REASONS FOR DISCONTINUATION OF INTRAVITREAL VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION ANAGHA VAZE, MBBS, DNB, SAMANTHA FRASER-BELL, PHD, FRANZCO, MARK GILLIES, PHD, FRANZCO Background: This study was aimed to identify the reasons for discontinuing intravitreal antivascular endothelial growth factor therapy in neovascular age-related macular degeneration. Methods: This study is a retrospective chart review of a single Australian private practice. Analysis included patients who discontinued treatment from March 2006 to June 2012. Results: Of 248 patients who commenced treatment, 105 (42.3%) had discontinued by June 2012. The reasons for discontinuation were available for 102 of the 105 (97.1%) patients. In 9 (3.6%) patients of the entire cohort, the doctor stopped the treatment as the lesion became inactive, whereas further treatment was thought to be futile in 27 (10.9%) patients. Twenty-six (10.5%) patients declined further treatment with 2 (0.8%) because of excessive treatment visits, 2 (0.8%) because of difficulty in attending, 2 (0.8%) because of the expense, 3 (1.2%) because of pain/discomfort, 6 (2.4%) thought that the treatment was not beneficial, and 11 (4.4%) had other medical conditions that were more severe. Treatment was discontinued in 40 (16.1%) patients for other reasons such as moving to another region in 27 (10.9%) and death in 11 (4.4%). Conclusion: These results indicate that the burden of intravitreal anti-vascular endothelial growth factor injections was a reason for treatment discontinuation in only a small minority of patients. RETINA 34:1774–1778, 2014
A
the two pivotal trials, MARINA2 and ANCHOR,3 demonstrated the efficacy of ranibizumab (Lucentis–Novartis) for wet AMD, regular intravitreal injections of ranibizumab have become the standard treatment for this condition. A detailed analysis of Phase 3 clinical trials has generated evidence-based guidelines for using ranibizumab for the treatment of neovascular AMD.4 Also, there have been numerous prospective5,6 and retrospective studies7–9 evaluating the optimal dosing regimen for anti-vascular endothelial growth factor (VEGF) treatment using individualized patient outcomes in routine clinical setting. Recently, there have been several studies comparing bevacizumab with ranibizumab in the treatment of neovascular AMD,10–12 which have shown that
ge-related macular degeneration (AMD) is the commonest cause of blindness in the developed world, with twice the prevalence of Alzheimer disease.1 It mainly affects people older than 50 years. Since
From the Save Sight Institute, University of Sydney, Sydney, Australia. Supported by grants from the RANZCO Eye Foundation, Sydney, and the National Health and Medical Research Council, Canberra. M. Gillies is a fellow in Sydney Medical School Foundation and is supported by an NHMRC Practitioner Fellowship. M. Gillies is listed as an inventor on a copyright of the FRB! Project software. The other authors have no conflict of interest to disclose. Reprint requests: Anagha Vaze, MBBS, DNB, Save Sight Institute, Sydney Eye Hospital, University of Sydney, Level 1, South Block, 8 Macquarie Street, Sydney, NSW 2000, Australia; e-mail: [email protected]
1774
DISCONTINUATION OF ANTI-VEGF TREATMENT VAZE ET AL
both drugs seem equally effective but require ongoing treatment. A positive effect of ranibizumab treatment on patients’ vision-related quality of life has also been reported by several studies.13,14 However, the ongoing nature of intravitreal therapy along with its financial implications places a strain on the patient, the health care system, and the treating physician. Thus, it is important to identify what issues affect the patients’ willingness and ability to undergo ongoing treatment, which will affect the long-term outcomes of intervention. Although patient compliance is clearly important for intravitreal therapy for AMD, few studies have specifically addressed it. The aim of our study was to give a detailed account of the reasons for discontinuation of anti-VEGF treatment in patients with neovascular AMD during a 6-year period from March 2006 to June 2012.
