A Systematic Review Assessing the Economic ... - Wiley Online Library

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ORIGINAL RESEARCH—ED PHARMACOTHERAPY A Systematic Review Assessing the Economic Impact of Sildenafil Citrate (Viagra®) in the Treatment of Erectile Dysfunction Amber L. Martin, BS,* Rachel Huelin, BA,* David Wilson, MA,* Talia S. Foster, MS,* and Joaquin F. Mould, PhD† *United BioSource Corporation, Lexington, MA, USA; †Pfizer, Inc., New York, NY, USA DOI: 10.1111/jsm.12068

ABSTRACT

Introduction. Sildenafil was the first oral phosphodiesterase type 5 (PDE5) inhibitor introduced as primary therapy for erectile dysfunction (ED). In the 7 years following its market launch, sildenafil was prescribed by more than 750,000 physicians to more than 23 million men worldwide. To date, few studies have evaluated the economic impact of sildenafil in treating ED. Aim. To evaluate the cost-effectiveness and impact of sildenafil on health care costs for patients with ED in multiple countries. Main Outcomes Measures. Economic outcomes including cost, cost-effectiveness, cost of illness, cost consequence, resource use, productivity, work loss, and willingness to pay (WTP) were investigated. Methods. Using keywords related to economic outcomes and sildenafil, we systematically searched literature published between July 2001 and July 2011 using MEDLINE and EMBASE. Included articles pertained to costs, WTP, and economic evaluations. Results. In the last 10 years, 12 studies assessed economic outcomes associated with sildenafil for ED. Most studies were conducted in the United States and the United Kingdom, with one study identified in Canada and one from Mexico. Six studies evaluated cost of illness, cost consequence, or cost of care, and four studies evaluated WTP or drug pricing by country in the United States and the United Kingdom. In the United States and the United Kingdom, costs to health care systems have increased with demand for treatment. Cost analyses suggested that sildenafil would lower direct costs compared with other PDE5 inhibitors. US and UK studies found that patients exhibited WTP for sildenafil. The two cost-effectiveness models we identified examined ED sub-groups, those with spinal cord injury and those with diabetes or hypertension. These models indicated favorable cost-effectiveness profiles for sildenafil compared with other active-treatment options in both Mexico and Canada. Conclusions. The relative value of sildenafil vs. surgically implanted prosthetic devices and other PDE5 inhibitors, is underscored by patients’ WTP, and cost-effectiveness in ED patients with comorbidities. Martin AL, Huelin R, Wilson D, Foster TS, and Mould JF. A systematic review assessing the economic impact of sildenafil citrate (Viagra®) in the treatment of erectile dysfunction. J Sex Med 2013;10:1389–1400. Key Words. Erectile Dysfunction; Cost; Cost Effectiveness; Sildenafil; Economic Impact of Sildenafil

Introduction

E

rectile dysfunction (ED) is the consistent inability of a man to achieve or maintain penile erection sufficient for sexual activity [1]. Common causes of ED include aging and endothelial dysfunction associated with behaviors such

© 2013 International Society for Sexual Medicine

as smoking or conditions including type 2 diabetes mellitus (T2DM), hypertension (HTN), and other cardiovascular diseases. Psychological issues, including performance anxiety, stress, and depression can also cause ED. Additionally, selective serotonin reuptake inhibitors (SSRIs) have been found to cause sexual dysfunction in 40% to 70% J Sex Med 2013;10:1389–1400

1390 of men seeking treatment for depression, amounting to 10 to 15 million patients worldwide [2]. According to the 2005 Global Better Sex Survey (GBSS), ED affects 13% to 28% of men aged 40 to 80 [3]. A 1999 study projected that the worldwide prevalence of ED would reach 322 million by 2025 [4]. In the United States, ED currently affects 18 million men and is expected to increase as the male population ages. US treatment costs are projected to approach $15 billion if all affected men sought treatment [5,6]. Phosphodiesterase type-5 (PDE5) inhibitors are accepted by many physicians as the standardof-care in first-line treatment of ED, with established efficacy and a favorable safety profile. PDE5 inhibitors work by preventing the degradation of cyclic guanosine monophosphate (cGMP), which relaxes smooth muscles, increasing blood flow to the penis. In 1998, sildenafil (Viagra®) was the first oral PDE5 inhibitor introduced as a primary therapy for ED. In the 7 years following its market launch, sildenafil had been prescribed by more than 750,000 physicians to more than 23 million men worldwide [7]. As a result of the wide uptake of sildenafil and other PDE5 inhibitors, recent worldwide trends suggest that the greatest increases in expenditures for ED will be for outpatient evaluation and treatment. The objective of this systematic literature review was to determine the economic impact of sildenafil on the direct costs of treatment for ED. Aims

