The Impact of Formulary Replacement of Sildenafil by Vardenafil at a Local VA Hospital

ORIGINAL ARTICLE The impact of formulary replacement of sildenafil by vardenafil at a local VA hospital

M Singh and AD Seftel

Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

The National Veterans Administration (VA) changed its formulary agent for the treatment of erectile dysfunction from sildenafil to vardenafil in January 2006 for economic reasons. The objective of this study was to assess the impact of this formulary change on the patients at a local VA hospital. All non-formulary requests for sildenafil between January 2006 and September 2006 were reviewed. A total of 169 non-formulary requests were made for sildenafil while 7657 patients filled vardenafil prescriptions. Overall, the formulary change from sildenafil to vardenafil appeared to be well tolerated by the vast majority of patients at this local VA hospital. The substantial cost savings to the VA seem to be justified by the minimal adverse effects on men treated for erectile dysfunction. International Journal of Impotence Research (2008) 20, 188–191; doi:10.1038/sj.ijir.3901606; published online 6 September 2007

Keywords: phosphodiesterase inhibitors; erectile dysfunction; sildenafil; vardenafil

Introduction The National Veterans Administration (VA) re- cently switched its preferred formulary agent for Oral phosphodiesterase type 5 (PDE5) inhibitors are the treatment of erectile dysfunction from sildenafil the recommended first-line option for the treatment of to vardenafil for financial reasons.4 This change erectile dysfunction. Currently, three PDE5 inhibitors provided a unique opportunity to evaluate the are approved for use in the United States: sildenafil interchangeability of two of the PDE5 inhibitors in citrate (sildenafil), vardenafil HCl (vardenafil) and the clinical setting. In contrast to the background of tadalafil. All three drugs have similar efficacy and other studies, the impetus for the formulary change toxicity profiles.1 Minor differences exist between the in this case was an economic one. The cost related to three PDE5 inhibitors. Tadalafil has a longer duration therapy for erectile dysfunction has greatly increased of action and its pharmacokinetic profile is not affected in recent years.5 As more men seek treatment, this by food, as compared to sildenafil and vardenafil. cost will continue to rise and the economics of Vardenafil does not alter color perception through pharmacological therapies will become increasingly inhibition of phosphodiesterase type 6, a rare side important. As part of the Urologic Diseases in effect of sildenafil.2 However, all three drugs are well America project, Wessells et al.5 estimated that the tolerated with few reported serious adverse events. cost of treatment for erectile dysfunction could reach Several studies have been conducted to evaluate $15 billion if all men sought treatment. In the face of patient preference for a particular PDE5 inhibitor. such substantial expenditures, price is a principal The majority of these studies seem to indicate a factor in the choice between phosphodiesterase preference for tadalafil, the longer acting agent, as inhibitors. According to data published by the VA opposed to sildenafil and vardenafil, the two shorter Pharmacy Benefits Management Strategic Healthcare acting agents. These preference studies have been Group, the cost to the VA for a 30-day supply of criticized for their design flaws, which hinder inter- vardenafil at a 20 mg dose is $173.83, while the same pretation of the data.3 quantity of a 50 or 100 mg dose of sildenafil cost the VA $228.32, resulting in a savings of $44.49 for every 30-day prescription filled.6 Correspondence: Dr M Singh, Department of Urology, Case The objective of this study was to assess the Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44112, USA. impact of the formulary change from sildenafil to E-mail: [email protected] vardenafil at a local VA hospital. Given the limited Received 21 June 2007; accepted 26 July 2007; published data comparing these medications, patient response online 6 September 2007 was difficult to predict. Under VA regulations, The impact of formulary replacement of sildenafil M Singh and AD Seftel 189 sildenafil remains available, but only after approval dizziness, nausea, stomach upset, flushing and of a non-formulary request initiated by the health visual changes. care practitioner prescribing the medication. This Finally, 35 (21%) requests were made for drug– availability provided the basis for carrying out the drug interactions with antiarrhythmic medications study design. To gain approval for sildenafil, the due to concerns over possible QT prolongation with patient must be classified as a vardenafil non- vardenafil. These patients did not try vardenafil. responder, be intolerant of vardenafil, or have a There were no serious adverse events reported by contraindication to vardenafil use. Criteria for any patients or providers. vardenafil non-responders have been established During the same time period, the pharmacy at this by VA guidelines.7 local VA hospital filled vardenafil prescriptions for 7657 patients.