Methods This was a retrospective single center study of patients with neovascular AMD who began treatment with ranibizumab from March 2006 to June 2012. Approval for data collection and analysis was obtained from the Human Research Ethics Committee of the Royal Prince Alfred Hospital, Sydney. The research adhered to the tenets set forth in the Declaration of Helsinki. The Fight Retinal Blindness! (FRB!) Project data tracking system was used to identify accurately all patients who discontinued treatment. The FRB! is a Web-based prospective audit system that anonymously tracks the outcomes of treatment of retinal disease, such as wet AMD, in large numbers of patients treated in routine retinal treatment centers. Baseline visit characteristics, such as lesion type and size, visual acuity (visual acuity in logarithm of the minimal angle of resolution letters), and treatments are recorded. The treatment outcomes (visual acuity and lesion activity status) and ocular adverse events are recorded at each follow-up visit, as well as treatment discontinuation along with its reason.15 Each patient had visual acuity measured at 4 m on a standard logarithm of the minimal angle of resolution chart, with their current spectacles if worn and pin hole. Whichever was better was entered. An ophthalmic examination included dilated fundoscopy and spectral domain optical coherence tomography (Spectralis HRAOCT; Heidelberg Engineering, Heidelberg, Germany). All patients underwent fluorescein angiography, indocyanine green angiography, or both before treatment to determine the type and size of the lesion. All patients with clinical signs of active subfoveal neovascularization were offered anti-VEGF treatment. Findings that
1775
were considered signs of lesion activity included fall in visual acuity from the previous visit, presence of macular hemorrhages, leakage on fluorescein angiography, and presence of subretinal or intraretinal fluid or both on optical coherence tomography examination. The reasons for discontinuation of the intravitreal anti-VEGF treatment for neovascular AMD during the 6-year period were ascertained from the FRB! database where available and hand searching the patient’s notes. Patients were not specifically contacted by the authors to explain their reasons for discontinuing the treatment. The FRB! fields for treatment discontinuation include the following possibilities: treatment being successful, further treatment being futile, patient goes to another doctor, patient declines, medically contraindicated, or deceased. Reasons for the doctor to discontinue the treatment were subdivided into lesion inactivity and further treatment futile; the latter including eyes that did not show improvement in the visual acuity and lesion activity or if the visual acuity deteriorated progressively despite receiving at least three to six injections. Other reasons for treatment discontinuation included treatment declined by the patient, transferring to another doctor, and death. Statistical analyses were performed using IBM SPSS software version 21. Differences among the groups were calculated using a one-way analysis of variance, differences between two groups were calculated using the independent samples t-test, and the changes over time were calculated using the paired-sample t-test. The chosen level of statistical significance was P , 0.05.
Results A total of 248 patients (284 eyes) began anti-VEGF treatment over the 6 years from March 2006 to June 2012. Of these 248, 105 (42.3%) patients (64 women, 101 whites, and 4 Asians; mean age, 81.5 [range, 56– 95] years) discontinued treatment permanently at this practice. The reasons for discontinuation were available for 102 of 105 (97.1%) patients. These were divided into three groups: treatment discontinued by the doctor, treatment declined by the patient, and other reasons. Eighty-three of the 105 patients (79.0%) were treatment-naive at baseline. Of the remaining 22 (21.0%) patients, 8 had pretreatment with laser, 13 were previously treated with photodynamic therapy, and 1 was previously treated with intravitreal triamcinolone. A summary of the clinical and demographic features of these patients is given in Table 1. In 9 of 248 (3.6%) patients, the doctor believed no further treatment was necessary because the lesion was
*Other reasons included death, patient seeing another doctor, one patient with bilateral disease who chose to continue treatment only in one eye because of poor general health, one patient experienced dysphasia and confusion 5 minutes after an injection. VA, visual acuity (number of letters read on the logarithm of the minimal angle of resolution chart).