To evaluate the cost-effectiveness and impact of sildenafil on health care costs for patients with ED in multiple countries. Methods

A systematic literature review was conducted in MEDLINE and EMBASE using search algorithms to identify relevant economic publications in English on sildenafil in ED. The search identified publications with sildenafil and keywords to identify economic outcomes specifically: cost, budget, expenditure, resource use, economic, pharmacoeconomic, productivity, work loss, or willingness to pay (WTP). Using this broad set of terms allowed the search to identify the largest number of publications reporting the costs of sildenafil use in ED patients. Articles were required to feature keywords in the title and/or abstract of full-length publications pertaining to humans, and J Sex Med 2013;10:1389–1400

Martin et al. published in the 10 years preceding the search (i.e., July 2001–July 2011). Relevant narrative (nonsystematic) reviews were included if they were published in the last 4 years (i.e., July 2007–July 2011). To supplement the search, material such as meeting abstracts that can be referenced, but are not published in peer-reviewed, indexed medical journals, were also examined for content. The search of MEDLINE identified 51 potentially relevant citations, and the search of EMBASE 51 citations. After removing 38 duplicate publications, a total of 64 unique citations remained for review at the abstract level. Of the 64 abstracts reviewed, 25 articles were selected for further review in full text, and 39 were excluded, primarily because the article did not evaluate ED patients or the article did not report any economic outcomes. Figure 1 presents the literature study attrition and reasons for exclusion, the primary reason being no economic outcomes reported. Abstracts were included when all of the following criteria were observed: the study pertained to adults with ED in which economic end points were evaluated, the study was published in the last 10 years ( July 2001–July 2011), and at least 20 patients were enrolled. Relevant economic outcomes included, but were not limited to: cost of treatment, cost-effectiveness, and cost of illness related to treatment of ED patients with sildenafil. Eleven articles [8–18] were identified for inclusion from the MEDLINE and EMBASE searches after full-text review. A supplement search of nonindexed publications and meeting abstracts identified one additional source for inclusion [19]. Results

In the last 10 years (July 2001–July 2011), 12 publications [8–18] were identified that assessed economic outcomes associated with sildenafil as treatment for ED. Most studies were conducted in the United States and the United Kingdom, with one study identified in Canada [11] and one literature source from Mexico [19], which was the only study from a developing country. Only two models (Mexico [19] and Canada [11]) in ED populations with comorbid conditions estimated cost-effectiveness for sildenafil compared with other active treatments for ED patients with comorbidities. Six studies evaluated cost of illness (COI), cost consequence, and cost of care, and four studies evaluated WTP and drug pricing by country in the United States and the United Kingdom. Cost analyses predicted the use of

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Economic Impact of Sildenafil

Figure 1 Study Attrition Diagram

sildenafil would lower direct medical costs compared with other PDE5 inhibitors. The time horizon over which economic assessments were performed was typically 1 year. Studies conducted in the United States and the United Kingdom found patients exhibited a WTP for sildenafil. Table 1 presents study summaries of the included articles. As in most economic studies, variability in analysis designs and assumptions, as well as differences in health care systems and costs of medical care, tends to hinder direct comparisons and synthesis of results.

Mexico Our literature search identified one publication evaluating economic outcomes in an area of the world that is in the process of rapid growth and industrialization [19]. This Mexican study from the perspective of the Instituto Mexicano del Seguro Social estimated separate costeffectiveness analysis (CEA) results for groups of patients with ED and either HTN or T2DM. In both groups, all ED treatments (sildenafil 50 mg and 100 mg, tadalafil 20 mg, and vardenafil 10 mg and 20 mg) were dominant (lower cost and greater effectiveness) compared to non-treatment, and sildenafil 100 mg was the most cost-effective treatment. The rationale for these results was that the use of ED treatments may improve T2DM and HTN treatment compliance, which could reduce costs related to hospitalization. A decision tree model was created to reproduce the clinical reality

of patients with ED and T2DM or HTN. Treatments for T2DM and HTN may be associated with the development of ED, leading patients to discontinue T2DM and HTN medications. By treating the ED with sildenafil, patients may exhibit better adherence to their T2DM and HTN treatments thereby avoiding future disease-related complications, such as hospitalization. Twelve-month costs, reported in 2006 US dollars, were estimated with projections at 5 and 10 years following initiation of ED treatment. Effectiveness, measured as the number of days of hospitalization (for HTN or T2DM related complications) avoided due to ED management per 1,000 patients treated with any of the study medications, was highest for sildenafil 100 mg (18 hospital days avoided in HTN or T2DM). Per capita/year costs (including direct medical and indirect costs) were significantly lower for all ED treatments in patients with HTN or T2DM compared to non-treatment (P = 0.0001). With respect to cost-effectiveness, sildenafil dominated the other active treatment comparators (tadalafil and vardenafil) in both HTN and T2DM and sildenafil 100 mg was more cost-effective than sildenafil 50 mg for both T2DM (incremental costeffectiveness ratio [ICER] of $0.25 per hospital day avoided) and HTN (ICER of $1.49 per hospital day avoided) [19]. Because this research pertains specifically to ED patients with HTN or T2DM comorbidites, additional research is needed in the general ED population in order to fully understand the economic impact of sildenafil in Mexico. J Sex Med 2013;10:1389–1400

