Background

Sexual dysfunctions are marked by impairment in sexual desire and the psychophysiological alterations associated with sexual response.¹ Both sexes experience sexual dysfunction; however, females (43%) are estimated to be at a higher risk than males (31%).² Little research on the epidemiology and treatment of sexual dysfunction has been focused on females, perhaps due to the multicausal and multidimensional aspects of this disorder in females.³ Conversely, there has been substantial research performed on sexual dysfunction, particularly erectile dysfunction (ED), epidemiology, and treatment in males.^{4, 5, 6, 7, 8}

ED is an age-related condition that can be associated with health conditions such as vascular disease, diabetes mellitus, depression, prostate disease, renal failure, Parkinson's disease and spinal cord injury.^{9, 10, 11} The causes of ED can be organic, psychogenic, and/or iatrogenic.⁷ Regardless of cause, intracavernosal/transurethral prostaglandin E1 injections, oral medications, surgery, and vacuum constriction devices are available as treatments. Understandably, patients have demonstrated a preference for oral therapies.^{12, 13}

In 1998, sildenafil (Viagra^®) became the first oral impotence agent to receive marketing approval from the United States (US) Food and Drug Administration for the treatment of sexual dysfunction in males.¹⁴ During clinical trials, sildenafil was found to be effective in relieving symptoms of ED in approximately 70% of subjects.¹⁵ Initial studies found sildenafil to provide results similar to placebo for the treatment of sexual dysfunction in postmenopausal women,¹⁶ but indicated improvements in sexual function in premenopausal women.¹⁷

With a direct to consumer advertising (DTCA) campaign, sildenafil has brought the recognition and treatment of ED to the forefront of public awareness.^{18, 19} Originally, sildenafil DTCA in the US was targeted to older males (eg using Bob Dole as spokesperson, print ad featuring gray-haired male dancing with gray-haired female), but it has been increasingly marketed to younger consumers (eg baseball player Rafael Palmeiro as a spokesperson, sponsoring Earth, Wind, and Fire concert tour).²⁰ Already concerned with the impact sildenafil has had on their pharmacy budgets,^{21, 22, 23, 24} health plan sponsors now face the prospect of increased use among a younger generation of ED patients. In addition, marketing approval of other impotence products (eg vardenafil, tadalafil) is forthcoming. Approval will likely increase utilization of oral impotence agents classwise.^{25, 26}

Sildenafil use is not without risks owing to its vasodilatory properties. Caution should be excercised in patients with one or more risk factors for cardiovascular or cerebrovascular disease, as cardiovascular events related to sildenafil include myocardial infarction, cardiac arrest, angina, ventricular tachycardia, hypertension, and other cardiac symptoms.²⁷ Concomitant use with organic nitrates (eg glyceryl trinitrate, isosorbide dinitrate) has resulted in cardiac deaths, possibly due to sildenafil potentiating the nitrate's hypotensive effects.^{28, 29}

Few, if any, nationwide studies profiling sildenafil use are available. Little is known about the characteristics of sildenafil users and prescribers and the use of sildenafil for underlying etiologic reasons. In addition, there is a dearth of information on the effect of messaging on sildenafil use, whether through DTCA of sildenafil to younger males or reports of cardiac deaths related to sildenafil use. Thus, the purpose of this study was to profile sildenafil use in a random, nationwide sample of commercially insured, adult beneficiaries from 1998 to 2002.

Materials and methods

Data were extracted from five 1-year databases (1998–2002) constructed for research purposes by Express Scripts, Inc. (ESI). ESI provides pharmacy benefit management services, including network pharmacy claims processing, mail pharmacy services, and other pharmacy consultive services, to small and large employer, third-party administrator, government, union, and managed care organization health plans. The databases were constructed annually with ambulatory pharmacy claims and eligibility information from a random sample of ESI commercially insured (ie not Medicare+Choice, Medicaid) beneficiaries with integrated mail order and network pharmacy benefits. Each random sample was composed of approximately 14% of ESI beneficiaries with an integrated benefit. For example, in 2002, a random sample of 3 million subjects was drawn from approximately 21 million beneficiaries enrolled in over 1000 commercially insured health plans representing all 50 US states and the District of Columbia.