Materials and methods

Approval for the study was obtained from the local Discussion VA institutional review board. Limited trials comparing the three PDE5 inhibitors The VA made the formulary change from sildenafil have been conducted. Moore et al.9 published an to vardenafil in January 2006. From pharmacy indirect comparison of PDE5 inhibitors for erectile records at a local VA hospital, a list of those patients dysfunction using published randomized trials for was obtained for whom sildenafil was requested each drug. Although analysis was severely limited by after the formulary replaced sildenafil with varde- differential reporting of outcomes, the three agents nafil as the preferred agent for the indication of were found to be similar for consistently reported erectile dysfunction. All non-formulary requests efficacy numbers. Berner et al.10 performed a were made consecutively between January 2006 comparative meta-analysis of PDE5 inhibitors look- and September 2006. ing at fixed-dose regimen randomized-controlled For all patients with non-formulary requests on trials using a common outcomes measurement, the file, retrospective chart review of their records was International Index of Erectile Function. Interest- conducted. The information from the non-formulary ingly, sildenafil was found to be significantly more requests was analyzed to assess the basis for effective than vardenafil although all three agents prescribing sildenafil. were highly efficacious. However, in a randomized, All patient information collected was de-identified double-blind crossover study in men with cardio- and kept confidential according to VA Research Data 11 8 vascular risk factors, Rubio-Aurioles et al. con- Security and Privacy policies. cluded non-inferiority of vardenafil for overall Patients for whom sildenafil was requested for an preference and nominal statistical superiority of indication other than erectile dysfunction (for vardenafil over sildenafil for several frequently used example pulmonary hypertension, post-prostatect- efficacy measures. omy daily therapy) were excluded from the review. Several studies have also been designed to evaluate patient preference between the available PDE5 inhibitors. The trend in these studies has been Results to conclude that patients prefer tadalafil over sildenafil and vardenafil. In an open-label study, A total of 169 non-formulary requests were made most patients currently taking sildenafil who were and accepted for sildenafil between January 2006 given tadalafil preferred to continue on tadalafil and September 2006 for the indication of erectile after 9 weeks of treatment.12 Similarly, 71% of men dysfunction at the study location. Eighty-nine (53%) naive to PDE5 inhibitor therapy chose to continue requests were made for therapeutic failure of on tadalafil versus 29% on sildenafil after 12 weeks vardenafil in patients who were previously satisfied of treatment with each agent in another open label with sildenafil. Seven (4%) requests were made for study.13 Two randomized trials found tadalafil to be therapeutic failure of vardenafil in patients who had preferred over sildenafil by patients with erectile never tried sildenafil. Thirty-five (21%) requests dysfunction but these trials did not compare were made for adverse reactions to vardenafil in equivalent dosages of the medications.14,15 Tolra patients who were previously satisfied with silde- et al.16 conducted a prospective, randomized, open- nafil. Six of these 35 patients also complained of label, crossover study to assess patient preference therapeutic failure of vardenafil. Three (2%) re- and found patients preferred tadalafil over sildenafil quests were made for adverse reactions to vardenafil as well as over vardenafil. Finally, in a recent in patients who had never tried sildenafil. One of prospective observational study of 2425 men, a these three patients also complained of therapeutic higher percentage of patients preferred tadalafil failure of vardenafil. The most common adverse after switching from sildenafil to tadalafil or vice reactions reported by patients included headache, versa.17