Study summaries

J Sex Med 2013;10:1389–1400

Canada, 2001

Mexico, 2006

Citation

Mittmann et al. [11]

Arreola-Ornelas et al. [19]

CI = Confidence interval

Country, Pricing Year

ED patients with type 2 diabetes mellitus or hypertension

Spinal cord injury patients with ED

Population

Cost-Effectiveness Analysis Studies (N = 2)

Table 1

Cost-effectiveness decision Tree model, Mexican Social Security Institute prospective 1 year, 5 years, 10 years

Cost-utility analysis, Canadian provincial government payer perspective 1 year

Type of Cost Analysis, Perspective, & Time Horizon

Tadalafil (PDE-5 inhibitor), vardenafil (PDE-5 inhibitor), or no treatment

Transurethral suppository, intracavernous injections (ICI), Vacuum Erection Device (VED), or Penile Prosthesis Surgery (PPS)

Comparator(s) to Sildenafil Cost-analysis estimated the annual cost of non pharmacological treatments and ICI for erectile dysfunction ranged from CAN$729.69 (VED) to CAN$7874.85 (PPS). The annual cost of treatment with sildenafil (CAN$1,534) was cheaper than the costs associated with alprostadil intracavernous injections (CAN$1,908), alprostadil transurethral suppositories (CAN$2,613) and surgery (CAN$7,875), but more expensive than Triple Mix: alprostadil/papaverine/phentolamine (CAN$858) and VED (CAN$730). When compared with Triple Mix and VED, the ICERs for sildenafil were CAN$9,656 and CAN$13,399, respectively, per QALY. Sildenafil 50 mg was associated with the lowest annual cost: In DM $2,609.11–$2,932.23 (CI 95%; P = 0.0001), and in HTN $2,812.13–$3,032.69 (CI 95%; P = 0.0001). In DM, a year of ED treatment with 50 mg of sildenafil vs. ED non-treatment option produced a savings of $753.13–$829.94 (CI 95%; P = 0.0001); $3,213.02–$3,624.21 (CI 95%; P = 0.0000) at 5 years of treatment; and $12,070.08–$13,301.39 (CI 95%; P = 0.0001) at 10 years of treatment. In HTN, a year of ED treatment with 50 mg of sildenafil vs. ED non-treatment option produced a savings of $1,540.54–$1,667.10 (CI 95%; P = 0.0001); $5,475.72–$7,190.28 (CI 95%; P = 0.0000) at 5 years; and $24,325.00–$26, 741.22 (CI 95%; P = 0.0001) at 10 years. 100 mg of sildenafil exhibited greater incremental effectiveness (4 avoided hospitalization days vs. 50 mg of sildenafil, and the best Incremental Cost Effectiveness [ICE] for DM ($0.13–$0.36 CI 95%; P = 0.0001) as well as for HTN ($1.07–$1.89 CI 95%; P = 0.0001) and superior to the other ED treatment alternatives. The ICER for sildenafil at the 100 mg dose was also superior to other treatments at $0.25.

Economic Outcomes

Sildenafil is predicted to be cost-saving vs. ED non-treatment and have superior cost-effectiveness vs. 20 mg of tadalafil and 10–20 mg of vardenafil in hypertensive and type 2 diabetic patients. A 50 mg dose of sildenafil represented a cost-saving ED therapy vs. non-treatment and other treatment options.

Sildenafil is the dominant economic strategy compared with non-pharmacological treatments such as intracavernous injections, transurethral suppository and surgery, as sildenafil is less expensive and has a higher utility than the other treatments.

Conclusions

+

+

Is Sildenafil Cost-effective?