2.7 (2.0–3.0) 7.3 (2.0–18.0) 7.4 (2.0–21.0) 3.7 (2.0–6.0) 7.3 (2.0–30.0)
8.9 (2.0–30.0)
8.3 (7.0–10.1) 66.8 (4.0–270.0) 62.7 (4.0–258.1) 14.4 (4.1 to 36.0) 62.1 (4.0–304.0)
74.6 (4.0–304.0)
47.3 (37–62) 54.0 (36–80) 55.7 (32–78) 55.6 (5–81) 53.4 (31–82) 53.3 (4–82) 53.3 (32–79) 62.5 (34–83) 52.9 (31–82) 49.6 (4–83)
48.2 (31–69) 31.5 (4–78)
3 69.0 (56–90) 1/2 3/0 3/0 40 82.0 (57–95) 25/15 37/3 32/8 26 83.2 (64–94) 16/10 26/0 20/6 27 81.2 (63–93) 16/11 26/1 20/7 9 79 (70–89) 6/3 7/2 8/1 105 81.5 (56–95) 64/41 101/4 83/22
No. of patients Age, mean (range), years Gender (female/male) Race (white/Asian) No. of patients with pretreatment at baseline (no/yes) Baseline VA letters, mean (range) VA at the time of last injection, mean (range) Time to treatment discontinuation, mean (range), weeks Total no. of injections, mean (range)
Missing (Patients Lost to Follow-up) Other Reasons* Treatment Declined by the Patient Treatment Stopped by the Doctor as Further Treatment Futile Treatment Stopped by the Doctor Because of Inactive Lesion Total No. of Patients Who Discontinued Treatment
Table 1. Summary of Demographic and Clinical Findings in Patients With Neovascular Age-Related Macular Degeneration Who Discontinued the Anti-VEGF Treatment Permanently
1776 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 9
inactive. In 27 (10.9%) patients, further treatment was thought to be futile. Twenty-six (10.5%) patients declined further treatment because of various reasons. These included pain/ discomfort (3 [1.2%]), too frequent visits (2 [0.8%]), difficulty in attending the practice (2 [0.8%]), treatment not being perceived to be beneficial (6 [2.4%]), treatment perceived to be too expensive (2 [0.8%]), and other medical condition that were more severe (11 [4.4%]). In 40 (16.1%) patients, the treatment was discontinued because of various other reasons, which included patients being referred to another doctor locally for ongoing management (27 [10.9%]) and death (11 [4.4%]). Of the remaining 2 (0.8%) patients, the treatment was discontinued in one after the patient experienced an episode of dysphasia and confusion 5 minutes after an injection, and the other patient experienced giddiness after the injection, and the treatment was discontinued in the view of her poor general health. In patients where treatment was discontinued because of the choroidal neovascularization becoming inactive, the mean visual acuity before the first injection was 53.3 (range, 32–79) letters improving to 62.5 (34–83) letters at the visit of the final injection (P = 0.013, paired-sample t-test). In the patients who themselves declined further treatment, there was no change in the mean visual acuity from presentation to time of their last injection (53.4 [31–82] letters on presentation and 53.3 [94–82] letters at the time of the last injection [P = 0.98]). The mean baseline visual acuity in patients of the further treatment futile group was 48.2 letters (range, 31–69 letters), which was lower than the other groups; however, the differences were not statistically significant (P = 0.28 and 0.13, respectively, t-test). The mean visual acuity at the time of the last injection in the group of patients in which further treatment was eventually deemed futile was 31.5 (4–78) letters, a highly significant decrease from their mean baseline visual acuity (P , 0.001, paired-sample t-test). In the 143 (56.4%) patients who did not discontinue treatment, the mean visual acuity before the first injection was higher, at 63.3 (35–85) letters with a significant improvement to 67.7 (20–85) letters (P , 0.001, paired-sample t-test) at their most recent visit. There was a significant difference among the 3 groups regarding the mean time to treatment discontinuation and mean total number of injections (P = 0.03 and 0.02, respectively, analysis of variance). The mean time to treatment discontinuation in patients whose lesions became inactive was 14.4 (range, 4.1– 36.0) weeks, which was significantly less than that of the patients with further treatment futile and in the patients who declined the treatment, which was 74.6 (4.0–304.0) weeks and 62.7 (4.0–258.1) weeks,
DISCONTINUATION OF ANTI-VEGF TREATMENT VAZE ET AL