International Journal of Impotence Research The impact of formulary replacement of sildenafil M Singh and AD Seftel 190 The methodology and design of these preference majority of non-formulary requests were made for studies has been criticized making interpretation of patients who were previously satisfied with silde- the results difficult.3 Moreover, there have been data nafil. It was unclear how many of the 7657 patients published that conflict with the conclusion that with active vardenafil prescriptions had previously tadalafil is preferred by most men with erectile tried sildenafil. It was also unclear what proportion dysfunction. Two separate studies, one in the of those patients who had not tried another PDE5 United States18 and one in the United Kingdom,19 inhibitor were offered sildenafil or other treatments showed that patients who were prescribed sildenafil for erectile dysfunction after vardenafil failure. were significantly less likely to switch to another Finally, there were unanswered questions on the PDE5 inhibitor compared with those who were status of those patients who had previously failed or initially prescribed vardenafil or tadalafil. were intolerant to sildenafil. It was unknown With such limited and conflicting data, the impact whether these patients were offered a trial of of switching patients from one PDE5 inhibitor to vardenafil or alternative treatments and the out- another was difficult to predict. The decision by the comes of these interventions. VA to change its formulary agent for erectile The biases and limitations mentioned above dysfunction treatment from sildenafil to vardenafil stemmed from the design of the study and set the provided the opportunity to assess such a move in stage for prospective randomized-controlled studies the clinical setting. Overall, the formulary change which could truly answer some of the questions from sildenafil to vardenafil appeared to be well regarding the differential efficacy and interchange- tolerated without complaints or serious side effects ability of the various PDE5 inhibitors in the clinical by the vast majority of patients at this local VA setting. In this retrospective review, it appeared that hospital. Therefore, the substantial cost savings to sildenafil and vardenafil were interchanged with the VA seemed to be justified by the minimal minimal disruption to those being treated for adverse effects on patients treated for erectile erectile dysfunction. dysfunction. When others have analyzed the economic impact of PDE5 inhibitor switching, changing medications have resulted in an increase in overall expenditures. Conclusions In a Pfizer study, costs attributable to erectile Overall, the national formulary change from silde- dysfunction and overall costs were 41 and 43% nafil to vardenafil was well tolerated by the vast higher, respectively, for patients who switched from majority of patients at this local VA hospital. The sildenafil to another PDE5 inhibitor compared with majority of non-formulary requests for sildenafil those who refilled sildenafil.20 These data were were made for patients who complained of ther- based on an aggregated health care claims database. apeutic failure of vardenafil and had previously Consequently, the differential costs between silde- been satisfied with sildenafil. Biases in the study nafil and the other PDE inhibitors were not directly included the lack of knowledge of the ability to reflected. The VA was able to save money with its switch back to sildenafil, sildenafil-naive patients formulary change by choosing the least expensive versus those who were previously treated with medication and directly achieving an economic sildenafil, and lack of efficacy or intolerance to advantage for each prescription filled. sildenafil. Prospective randomized studies are Several interesting questions highlighted the needed to truly compare the various PDE5 inhibitors limitations of this retrospective study and could and evaluate their interchangeability in the clinical provide the framework for further research on PDE5 setting. inhibitor comparison. For example, an extremely Source of funding: none small proportion of patients made a non-formulary Disclosures for M Singh: none. request for sildenafil after receiving vardenafil. Disclosures for A Seftel: Pfizer, consultant. However, the majority of these non-formulary requests were made by patients who were previously satisfied with sildenafil and complained of therapeutic failure of vardenafil. This observation References raised the issue of whether patients who were switched to vardenafil were aware of the formulary 1 Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) change and if they had knowledge of the ability to inhibitors. Int J Clin Pract 2006; 60: 967–975. 2 Doggrell SA. Comparison of clinical trials with sildenafil, switch back to sildenafil if they were not satisfied. vardenafil and tadalafil in erectile dysfunction. Expert Opin This question of access may have biased the results Pharmacother 2005; 6: 75–84. of the study. 3 Mulhall JP, Montorsi F. Evaluating preference trials of oral Another limitation of the study was in its ability phosphodiesterase 5 inhibitors for erectile dysfunction. Eur Urol 2006; 49: 30–37. to evaluate the response of vardenafil in patients 4 Chair, VHA Medical Advisory Panel and Chief Consultant who were sildenafil-naive versus those who were Pharmacy Benefits Management-Strategic Healthcare Group. previously taking sildenafil. As noted earlier, the National Contract Award for the phosphodiesterase type 5