1392 Martin et al.

UK, 1999

UK, 2000

US, 2003– 2004

Ashton-Key et al. [8]

Wilson et al. [17]

Harnett et al. [10]

Citation


ED

ED

ED

Population

Retrospective claims database analysis, Direct cost of maintaining sildenafil vs. switching to another PDE-5 drug 5 months

Prevalence-based cost-of-illness study from the NHS perspective 3 years

Economic analysis, UK NHS perspective 2 years

Study Design, Perspective, & Time Horizon

vardenafil (PDE-5 inhibitor) or tadalafil (PDE-5 inhibitor)

ICIs alprostadil, yohibine (Prostaglandin E1)

Alprostadil (Prostaglandin E1)

Comparator(s) to Sildenafil

Cost-consequence, Cost of Illness, Cost-of-care Studies (N = 6)

Although pre-index costs attributable to ED were similar between those who initially refilled sildenafil ($19.32) and those who switched ($20.81) from sildenafil (P = 0.72), post index ED costs were significantly higher (P < 0.001) in patients who switched ($173.38) relative to patients who refilled their sildenafil prescription ($131.51). Linear regression analysis revealed the ED-attributable costs incurred during the post-index period by patients who switched medications were approximately 41% greater than the ED-attributable costs incurred by patients who refilled their prescription for sildenafil (P < 0.001).

In the primary care setting, the monthly costs for sildenafil doubled from approximately £7,500 to £15,000 between May 1999 and May 2000 while specialist care and associated costs reduced. The overall cost for 1999–2000 (£225 108) was similar to the cost for 1998–1999 uplifted to 1999–2000 (£232 619) values because of reduced specialist-care costs. The largest component of direct costs involved with ED treatment was specialist consultations at £23.6 million (32.0%), followed by sildenafil therapy at £19.3 million (26.2%), psychosexual therapy at £10.1 million (13.6%), and general practice consultations (12.0%). The annual cost was most sensitive to the number of drug prescriptions and specialist consultations.

Economic Outcomes

The increased NHS cost of managing ED was due mainly to a three-fold increase in the number of men presenting to general practitioners, substantial numbers of whom were then referred for specialist consultations. This resulted in the increased use of all resources including sildenafil. The cost effectiveness of transferring prescribing responsibility in cases of severe distress from specialists to GPs in primary care remains to be determined. Patients who switch to another PDE-5 inhibitor agent after receiving an initial prescription for sildenafil incur greater ED-attributable and overall costs than patients who refill their sildenafil prescription.

The Department of Health guidance on the management of impotence treatment reduced specialist care activity while primary care cost increased, however the overall costs remained stable.

Conclusions

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Continued

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Veterans with ED

US, 2006

US, 2000

Singh and Seftel, 2008 [15]

Stafford and Radley, 2002 [16]

Working-age beneficiaries receiving employerbased health insurance

Selective serotonin reuptake inhibitor (SSRI)induced ED

Population

Nurnberg and US, year Duttagupta not [13] reported

Citation


Pill splitting cost analysis, Commercial HMO Health Plan perspective, 10 months

Direct cost, National Veterans Administration perspective 9 months

Cost consequence analysis, health care payer perspective 6 months


N/A

Vardenafil (PDE-5 Inhibitor)

Discontinuation of SSRI, switch to a different SSRI, or addition of a non-SSRI add-on therapy

Comparator(s) to Sildenafil

Cost-consequence, Cost of Illness, Cost-of-care Studies (N = 6)

Table 1

Conclusions

The sildenafil add-on group had the lowest cost Sildenafil can be a cost-effective add-on therapy to estimates compared with groups that discontinued control SSRI-induced ED. Health care payers need SSRIs, substituted another SSRI (switching), or to consider this in developing optimum treatment added a non-SSRI to the existing SSRI strategies for men with depression. (augmentation) after 6 months of SSRI treatment. The physician or specialist visit was the single most important cost component in this hypothetical population. The model predicted 7.6 and 2.8 office visits for those who discontinued or switched SSRIs, respectively, compared with 1 visit for sildenafil users and those who added a non-SSRI. Sildenafil remained the most cost-effective treatment even when treatment failure costs were removed from the model; additionally, the model is based on 10 doses/month, and savings may be even greater if based on a more realistic pattern of four to six doses/month was applied. A 30-day supply of vardenafil at a 20 mg dose is The substantial cost savings to the VA of switching $173.83, while the same quantity of a 50 or 100 mg from sildenafil to vardenafil seem to be justified by dose of sildenafil cost the VA $228.32. the minimal adverse effects on men treated for The VA was able to save money with its formulary erectile dysfunction. change from sildenafil to vardenafil by choosing the least expensive medication and directly achieving an economic advantage for each prescription filled. If a 25 mg sildenafil pill is split, annual savings would Pill splitting of higher dose sildenafil tablets can be a be $610. If a 50 mg pill is split, annual savings cost-saving practice when implemented judiciously would be $8461. using drug- and patient-specific criteria aimed at The annual number of prescriptions of 25 mg tablets is clinical safety, although this strategy is used 37, while the annual number of prescriptions of infrequently. 50 mg tablets is 513 in this health care system. The potential average cost savings from splitting was 50% for sildenafil (25 and 50 mg).