Individuals aged 18 y who were continuously eligible for subsidized pharmacy benefits during the year the database was constructed were used in the analysis, resulting in a final sample of over five million life-years. Subjects were categorized by age groups that were based on life stages that could affect the development of ED (ie 18–45, 46–55, 56–65 and >65 y).³⁰ No patient-identifiable information was included in the study as only aggregate analyses were conducted.

Pharmacy claims for sildenafil were identified using the Generic Product Identifier code 40-30-40-70-10.³¹ Prevalence was defined as the frequency of one or more prescription claims for sildenafil (ie users) per 100 beneficiaries. Sildenafil users who had 2 pharmacy claims for an antidepressant, antidiabetic, anti-Parkinsonian, anticholinergic, sedating antihistamine, beta blocker, butyrophenones, clonidine, cyclobenzaprine, digoxin, finasteride, methyldopa, metoclopramide, orphenadrine, phenothiazines, propantheline, or thiazide diuretic over the respective years were classified as possibly having an underlying etiological reason (ie drug- or disease-induced ED) for being prescribed sildenafil.^{7, 9, 10, 11} Users whose first claim for sildenafil was in April were identified for each of the respective years and the number of tablets dispensed for the remainder of the year for these users was summed. This analysis facilitates the examination of naive users and their subsequent medication-taking behaviors (eg discontinuations due to adverse events). Healthcare providers who prescribed one or more sildenafil prescriptions were categorized as primary care (ie general practice, family practice, and internal medicine physicians), urology, and other.

Point prevalence and standard errors were estimated by gender and age groups for each year. Trend analyses (ie Poisson log-rate regression modeling), while controlling for gender, age, and possible homogeneity of subjects across random samples, was performed to determine trends in the prevalence of use over time.

Results

Pharmacy claims from a total of 5 083 582 continuously eligible, adult beneficiaries were available for examination over the 5-year study period (Table 1). There was a slight increase in the absolute proportion of females in the sample overtime, but a 58% decrease in the proportion of females among sildenafil users over the 5 years. There was a 3.5% increase in the mean age of the sample, but a 4.6% decrease in the mean age of sildenafil users over the study period.

Table 1 - Sample and sildenafil user characteristics.

Full table

Overall, the prevalence of use of sildenafil grew among commercially insured beneficiaries from 0.77% in 1998 to 1.42% in 2002, an 84% increase (Table 2). A total of 162 490 prescriptions for sildenafil were dispensed to 48 164 patients over the 5 years of the study. The prevalence in males increased, while the prevalence in females decreased over the study period. The largest increase in absolute prevalence during the study period was found in males aged 46–55 y (2.32 percentage points). The largest decrease in absolute prevalence during the study period was found in females aged 56–65 y (0.08 percentage points).

Table 2 - Prevalence of sildenafil use stratified by age and gender (1998–2002).

Full table

After controlling for differences in gender and age and any homogeneity of subjects across random samples during the study period, there were significant trends in prevalence across age and gender strata over the 5 years (Table 3). Generally, the prevalence of use among females decreased, and males' prevalence increased relative to the first year sildenafil was marketed (1998). One exception was females aged 18-45 y, who experienced overall increased use over the study period (P<0.001). All groups except males aged 18–45 y experienced a decrease in use in 1999 (P<0.001). The largest increasing trends were found among younger males 18–45 y and 46–55 y, who experienced overall prevalence changes of 312 and 216%, respectively, over the study period (P<0.001). The largest decreasing trends were found among older females 56–65 and >65 y, who experienced overall prevalence changes of 48 and 63%, respectively, over the study period (P<0.001).

Table 3 - Relative changes in the prevalence of sildenafil use by year.