respectively (P , 0.001 for both comparisons). Similarly, the mean total number of injections in the group whose lesions became inactive was 3.7 (range, 2.0– 6.0), which was significantly less than that of the patients in further treatment futile group and the patients who declined further treatment (8.9 [2.0–30.0] and 7.4 [2.0–21.0], respectively [P , 0.001 for both]). However, the difference in the time to treatment discontinuation and the total number of injections was not statistically significant between the further treatment futile group and the group that declined further treatment (P = 0.47 and 0.28, respectively). Eight (88.9%) of the 9 patients in the lesion inactive group, 20 (74.1%) of the 27 patients in the further treatment futile group, and 20 (76.9%) of the 26 patients in the treatment declined by the patient group had not had any previous treatments at baseline. Of the seven patients who had received previous treatment in the further treatment futile group, four were treated with photodynamic therapy, two with laser, and one with intravitreal triamcinolone. In the group of patients who declined further treatment, four of six had been previously treated with laser and two with photodynamic therapy.
Discussion In this study, we have examined the various reasons for discontinuation of intravitreal therapy because these will obviously influence the long-term outcomes of intervention. Treatment was discontinued in 42.3% of patients in the practice studied over a 6-year period. Of these, the treatment was discontinued in 14.5% by the doctor, in 10.5% by the patient, and in 16.1% because of other reasons. In 1.2% of patients, the reason was not found. The visual acuity of the group in which treatment was eventually deemed futile fell significantly, whereas in those in whom further treatment was believed unnecessary because of inactivity improved. The ongoing nature of intravitreal therapy has prompted studies into the ways to reduce the treatment load and optimize the treatment outcomes.4–12 Two other studies have recently examined the rates and reasons for discontinuing intravitreal therapy for wet AMD. Hjelmqvist et al16 evaluated 1-year outcomes of ranibizumab for neovascular AMD, reporting that a total of 101 of 471 patients (24.1%) discontinued the treatment within 1 year of starting the treatment. In approximately one third of these cases (n = 34), this was due to the physician’s decision that no further follow-up was required, although the exact reason for this was not reported. Forty-three patients discontinued for “other reasons” that included poor vision (n = 17), lack of visual improvement (n = 3), nonattendance at follow-
1777
up visits (n = 7), change in therapy (n = 6), death (n = 5), and other reasons (n = 5). Six patients declined further injections, two patients withdrew consent, one had a serious adverse event, seven were referred for treatment elsewhere, and the reason was unknown in eight patients. This study did not provide more detailed account of the reasons and had a very short follow-up period of only 12 months, whereas the treatment for wet AMD can be lifelong. Kruger Falk et al17 reported the reasons for treatment discontinuation over a 4-year period. In 21% of patients, the treatment was discontinued because the lesions were believed to be inactive; only 4% of patients declined further treatment. By contrast, in this study, we found that the treatment was discontinued because of inactivity of the lesion only in 3.6% patients and the patient declined the treatment in 10.5%. The proportion of patients in which further treatment was believed to be futile was similar between our study and the study by Kruger Falk et al.17 We found that such patients had a lower baseline visual acuity compared with the patients with inactive lesions. Although the difference was not statistically significant, this suggests that low vision at baseline, which might be due to preexisting structural foveal damage or other confounding ocular disease, might have a less favorable prognosis in the long-term. We found a highly significant decrease in the mean visual acuity of these patients from the beginning of treatment to the time of the last injection, which is consistent with a poor response to treatment. There was a significant increase in the mean visual acuity in the patients in the lesion inactive group, whereas there was no change in the mean visual acuity in the group of patients who eventually declined the treatment. Thus, patients who lost vision tended to discontinue treatment; however, the doctor and not the patient mainly made this decision. The analysis of time to treatment discontinuation and total number of injections received by the above three groups showed that the patients in the group with inactive lesions were good responders to the treatment requiring fewer injections and shorter treatment duration. The patients in the further treatment futile group were poor responders who failed to show improvement despite receiving more injections over a longer period of time. Patients who declined treatment tended to do so later during the treatment, which apparently was not on the basis of the response to the treatment but because of various other reasons. Only 2.8% of patients declined treatment because they did not perceive that it was beneficial. The proportion of treatment-naive patients at baseline was 79.0%. The large majority (88.9%) of patients, in whom treatment was discontinued because the lesion was inactive and no further treatment was
