Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Cost Comparison of Intravitreal Aflibercept With Bevacizumab and Ranibizumab for the Treatment of Wet Age-Related Macular Degeneration

Adeel H. Shaikh, MD; Brian W. Toussaint, MD; Daniel M. Miller, MD; Michael R. Petersen, MD; Robert E. Foster, MD; Christopher D. Riemann, MD; Robert K. Hutchins, MD; Robert A. Sisk, MD

Abstract

BACKGROUND AND OBJECTIVE:

To test the hypothesis that although intravitreal aflibercept (IVA) is expected to be more expensive, the extra cost of treatment would not result in additional vision gain compared with intravitreal bevacizumab (IVB) for the treatment of wet age-related macular degeneration (AMD).

PATIENTS AND METHODS:

A retrospective chart review of patients receiving IVB or intravitreal ranibizumab (IVR) who were subsequently changed to IVA for active wet AMD.

RESULTS:

Thirty-three eyes were included in the study. The mean number of IVB, IVR, and IVA injections per eye over a 6-month period was seven, six, and five, respectively. Visual outcomes were similar in all three groups at the end of the study period. The average drug cost of IVB, IVR, and IVA injections per eye over 6 months was $326, $11,400, and $9,720, respectively.

CONCLUSION:

Aflibercept may allow a modest extension of the treatment interval, but cost makes IVA an expensive alternative without a visual benefit compared with IVB in patients with active wet AMD.

[Ophthalmic Surg Lasers Imaging Retina. 2015;46:62–66.]

From the Department of Ophthalmology, University of Cincinnati College of Medicine (AS, BT, DM, CR, RH, RS) and the Cincinnati Eye Institute (AS, BT, DM, MP, RF, CR, RH, RS), Cincinnati, Ohio.

The authors have no financial or propriety interest in the materials presented herein.

Address correspondence to Robert A. Sisk, MD, Cincinnati Eye Institute, 1945 CEI Drive, Cincinnati, OH 45242; email: rsisk@cincinnatieye.com.

Received: November 15, 2013
Accepted: August 21, 2014

Abstract

BACKGROUND AND OBJECTIVE:

To test the hypothesis that although intravitreal aflibercept (IVA) is expected to be more expensive, the extra cost of treatment would not result in additional vision gain compared with intravitreal bevacizumab (IVB) for the treatment of wet age-related macular degeneration (AMD).

PATIENTS AND METHODS:

A retrospective chart review of patients receiving IVB or intravitreal ranibizumab (IVR) who were subsequently changed to IVA for active wet AMD.

RESULTS:

Thirty-three eyes were included in the study. The mean number of IVB, IVR, and IVA injections per eye over a 6-month period was seven, six, and five, respectively. Visual outcomes were similar in all three groups at the end of the study period. The average drug cost of IVB, IVR, and IVA injections per eye over 6 months was $326, $11,400, and $9,720, respectively.

CONCLUSION:

Aflibercept may allow a modest extension of the treatment interval, but cost makes IVA an expensive alternative without a visual benefit compared with IVB in patients with active wet AMD.

[Ophthalmic Surg Lasers Imaging Retina. 2015;46:62–66.]

From the Department of Ophthalmology, University of Cincinnati College of Medicine (AS, BT, DM, CR, RH, RS) and the Cincinnati Eye Institute (AS, BT, DM, MP, RF, CR, RH, RS), Cincinnati, Ohio.

The authors have no financial or propriety interest in the materials presented herein.

Address correspondence to Robert A. Sisk, MD, Cincinnati Eye Institute, 1945 CEI Drive, Cincinnati, OH 45242; email: rsisk@cincinnatieye.com.

Received: November 15, 2013
Accepted: August 21, 2014

Introduction

Wet age-related macular degeneration (AMD) is the most common cause of blindness in the United States in people over age 60. Intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors have become the standard of care for the treatment of wet AMD.1 The 2012 American Society of Retinal Specialists Preferences and Trends Survey revealed that among the four available anti-VEGF agents, most retina specialists use either intravitreal ranibizumab (IVR) or intravitreal bevacizumab (IVB) as their first-line agent for treating active wet AMD. Ranibizumab was approved by the US Food and Drug Administration (FDA) for the treatment of wet AMD based on the results from the MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the treatment of Neovascular AMD) and ANCHOR (Anti VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) trials.2