Full table

The mean number of sildenafil tablets dispensed per user per 9-month period declined slightly over the study period (Table 4). The use of sildenafil for a potential underlying etiologic reason declined in all age groups over the 5 years. Among all sildenafil users, use for a potential underlying etiologic reason decreased 11.5% from 1998 (45.2%) to 2002 (40.0%). Users aged 18–45 y had the lowest (33.1%) and >65 y had the highest (43.7%) proportion of use for a potential underlying etiologic reason in 2002. The largest absolute decrease in use for an underlying etiologic reason over the study period was found in males 18–45 y (8.5 percentage points).

Table 4 - Characteristics of sildenafil users by year.

Full table

The majority of sildenafil prescriptions were written by primary-care physicians in all 5 years of the study and that majority grew over the 5 years (Table 5). The proportion of sildenafil pharmacy claims attributed to urologists declined by nearly half, while the proportion attributed to other healthcare professionals increased slightly over the study period.

Table 5 - Characteristics of prescribers of sildenafil by year.

Full table

Discussion

This is the first published study to profile trends in use of sildenafil using a diverse, nationwide database. Although the overall prevalence of sildenafil use increased substantially during the study period, certain categories of beneficiaries increased, while others decreased their prevalence of use. Use became more pronounced in younger males and females and decreased in older females, while the growth in use slowed in older males. The fastest growing segment of users was found to be males aged 18–45 y.

Our results were consistent with research in a regional sample of patients who found that prescribers of sildenafil were predominantly primary-care physicians.³⁰ Also consistent with this research,³⁰ we found that males in general and those aged 56 y and older specifically continued to receive the vast majority of sildenafil prescriptions. We found a decrease in prevalence among most groups in 1999, particularly among older males. This decrease coincided with the publicizing of cardiac deaths associated with the concomitant use of sildenafil and organic nitrates,^{28, 29} suggesting that among healthcare consumers and professionals, awareness of sildenafil's risks were heightened with this messaging.

We attempted to discern the prevalence of use for an underlying etiologic reason (ie medical necessity) in our sample by examining the concomitant use of medications that may be causative for drug-induced ED and/or are a marker for a disease that may be causative of ED. Certainly, not everyone with an ED-inducing medication claim was using sildenafil because of that medication. In addition, not all health conditions that are risk factors for ED (eg atherosclerosis, spinal cord injury) were examined. However, the decreasing proportion of sildenafil users with a claim for a suspected ED-inducing drug and/or a marker of a suspected ED-inducing disease suggests increased use of sildenafil as an enhancement/recreational agent.^{32, 33}

Our observations of increased prevalence of use in younger beneficiaries and a decreased prevalence of concomitant use of medications that cause ED and/or are markers of ED-inducing diseases may be reflective of historical and/or healthcare reasons that may or may not be related to DTCA messaging. First, liberalization of pharmacy benefits with regard to sildenafil coverage may have stimulated use among less morbid and younger beneficiaries. This seems unlikely since plans have minimal incentive (eg pressure from patient advocacy groups) to provide less restrictive coverage for sildenafil.²¹ Second, a change in prescriber behavior whereby prescribers became more likely to prescribe sildenafil without the presence of a comorbid condition. This scenario may be related to healthcare providers' perceptions of patients' hopes of receiving a prescription^{30, 34} and/or the observed decreased proportion of sildenafil prescriptions prescribed by specialists.

Substantial debate continues in the healthcare sector over the coverage of 'lifestyle' medications.^{24, 35} With healthcare resources becoming more scarce, sildenafil has received considerable focus during this debate,^{25, 36, 37} perhaps owing to the perception of a low priority for ED treatment compared with other more pressing demands for healthcare dollars.²² The coverage of sildenafil by health plans remains a potpourri with some plans having no restrictions on coverage, others requiring prior authorization for 'medical necessity' and/or placing quantity limits, and others still offering no coverage.^{21, 37} Our finding of a stable mean number of tablets dispensed over the 5 years suggests that there was no substantial change in the use of quantity limits by plan sponsors.