Economic Outcomes

1394 Martin et al.

UK, 2000

Sairam et al. [14]

UK, 2002

US, 1998– 1999

Yu et al. [18]

Mostyn et al. [12]

US, 2001

Cooke et al. [9]

Citation


Pharmacists

ED

Veterans with ED

ED

Population

Drug Pricing/Willingness to Pay (N = 4)

Survey of the cost of four 100 mg sildenafil tablets as a private prescription within the NHS, 2002

Willingness-to-pay (WTP), patient perspective 6 months

Survey, Costsharing (WTP) analyses 1 year

Pharmacy claims database analysis, large managed care organization, 2001


The cost of the four tablets of sildenafil as listed in the British National Formulary 2002 is £23.5. In local pharmacies across England, the cost of a private prescription for four 100 mg tablets of sildenafil ranged from £28.20 to £42.33. The difference in price according to the areas surveyed can be explained by the difference in the local economies with supermarket pharmacies offering the lowest mean price. The survey found that the cheapest price for sildenafil was from the one registered mail order community pharmacy.

Thirty of 141 men (21.3%) wanted ED treatment to be covered on NHS and free of charge, 100 (70.9%) wanted it to be free, but were willing to pay some cost if necessary and 11 (7.8%) felt that it was inappropriate for ED to be covered by the NHS and were willing to pay for it “at cost.” Following treatment with sildenafil, those who failed to have better erections were not willing to pay any amount, while those who succeeded there were no statistically significant changes, i.e., the 3 WTP groups did not show any significant upward or downward trend following success with sildenafil therapy.

A total of 1,681 members (8.3%) exceeded their quantity restrictions for sildenafil tablets in 2001, of which 1,362 (81.0%) paid cash for the additional tablets, and 319 (19.0%) appealed and received approval from the MCO for additional sildenafil tablets beyond the limit of 6 tablets per month. Total pharmacy benefit expenditures in 2001 were $516 million for this MCO with 1.2 million members or about $36 PMPM in MCO costs after subtraction of member cost-share but before the effect of manufacturer rebates. The MCO spent $2.6 million on sildenafil prescriptions in 2001, approximately $0.18 PMPM, or about 0.5% of the annual pharmacy budget. Costs for the MCO were divided nearly equally between the 50 mg ($1.2 million) and the 100 mg ($1.3 million) doses of sildenafil, with the 25 mg dose accounting for $36,726 of the pharmacy budget in 2001. The total allowed charges for sildenafil pharmacy claims in 2001 were $3.56 million, of which members paid 26.6% ($0.944 million) in average cost-share and the MCO net cost was $2.61 million. The average copayment per sildenafil pharmacy claim in 2001 was $13.90 ⫾ $8.67 (mean ⫾ SD; median = $15), with a range of $0 to $240. The average member copayment in 2001 for any sildenafil claim was $14.70 ⫾ $8.82 (median = $15), with a range of $0 to $240. The total out-of-pocket cost for sildenafil per member for the year was $46.55 ⫾ $45.01 (median = $30), with a range of $0 to $623. Respondents reported a mean willingness to cost-share $5.40 for four sildenafil pills which represented 27% of the VA wholesale cost of $20.Younger patients (P = 0.03) and those with fewer comorbidities (P = 0.006) were associated with greater willingness to cost-share for sildenafil.

Economic Outcomes

Results suggest that in patients in the low-income veteran population with self-reported need may be willing to share one quarter of the VA acquisition costs for sildenafil, should the VA decide to offer this medication. There were no statistically significant changes in the WTP within or between the 3 WTP groups, in those who succeeded with sildenafil therapy. This lack of change in the WTP seems to reflect the perception of health care delivery by the NHS, as, in spite of successful treatment of their ED, patients were unwilling to change their WTP stance. Men in the UK with impotence are subject to restricted access to the drugs they require, and may also have to shop around with their private prescription for the best price. The range in prices and work involved with finding the best price may lead men to purchase the medication from unlicensed mail order, internet or “street” sources.

A quantity limit of six tablets of sildenafil per 30-day period was associated with a drug cost to users and the MCO of $0.25 PMPM. Sildenafil users paid an average cost-share of 26.6%, resulting in a net drug cost of $0.18 PMPM to the MCO. The impact of sildenafil on the MCO’s pharmacy budget was 0.5% and 91.7% of members did not exceed their sildenafil quantity restriction.