Two years ago, intravitreal aflibercept (IVA), a pan-VEGF inhibitor that also inhibits placental growth factor,5,6 was FDA-approved for treating wet AMD. Phase 3 studies (Investigation of Efficacy and Safety in Wet AMD [VIEW 1 and VIEW 2]) comparing injections every 4 and 8 weeks with IVA with injections every 4 weeks with IVR for wet AMD demonstrated similar efficacy and safety outcomes.5 The second year of these trials demonstrated that as-needed treatment with IVA maintained vision with fewer required injections compared with IVR. However, all patients in the aforementioned trials were naive to treatment prior to their enrollment or were excluded for significant subretinal scarring, hemorrhage, geographic atrophy, or choroidal neovascularization that was not subfoveal. This is not reflective of the majority of current wet AMD patients within most retina practices who have established disease and have received numerous prior treatments.

For the vast majority of patients, the development of wet AMD marks the beginning of a chronic disease that will require continued periodic or regular treatment with intravitreal anti-VEGF for visual and anatomic stabilization. Because most patients require frequent and ongoing treatment for wet macular degeneration, the cost associated with intravitreal injections with different agents and office visits is an important consideration for the cost of health care in any system. Drug-related costs, per Medicare J code reimbursement value, of current intravitreal agents per injection varies greatly, with IVR averaging $1,900, IVA $1,944, and IVB $47. Because of the cost associated with IVR, IVB, which was recently validated in the CATT and IVAN trials, has been adopted in most clinical practices worldwide as a low-cost alternative to IVR.7–9 In August 2011, the FDA issued an alert to physicians regarding concerns of endophthalmitis associated with compounded IVB injections, raising concerns about the safety of compounded injectable medications.

Aflibercept appears to be promising in decreasing the treatment burden of wet AMD by reducing the number of office visits, intravitreal treatments, and injection procedure–related complications if a treat-and-extend protocol is followed. In our study, we hypothesize that although IVA may reduce injection frequency, the cost of treatment per vision gain will be similar to treatment with IVR but would be significantly higher compared with treatment with IVB.

Patients and Methods

Records of all consecutive patients with a diagnosis of wet AMD seen at the Cincinnati Eye Institute from February 17, 2011, and November 1, 2012, were retrospectively reviewed after obtaining approval from the institutional review board (Quorum Review Institutional Review Board). Patients receiving regular IVB or IVR for at least 6 months who were changed to IVA for persistently active wet AMD and had at least a 6-month follow-up after this change were included in the study. Eyes with recent photodynamic treatment and exudation from retinovascular disease or choroidal neovascularization from causes other than wet AMD were excluded from the study. Patients were observed approximately monthly according to the PRONTO or “treat-and-extend” protocols. The PRONTO protocol or “treat-and-observe” is an individualized strategy initiating treatment with three monthly injections but then assessing monthly and dosing on an as-needed basis depending on changes in clinical findings and optical coherence tomography evaluation.10 The multicenter Lucentis Compared to Avastin Study (LUCAS) trial presented at the American Academy of Ophthalmology 2013 annual meeting compared IVB and IVR following a treat-and-extend protocol. With this approach, patients are treated during each visit regardless of disease activity, and if there is no sign of activity, the treatment intervals are extended gradually. If there are signs of recurrence, the intervals are shortened.

In each eye, the intravitreal injection was administered in an outpatient office setting and at the discretion of the treating retina specialist. After obtaining informed consent, the eye was prepped with topical proparacaine drops and 5% betadine solution. Use of a sterile lid speculum varied by the preference of the treating specialist. Intravitreal injection was then injected inferotemporally 3 mm posterior to the limbus in aphakic or pseudophakic eyes and 4 mm in phakic eyes. A sterile cotton tip was variably used to apply pressure at the site of entry after each injection. No immediate complications were observed in any case.

Demographic data and ocular examination characteristics including best corrected visual acuity (BCVA) at each office visit were collected. Office visits, testing, and injection costs were collected using Medicare reimbursement codes and analyzed. The primary outcome measures were BCVA and the cumulative and mean cost of office visits, testing, injection procedures, and intravitreal injectables for each eye. A secondary outcome measure was the treatment interval between injections for each eye. The Student’s t test, performed by Microsoft Excel 2011 software (Microsoft, Redmond, WA), was applied to compare Snellen BCVA values converted to log of the minimum angle of resolution (logMAR) values in each group.