Several factors should be considered when interpreting our findings. As in any analysis involving the use of administrative claims data, a claim does not indicate whether the patient actually took the medication. We did not have access to subjects' medical records; thus, we were unable to ascertain practitioner-reported etiologic reasons for sildenafil use. Our criteria for an underlying etiologic reason for use may not have contained an exhaustive list of medications that cause ED and/or are markers of ED-inducing diseases. However, we believe we utilized the most common and medically appropriate medications that induce ED and/or are markers of ED-inducing diseases.³⁸ In addition, we were unable to control for changes in benefit designs, whereby health plans placed more or less restrictions on sildenafil coverage over the study period. However, there is no empirical evidence to suggest a systematic change in coverage status over these 5 years.

While research suggests the prevalence of ED ranges from 11 to 35% in males aged 40–70 y,^{2, 9, 39} we found that the prevalence of use of sildenafil only approached 7% in males aged 56–65 y. These findings suggest that the overall utilization of impotence agents will increase. In addition, our findings suggest that use may increase among younger male and female patients and those without an underlying etiologic reason for use. Future research is required to understand the reasons for the increased use of sildenafil among younger beneficiaries as well as to confirm a decreased use for underlying etiologic reasons.

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC, 1994, pp 493–522.
2. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281: 537–544. | Article | PubMed | ISI | ChemPort |
3. Ragucci KR, Culhane NS. Treatment of female sexual dysfunction. Ann Pharmacother 2003; 37: 546–555. | Article | PubMed |
4. Chew KK et al. Erectile dysfunction in general medicine practice: prevalence and clinical correlates. Int J Impot Res 2000; 12: 41–45. | Article | PubMed | ISI | ChemPort |
5. Slag M et al. Impotence in medical clinic outpatients. JAMA 1983; 249: 1736–1740. | Article | PubMed |
6. Benet AE, Melman A. The epidemiology of erectile dysfunction. Urol Clin N Am 1995; 22: 699–709. | ISI | ChemPort |
7. NIH Consensus Conference. Impotence: NIH Consensus Development Panel on Impotence. JAMA 1993; 270: 83–90. | PubMed | ISI |
8. Gingell C et al. Guidance on the management of erectile dysfunction in primary care. Prescriber 1999; 5(Suppl): 1–19.
9. Feldman HA et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts male aging study. J Urol 1994; 151: 54–61. | PubMed | ISI | ChemPort |
10. Kaiser FE et al. Impotence and aging: clinical and hormonal factors. J Am Geriatr Soc 1988; 36: 511–519. | PubMed | ISI | ChemPort |
11. Mulligan T, Katz PG. Why aged men become impotent. Arch Intern Med 1989; 149: 1365–1366. | Article | PubMed |
12. Hanash KA. Comparative results of goal oriented therapy for erectile dysfunction. J Urol 1997; 157: 2135–2138. | Article | PubMed | ISI | ChemPort |
13. Jarow JP et al. Outcome analysis of goal directed therapy for impotence. J Urol 1996; 155: 1609–1612. | Article | PubMed | ISI | ChemPort |
14. Lamberg L. New drug for erectile dysfunction boon for many, 'viagravation' for some. JAMA 1998; 280: 867–869. | Article | PubMed |
15. Viagra Package Insert. Available at: http://www.viagramd.com/pi/proPackInsert.asp. Accessed July 21, 2003.
16. Kaplan SA et al. Safety and efficacy of sildenafil in postmenopausal women with sexual dysfunction. Urology 1999; 53: 481–486. | Article | PubMed | ISI | ChemPort |