Conclusions

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United States, Canada, and the United Kingdom Eleven of 12 studies identified were conducted in industrialized Western countries, including the United States, United Kingdom, and one analysis in Canada. Models evaluating patients with spinal cord injuries (SCI) and SSRI-induced ED estimated that sildenafil was the dominant treatment option compared to other drugs, devices, and procedures. In cost studies of the general ED population, sildenafil exhibited cost savings compared to other active treatments. Generally, sildenafil was found to be an economically favorable option for ED patients in the United States, Canada, and the United Kingdom. United States In the United States, the economic literature related to sildenafil was variable in design and no models in the general ED population were identified. Sildenafil was projected to be a cost-effective add-on therapy for SSRI-induced ED, and WTP findings indicated that patients not covered by private insurance were willing to share costs associated with sildenafil. As a source of possible cost savings to the patient, formulary changes provided inconclusive results regarding savings. Patients suffering from depression often experience side effects from treatment, including ED, resulting in reduced adherence to antidepressants. A US cost-consequence model of patients with ED associated with SSRI antidepressant use projected that the strategy of adding sildenafil to SSRI therapy had the lowest cost estimates from the payer perspective, compared with groups that discontinued SSRIs, switched to another SSRI, or added another non-SSRI to existing SSRI treatment. To increase SSRI treatment adherence, sildenafil may be considered as a cost-effective treatment option for men with depression [13]. Formulary changes have inconsistent results for potential cost savings from sildenafil based on two studies. A review of formulary requests for 7,657 Veterans Health Administration (VA) patients who switched ED treatment from sildenafil to vardenafil, following a formulary change in 2006, determined this change provided savings to the VA, which averaged $44.49 per monthly prescription [15]. For the 7,657 patients who switched, 169 (2.2%) non-formulary requests to receive sildenafil again were accepted by the VA, mainly due to treatment failure (53%) or adverse events (AEs) (23%) experienced while taking vardenafil. The VA determined the substantial cost savings with the formulary switch from sildenafil to vardenafil J Sex Med 2013;10:1389–1400

Martin et al. outweighed the small number of AEs and justified the switch to vardenafil. Conversely, a retrospective database review of MCO claims processed for 10,863 patients from 2003 to 2004 found health care costs were significantly higher (P < 0.001) for 726 ED patients who switched from sildenafil to vardenafil or tadalafil ($173.38) vs. 10,137 patients who refilled sildenafil ($131.51) (costing year not reported) [10]. This study did not report whether the switch was cost-based or due to lack of efficacy while receiving sildenafil as investigators only reviewed pharmacy transaction data. In men whose ED treatment is not covered by private insurance, patients exhibit WTP for ED medications. A 2001 pharmacy claims analysis of an MCO covering 1.2 million patients found that cost sharing lowered the monthly costs per member for sildenafil. A quantity limit of six tablets of sildenafil per 30-day period was associated with a drug cost to the MCO of $0.25 per member per month (PMPM). Sildenafil users paid an average cost share of 26.6%, resulting in a net drug cost of $0.18 PMPM to the MCO [9].

Canada A Canadian cost-utility analysis of ED patients with SCI from the perspective of the provincial government estimated that sildenafil is a dominant therapy when compared with surgically implanted prosthetic devices, MUSE® and Caverject®, and was determined to be cost-effective relative to the threshold of CAN $20,000 noted to reflect “excellent” value [11]. In the model, one- year treatment costs associated with each ED treatment was calculated using clinical scenarios approved by a five member Delphi panel. The ICER for sildenafil compared with intracavernous injection was CAN$9,656 and CAN$13,399 when compared with vacuum erection device (VED), per qualityadjusted life year (QALY) gained (2001 Canadian dollars) [11]. United Kingdom In the UK, following the introduction of sildenafil as an oral ED treatment, the number of men presenting with ED increased from 79,800 to 257,984 over a three-year period (1997–2000), resulting in a cost increase to the National Health Service (NHS) from £29.4 million to £73.8 million [17]. Subsequently, recent data show that costs to the NHS to cover 2.2 million prescriptions for ED drugs was £78 million in 2010 [20]. Supplemental searches did not yield more recent data on the costs specific to sildenafil. Starting in 1998,

