sexual function is a significant component of the quality of life for aging men (11)(12), and elderly men with ED may seek treatment on their own or at the suggestion of their partners (28). Although studies have shown that success with treatments for ED improves the quality of life of men with ED (13)(14)(15)(16), the efficacy and tolerability of other ED treatment options, such as injections of vasoactive drugs, intraurethral suppositories, vacuum devices, and prosthetic devices (29)(30)(31)(32), have not been extensively examined in the elderly patient population. Additionally, these treatments are often not very well accepted by men in the general population of patients with ED or their partners, which contributes to a high patient dropout rate (33)(34)(35). Elderly patients, who often have problems with manual dexterity, may find such treatments particularly difficult to use (1)(2).
In conclusion, the results of the combined analysis reported here indicate that sildenafil is well tolerated in elderly patients, many of whom were receiving concomitant medications for other diseases and ailments. Because of the similarity in the safety profile for the elderly patients here and that for the general population of men with ED, it is expected that most elderly patients may be started on a dose of 50 mg, which is the recommended dose for the majority of patients. Oral sildenafil, which is efficacious and well tolerated by elderly men with ED and can be taken discreetly approximately 1 hour before sexual activity, is a welcome alternative to other treatment modalities currently available for ED.
Received November 17, 1999
Accepted March 27, 2000
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