17. Caruso S, Intelisano G, Lupo L, Agnello C. Premenopausal women affected by sexual arousal disorder treated with sildenafil: a double-blind, cross-over, placebo-controlled trial. Br J Obstet Gynaecol 2001; 108: 623–628. | Article | ISI | ChemPort |
18. Rosen RC. Sildenafil: medical advance or media event. Lancet 1998; 351: 1599–1600. | Article | PubMed |
19. Braun M, Klotz T, Mathers MJ. 'Viagra Effect' —influence of mass media on patient behavior. Urol Int 2001; 66: 145–148. | Article | PubMed | ChemPort |
20. Leland J. Ideas and Trends: Big Pharma Ogles Yasgur's Farm, The New York Times, 2001, July 29, Section 4 p 3.
21. Klein R, Sturm H. Viagra: a success story for rationing? Health Aff (Millwood) 2002; 21: 177–187. | Article | PubMed |
22. Keith A. The economics of Viagra. Health Aff (Millwood) 2000; 19: 147–157. | Article | PubMed |
23. Titlow K, Randel L, Clancy CM, Emanuel EJ. Drug coverage decisions: the role of dollars and values. Health Aff (Millwood) 2000; 19: 240–247. | Article | PubMed |
24. Mitrany D. Lifestyle drugs: determining their value and who should pay. Pharmacoeconomics 2001; 19: 441–448. | PubMed |
25. Rosenthal MB et al. Promotion of prescription drugs to consumers. N Engl J Med 2002; 346: 498–505. | Article | PubMed | ISI |
26. Loyd L. Pharmaceutical Firms take Fight for Impotence Drug Users to the Mat, Philadelphia Inquirer, 2003, July 6, p. E01.
27. Lim PH, Moorthy P, Benton KG. The clinical safety of Viagra. Ann NY Acad Sci 2002; 962: 378–388. | PubMed |
28. Kloner RA. Viagra: what every physician should know. Ear Nose Throat J 1998; 77: 783–786. | PubMed |
29. Kloner RA, Jarow JP. Erectile dysfunction and sildenafil citrate and cardiologists. Am J Cardiol 1999; 83: 576–582, A7. | Article | PubMed | ISI | ChemPort |
30. Harrold LR et al. The diffusion of a novel therapy into clinical practice: the case of sildenafil. Arch Intern Med 2000; 160: 3401–3405. | Article | PubMed | ISI | ChemPort |
31. First DataBank (Medi-Span). Generic Product Identifier Number. First DataBank (Medi-Span): Indianapolis, IN, 2001.
32. McLeod AL, McKenna CJ, Northbridge DB. Myocardial infarction following the combined recreational use of Viagra and cannabis. Clin Cardiol 2002; 25: 133–134. | PubMed |
33. Colfax GN et al. Drug use and sexual risk behavior among gay and bisexual men who attend circuit parties: a venue-based comparison. J Acquir Immune Defic Syndr 2001; 28: 373–379. | PubMed |
34. Schwartz RK, Soumerai SB, Avorn J. Physician motivations for nonscientific drug prescribing. Soc Sci Med 1989; 28: 577–582. | Article | PubMed |
35. Ashworth M, Clement S, Wright M. Demand, appropriateness and prescribing of 'lifestyle drugs': a consultation survey in general practice. Fam Pract 2002; 19: 236–241. | Article | PubMed |
36. Wilson ECF et al. The cost to the United Kingdom National Health Service of managing erectile dysfunction: the impact of sildenafil and prescribing restrictions. Pharmacoeconomics 2002; 20: 879–889. | PubMed | ISI |
37. Maguire P. How direct to consumer advertising is putting the squeeze on physicians. Available at: http://www.acponline.org/shell-cgi/printhappy.pl/journals/news/mar99/squeeze.htm. Accessed July 22, 2003.
38. Lewis RW. Epidemiology of erectile dysfunction. Urol Clin N Am 2001; 28: 209–216.
39. McKinlay JB. The worldwide prevalence and epidemiology of erectile dysfunction. Int J Impot Res 2000; 12(Suppl 4): S6–S11. | Article | PubMed | ISI |

Acknowledgements

We express our appreciation to Dr Jagat Sheth for his assistance. This study was funded by Express Scripts, Inc.