Results

Demographics and baseline characteristics of the study population are listed in Table 1. Thirty-three eyes of 30 patients with active wet AMD were included in the study. There were 15 women and 15 men in the study. The mean patient age was 79 years (range, 68–93 years). The mean follow-up was 12 months. There were 16 left eyes and 17 right eyes. The baseline mean BCVA was 0.52 logMAR (Snellen equivalent 20/70) in the IVB group and 0.39 logMAR (Snellen equivalent 20/50) in the IVR group. The mean baseline BCVA in the IVA group was 0.48 logMAR (Snellen equivalent 20/60). The mean baseline intraocular pressure was 14.6 mm Hg in the IVB group and 15 mm Hg in the IVR group. The mean baseline IOP in the IVA group was 15.4 mm Hg. Twenty-six eyes were treated using a PRONTO regimen, whereas seven eyes were treated with a treat-and-extend protocol throughout the study period (Table 2). The same protocol was used to treat the eyes before and after switching to IVA. Eight eyes received IVR, and 25 eyes received IVB initially. The average treatment interval per eye with IVB, IVR, and IVA injections was 28, 32, and 34 days (P < .0004), respectively. The mean number of IVB, IVR, and IVA injections per eye over a 6-month period was seven, six, and five, respectively (P < .0004). Visual outcomes were similar in all three groups. A mean gain of 0.06 logMAR (P = .32) in the IVB group and a loss of 0.06 logMAR vision in the IVR (P = .35) and IVA groups (p = .16) were noted during the study period. The mean central macular thickness in the IVR and IVB groups at 6 months was 311 µm. The mean central macular thickness in the IVA group at the end of the study period was 326 µm. The average office and testing-related costs per eye in the IVB, IVR, and IVA groups over 6 months were $804, $690, and $353, respectively. The average drug cost of IVB, IVR, and IVA injections per eye over 6 months was $326, $11,400, and $9,720, respectively. The average total cost including office visits, testing, and drug cost per eye in the IVB, IVR, and IVA groups over 6 months was $1,130, $12,090, and $10,073, respectively (Table 3).

Patient Demographics and Baseline Ocular Characteristics

Table 1:

Patient Demographics and Baseline Ocular Characteristics

Treatment Protocol Used in Eyes in Each Group Before and After Switching to Aflibercept

Table 2:

Treatment Protocol Used in Eyes in Each Group Before and After Switching to Aflibercept

Average Treatment Costs with Bevacizumab, Ranibizumab and Aflibercept

Table 3:

Average Treatment Costs with Bevacizumab, Ranibizumab and Aflibercept

Discussion

Wet AMD has been demonstrated to respond to a variety of medications that block VEGF.1 However, because of its much lower cost and similar efficacy, many physicians initiate the treatment of wet AMD with IVB.7 Although monthly intravitreal injections of anti-VEGF have consistently offered the best visual acuity outcomes based on numerous studies, CATT and IVAN showed that other strategies may be just as effective.8,9 These studies used the protocol from the PRONTO study in which Lalwani et al10 followed patients with wet AMD monthly but gave injections on an as-needed basis guided by clinical data and optical coherence tomography findings. Another popular strategy known as treat-and-extend involved giving patients injections to maintain minimal or no macular exudation while extending subsequent follow-up between injections until exudation worsened or visual acuity declined. At that point, the previously acceptable interval is maintained.11 Recently, the multicenter LUCAS trial presented at the American Academy of Ophthalmology 2013 annual meeting compared IVB and IVR following the treat-and-extend protocol. With this protocol, patients are treated during each visit regardless of disease activity, and if there is no sign of activity, the treatment intervals are extended gradually. If there are signs of recurrence, the intervals are shortened. This trial also demonstrated that IVB and IVR had equivalent effects on visual acuity. The advantages of the latter strategies are reduction in office visits, testing, and treatment.

Although these therapeutic strategies appear to stabilize or improve vision in most cases of treatment-naive wet AMD, prospective data are lacking regarding optimal management strategies for patients with established disease or those who have received other modalities, such as focal laser or photodynamic therapy. Early choroidal neovascularization may regress with anti-VEGF therapy, but mature choroidal neovascularization is more resistant to anti-VEGF agents and may require more frequent dosing or use of adjuvant treatments in order to stabilize vision. It has been hypothesized that eyes that initially responded to anti-VEGF therapy may develop tachyphylaxis to individual agents.12 In these “poor responders,” increasing the frequency of injections or changing the anti-VEGF agent may yield an improved response.13 However, no consistent definition of “poor responders” or “treatment failure” exists among retina specialists, which confounds the evaluation of the published literature to determine the most appropriate treatment. Although the results from the VIEW 1 and VIEW 2 studies for IVA suggested a duration benefit over IVR in treat-naive eyes,5 annual surveys performed by the 2012 American Society of Retinal Specialists demonstrate that most vitreoretinal specialists are using IVA as a salvage treatment for patients who are failing IVB or IVR therapies rather than in treatment-naive patients.