Economic Impact of Sildenafil Schedule 11 restrictions were implemented, requiring patients to have an approved comorbidity (including diabetes and patients with renal failure undergoing dialysis) or significant sexual distress confirmed by a specialist to qualify for NHS coverage of sildenafil. An economic analysis evaluated the impact of this policy change on specialist care activity and costs to the NHS compared with primary care prescribing costs between 1998 and 1999. Findings from the study showed that specialist care activity and associated costs fell by 70% in the first year, while primary care prescribing costs doubled for sildenafil, as a result of the new restrictions [8]. Despite this shift in prescribing patterns, the overall cost for providing impotence services remained stable in the first year following the restriction [8]. A survey on pharmacy pricing for sildenafil highlighted the variability in pricing for patients who obtained the drug through private prescriptions, with cost ranging from £29.20 to £42.33 for four 100 mg pills [12]. The authors concluded this variability in cost may lead men with ED to purchase sildenafil online or through unlicensed mail order in an effort to save time and money. The majority of internet sites offering ED treatments are unregulated and may not be trustworthy [21]. Unless ordering from an accredited online pharmacy (i.e., http:// www.napb.net/programs/accreditation/vipps/finda-vipps-online-pharmacy/), patients could be at risk for receiving fake medications which may contain potentially harmful ingredients. In the UK, despite the cost of treatment, a majority of men were willing to pay for part of the prescription costs, if it were covered on the NHS. An observational study assessing the perception of health benefits demonstrated that over two-thirds (70.9%) of patients wanted free ED treatment but were willing to pay some of the cost for sildenafil [14]. In reality, although 92% of men expect their ED to be covered by the NHS, only 30% qualify for NHS treatment for clinical comorbidities and 18% for the sexual distress category [14]. Discussion

This systematic review assessed the current literature and evidence on the economic impact for patients with ED treated with sildenafil. To our knowledge, this is the first literature review evaluating the body of evidence. We identified 12 economic studies published in the past 10 years, one of which focused on a developing country, Mexico. The remaining 11 studies evaluated economic out-

1397 comes in North America and the UK. In the past 10 years, no cost-effectiveness models have been published on the general ED population; however, two CEAs (in Canada and Mexico) using ED patients with comorbidities have shown sildenafil to be either dominant by providing cost savings and improved effectiveness or generating favorable ICERs compared with other oral agents, devices, and procedures. A separate cost-consequence model in depression patients with SSRI-induced ED predicted that add-on treatment with sildenafil was more cost-effective than discontinuing SSRI treatment. The remaining economic literature employed retrospective designs on a myriad of topics. Patient questionnaires evaluated patients’ WTP for sildenafil, while potential cost saving practices for MCOs such as formulary changes were investigated using pharmacy claims analyses. Sildenafil treatment may provide secondary economic value. In patients with HTN or T2DM, presence of ED can cause poor adherence or discontinuation of treatment due to patients’ perception that treatments for these conditions cause their ED [19]. Lack of adherence or discontinuation of treatment results in increased costs related to higher rates of complications (e.g., amputation/ ulcers, retinopathy) and hospitalizations [19]. Improving sexual function with coadjuvant use of sildenafil in these patients may increase adherence with medications to treat their comorbidity, improving overall health status by preventing downstream costs related to comorbid conditions. In diabetic and hypertensive patients with ED, all ED treatments (sildenafil 50 mg and 100 mg, tadalafil 20 mg, and vardenafil 10 mg and 20 mg) were dominant compared to non-treatment, while sildenafil 100 mg was the most cost-effective treatment compared with all other ED treatments and a variety of doses. The underlying reductions in hospitalizations generated significant cost savings, presumably driven by improved treatment adherence overall [19]. In patients with SSRI-induced ED, reduced treatment adherence can lead to diminished quality of life associated with unmanaged disease, increasing the cost of illness. Relapse of major depression resulting from noncompliance leads to both substantial costs and increased patient suffering. A cost-consequence model calculated that physician visits and relapse of depression were the most costly outcomes related to reduced adherence [13]. Add-on therapy with sildenafil was shown to be a cost-effective approach as the cost per patient per month was three times lower for patients receiving sildenafil than a group that disJ Sex Med 2013;10:1389–1400

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continued SSRIs to manage their ED [13]. Additional research is needed for ED patients with comorbidities, as the value of increasing treatment adherence and reducing downstream events for these comorbid conditions with sildenafil warrants further investigation. As the sildenafil compound patent continues to expire in various jurisdictions, the relative price of sildenafil compared to treatment alternatives in those jurisdictions may fall. This may in turn influence the cost-effectiveness of sildenafil and may also affect treatment patterns and the budget impact to payers of treating ED. Aside from increased costs resulting from poor adherence, ED also has a significant impact on the quality of life of patients, and the physical restrictions can be accompanied by psychological and emotional effects. Pharmacological treatments have become the standard of care for managing ED and have been important tools in reducing the humanistic disease burden of ED. Of the available treatments, sildenafil has a positive efficacy profile with many studies reporting successful management of ED in more than 90% of participants [14]. WTP for ED treatment is exhibited in the consumer response. Depending on the particular country’s health care system, sildenafil treatment may not be covered or may be high in cost. Despite this, several studies in the US and UK have demonstrated patients’ willingness to pay for a portion or all of sildenafil prescriptions when not covered by private insurance [9,14,18]. This demonstrates value in the treatment, as patients would not pay the high cost without a benefit they perceive as substantially improving upon their ED experience and other available therapies. In the eight months following the introduction of sildenafil, the market for ED treatment in the US nearly quadrupled. In 2010, Table 2