International Journal of Impotence Research The impact of formulary replacement of sildenafil M Singh and AD Seftel 191 inhibitors. Department of veterans affairs, memorandum, 13 Eardley I, Mirone V, Montorsi F, Ralph D, Kell P, Warner MR January 12, 2006. http://www.pbm.va.gov/tig/VardenafilPro- et al. An open-label, multicentre, randomized, crossover study viderMemo.pdf. comparing sildenafil citrate and tadalafil for treating erectile 5 Wessells H, Joyce GF, Wise M, Wilt TJ. Erectile dysfunction. dysfunction in men naive to phosphodiesterase 5 inhibitor J Urol 2006; 177: 1675–1681. therapy. BJU Int 2005; 96: 1323–1332. 6 Pharmacy Benefits Management Strategic Healthcare Group. 14 Govier F, Potempa AJ, Kaufman J, Denne J, Kovalenko P, Ahuja Drug pharmaceutical prices. http://www.pbm.va.gov/Drug- S. A multicenter, randomized, double-blind, crossover study PharmaceuticalPrices.aspx. of patient preference for tadalafil 20 mg or sildenafil citrate 7 VHA Pharmacy Benefits Management Strategic Healthcare 50 mg during initiation of treatment of erectile dysfunction. Group and Medical Advisory Panel. Criteria-for-use checklist Clin Ther 2003; 25: 2709–2723. vardenafil non-responders. http://www.pbm.va.gov/criteria/ 15 von Kietz A, Rajfer J, Segal S, Murphy A, Denne J, Costigan T Vardenafil%20Non-Responders.pdf. et al. A multicenter, randomized, double-blind, crossover 8 VA Research Development. Privacy and confidentiality: study to evaluate patient preference between tadalafil and memoranda, directives and policies. http://www.research.va. sildenafil. Eur Urol 2004; 45: 499–507. gov/resources/data-security/policies_privacy.cfm. 16 Tolra JR, Campana JM, Ciutat LF, Miranda EF. Prospective, 9 Moore RA, Derry S, McQuay HJ. Indirect comparison of randomized, open-label, fixed-dose, crossover study to estab- interventions using published randomised trials: systematic lish preference of patients with erectile dysfunction after review of PDE-5 inhibitors for erectile dysfunction. BMC Urol taking the three PDE-5 inhibitors. J Sex Med 2006; 3: 901–909. 2005; 5: 18. 17 Brock G, Chan J, Carrier S, Chan M, Salgado L, Klein AH et al. 10 Berner MM, Kriston L, Harms A. Efficacy of PDE-5 inhibitors The treatment of erectile dysfunction study: focus on treat- for erectile dysfunction. A comparative meta-analysis of fixed- ment satisfaction of patients and partners. BJU Int 2007; 99: dose regimen randomized controlled trials administering the 376–382. international index of erectile function in broad-spectrum 18 Mulhall JP, McLaughlin TP, Harnett JP, Scott B, Burhani S, populations. Int J Impot Res 2006; 18: 229–235. Russell D. Medication utilization behavior in patients receiv- 11 Rubio-Aurioles E, Porst H, Eardley I, Goldstein I, Vardenafil- ing phosphodiesterase type 5 inhibitors for erectile dysfunc- Sildenafil Comparator Study Group. Comparing vardenafil tion. J Sex Med 2005; 2: 848–855. and sildenafil in the treatment of men with erectile dysfunc- 19 Kell PD, Hvidsten K, Morant SV, Harnett JP, Bridge S. Factors tion and risk factors for cardiovascular disease: a randomized, that predict changing the type of phosphodiesterase type 5 double-blind, pooled crossover study. J Sex Med 2006; 3: inhibitor medication among men in the UK. BJU Int 2007; 99: 1037–1049. 860–863. 12 Stroberg P, Murphy A, Costigan T. Switching patients with 20 Harnett JP, McLaughlin TP, Mulhall JP, Russell D, McLean S. erectile dysfunction from sildenafil citrate to tadalafil: results The economic effect of switching from sildenafil to another of a European multicenter, open-label study of patient phosphodiesterase type 5 inhibitor. Manag Care Interface preference. Clin Ther 2003; 25: 2724–2737. 2006; 19: 22–26.

International Journal of Impotence Research