Our study examines the real-world efficacy and cost outcomes of changing intravitreal anti-VEGF drugs in eyes with established, active wet AMD. In our series, eyes that had not responded to traditional anti-VEGF treatment appeared to have a statistically significant decreased frequency of injections with IVA. The total cost value of office visits, testing, and drug cost of the IVB treatment group exceeded the IVR and IVA groups while maintaining similar short-term visual outcomes. Although IVA marginally increased the treatment interval and lowered office visit costs compared with both IVB and IVR, treatment cost makes it an expensive alternative with no other observed benefit in this cohort with active, established wet AMD.

Limitations of our study include the retrospective study design, the relatively short period of follow-up, and the lack of crossover comparison switching patients from IVE to IVR or IVB. The determination of necessity of treatment was subjective and may have varied from one specialist to another. Retina specialists must weigh existing clinical research and individual patient considerations when determining treatment plans for individuals with wet AMD. However, retina specialists should also respect the treatment cost to patients and the health care system and consider reserving the use of more expensive agents for selected patients after exhausting other options.

References

  1. Ciulla TA, Rosenfeld PJ. Anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2009;20:158–165. doi:10.1097/ICU.0b013e32832d25b3 [CrossRef]
  2. Rosenfeld PJ, Brown DM, Heier JSMARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419–1431. doi:10.1056/NEJMoa054481 [CrossRef]
  3. Brown DM, Kaiser PK, Michels MANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432–1444. doi:10.1056/NEJMoa062655 [CrossRef]
  4. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology. 2009;116:57–65.e5. doi:10.1016/j.ophtha.2008.10.018 [CrossRef]
  5. Heier JS, Brown DM, Chong VVIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–2548. doi:10.1016/j.ophtha.2012.09.006 [CrossRef]
  6. Thomas M, Mousa SS, Mousa SA. Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration. Clin Ophthalmol. 2013;7:495–501.
  7. Fong DS, Custis P, Howes J, Hsu JW. Intravitreal bevacizumab and ranibizumab for age-related macular degeneration, a multicenter, retrospective study. Ophthalmology. 2010;117:298–302. doi:10.1016/j.ophtha.2009.07.023 [CrossRef]
  8. Chakravarthy U, Harding SP, Rogers CAIVAN Study Investigators. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399–1411. doi:10.1016/j.ophtha.2012.04.015 [CrossRef]
  9. Martin DF, Maguire MG, Fine SLComparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388–1398. doi:10.1016/j.ophtha.2012.03.053 [CrossRef]
  10. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009;148:43–58.e1. doi:10.1016/j.ajo.2009.01.024 [CrossRef]
  11. Gupta OP, Shienbaum G, Patel AH, et al. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology. 2010;117:2134–2140. doi:10.1016/j.ophtha.2010.02.032 [CrossRef]
  12. Funk M, Karl D, Georgopoulos M, et al. Neovascular age-related macular degeneration: intraocular cytokines and growth factors and the influence of therapy with ranibizumab. Ophthalmology. 2009;116:2393–2399. doi:10.1016/j.ophtha.2009.05.039 [CrossRef]
  13. Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor trap-eye). Retina. 2012;32(3):343–457.

Patient Demographics and Baseline Ocular Characteristics

Bevacizumab GroupRanibizumab GroupP Value
Age (years).76

  Mean8079

  Range68–9378–87

Gender, n.37

  Male132

  Female105

Eyes, n.21

  Right161

  Left97

Baseline BCVA (logMAR).4

  Mean0.520.39

  Range0.1–1.30.2–0.7

Baseline BCVA (Snellen).4

  Mean20/7020/50

  Range20/25–20/40020/30–20/100

Baseline IOP (mm Hg).63

  Mean14.615

  Range9–2810–19

Treatment Protocol Used in Eyes in Each Group Before and After Switching to Aflibercept

BevacizumabRanibizumabTotal
PRONTO protocol19726
Treat-and-extend protocol617

Average Treatment Costs with Bevacizumab, Ranibizumab and Aflibercept

BevacizumabRanibizumabAflibercept
Mean drug cost over 6 months$326$11,400$9,720
Mean office visit & testing cost/eye over 6 months$804$690$353
Mean total cost/eye over 6 months$1,130$12,090$10,073

10.3928/23258160-20150101-10

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