sildenafil generated nearly $2 billion in worldwide sales, of which half originated from the US. Formulary changes also were investigated as a source of cost savings for MCOs. A study on formulary changes from sildenafil to vardenafil or tadalafil found patients who refilled sildenafil incurred less cost to the MCO than those who switched treatment [10]. Conversely, a study of the VA health care system found cost savings in switching patients from sildenafil to vardenafil [15]. The VA study did not investigate the differences in efficacy between these two treatments and noted no studies had been conducted to investigate the interchangeability of the various PDE5 inhibitors in the clinical setting. Until that evidence is available, the authors concluded that cost should not be the only factor affecting treatment choice. A significant limitation of this systematic literature review is that no studies addressed the fundamental value of sildenafil as measured by the cost-effectiveness of treating a general ED population. Prior to the 10-year time period for this systematic review ( July 2001–July 2011), there is a study of cost-effectiveness of sildenafil in 60-yearold men with ED without comorbidities, which represents only a subset of the overall ED patient population [24]. This model estimated a generally favorable cost per QALY gained for sildenafil of $11,290 compared to no therapy (1998 US dollars). However, based on the restricted population, the result is not generalizable as ED affects a large number of patients between 40 and 60, who were not factored into the model. The cost per QALY for ED treatment of sildenafil is lower than that of other treatments for common chronic conditions in middle aged men, such as diabetes and renal insufficiency (Table 2). The gap in evidence

Effectiveness (QALY) of therapies for several chronic conditions in the US

Condition

Intervention

Type 2 Diabetes (T2DM)

Conventional glycemic control* Intensive glycemic control* Reduction in serum cholesterol level Aliskiren and losartan† Losartan† Antihypertensive therapy (no angiotensin converting enzyme [ACE] inhibitors) and placebo‡ Antihypertensive therapy and benazepril‡ Sildenafil§

Renal insufficiency

Erectile dysfunction

Effectiveness (QALY)

Cost-effectiveness ratio (cost/ QALY) (in US$)

11.88 10.40 11.5 5.98 5.88 4.90

41,384 -1,959 51,889 64,746 61,794 10,564

4.99 10.56

11,847 11,290

*CDC Diabetes cost–effectiveness group, 2002. QALY discounted at a 3% annual rate, costs 1997 USD. Conventional glycemic control consisted of standard treatment for type 2 diabetes. Insulin or sulfonylurea therapies were used for intensive glycemic control. Moderate glycemic control consisted of standard treatments for hypertension. Intensified control consisted of ACE inhibitor or b-blocker regimens. † Delea, 2009 [22]. Discounted at a rate of 3% annually. Aliskiren is a direct renin inhibitor. Losartan is an angiotension II receptor blocker (ARB). ‡Hogan, 2002 [23]. Benazepril is a member of the ACE inhibitor class of antihypertensives. §Smith, 2000 [24]. Discounted at a rate of 3% annually.

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Economic Impact of Sildenafil of cost-effectiveness data is offset by the other economic evaluations on cost savings and sharing measures related to sildenafil and it may not represent an important gap to decision makers. ED is a non-life threatening and non-painful condition, so patients’ willingness to pay for treatment may represent the appropriate way to demonstrate value for sildenafil. Source of Funding

Amber Martin, Rachel Huelin, David Wilson, and Talia Foster are employees of UBC who were paid consultants to Pfizer in connection with the development of this manuscript. This study was funded by Pfizer Inc. Corresponding Author: Amber L. Martin, BS, United BioSource Corporation, 430 Bedford St., Suite 300, Lexington, MA 02420, USA. Tel: +1-781-960-0230; Fax: +1-781-761-0147; E-mail: amber.martin@ unitedbiosource.com Conflict of Interest: The authors have no conflicts to report. Statement of Authorship

Category 1 (a) Conception and Design Amber L. Martin; Rachel Huelin; Talia S. Foster; Joaquin F. Mould (b) Acquisition of Data Amber L. Martin; Rachel Huelin (c) Analysis and Interpretation of Data Amber L. Martin; Rachel Huelin; David Wilson; Talia S. Foster; Joaquin F. Mould

Category 2 (a) Drafting the Article Amber L. Martin; Rachel Huelin; David Wilson; Talia S. Foster (b) Revising It for Intellectual Content Amber L. Martin; Rachel Huelin; David Wilson; Talia S. Foster; Joaquin F. Mould

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