1778 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
believed necessary, was treatment-naive at baseline compared with 74.1% in the further treatment futile group, which indicates that some patients in the latter group might have had some structural damage at the fovea from the previous treatments. Our study gives a more detailed account of the reasons for which the patient declined the treatment. Surprisingly, expense, treatment frequency, difficulty attending the practice, pain and discomfort, or treatment not perceived beneficial were relatively uncommon causes of treatment discontinuation with a combined proportion of 6.0%. Ranibizumab has been available with prescription on the Pharmaceutical Benefits Scheme since August 2007 in Australia. Before this date, it cost the patient $2,000 per dose, now it costs a maximum of $30.70 on the Pharmaceutical Benefits Scheme or $4.90 for patients receiving social security support. This may explain the relatively low number of patients declining treatment because of expense (0.8%). Many (4.4% of the total) of the patients who chose to discontinue treatment themselves did so because of intercurrent medical conditions that might be expected in the patients of this age group. Many patients (10.9%) did not actually discontinue the treatment but were referred for treatment elsewhere for their greater convenience. The practice studied was in the central business district of a large city. The results of this study should be viewed with some qualifications. Some patients may have withheld the true reason for their decision to discontinue treatment if it related to a sensitive matter, such as the cost of treatment. There were no clear guidelines used for the treating doctor to discontinue treatment, and thus, these are likely to vary from one doctor to the next. Also, as the study involved a single center, the results need to be validated using larger data sets involving more centers. This study indicates that quality of life issues such as financial burden, frequent treatment visits, and pain and discomfort that are associated with the treatment have a lower influence on permanent treatment discontinuation than we had expected, given the heavy burden of ongoing intravitreal therapy for wet AMD. We also found that patients with low baseline visual acuity and previous treatment may be associated with less favorable prognosis. Many patients who lost vision eventually gave up treatment; however, it was the doctor rather than the patient who made this decision more often. Ongoing analyses of reasons for discontinuing treatment using data from larger data sets from disease registries, such as the FRB! project, will be useful to optimize patient outcomes. Key words: age-related macular degeneration, vascular endothelial growth factor inhibitors, treatment efficacy, patient acceptance, quality of life, patient outcomes, treatment discontinuation.
2014 VOLUME 34 NUMBER 9
References 1. Hampton T. Genetic research provides insights into age-related macular degeneration. JAMA 2010;304:1541–1543. 2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 3. 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. 4. Mitchell P, Korobelnik JF, Lanzetta P, et al. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol 2010;94:2–13. 5. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007;143:566–583. 6. Spielberg L, Leys A. Treatment of neovascular age-related macular degeneration with a variable ranibizumab dosing regimen and one-time reduced-fluence photodynamic therapy: the TORPEDO trial at 2 years. Graefes Arch Clin Exp Ophthalmol 2010;248:943–956. 7. Cohen SY, Dubois L, Tadayoni R, et al. Results of one-year’s treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting. Am J Ophthalmol 2009;148: 409–413. 8. Michalova K, Wickremasinghe SS, Tan TH, et al. Ranibizumab treatment for neovascular age-related macular degeneration: from randomized trials to clinical practice. Eye (Lond) 2009;23:1633–1640. 9. Querques G, Azrya S, Martinelli D, et al. Ranibizumab for exudative age-related macular degeneration: 24-month outcomes from a single-centre institutional setting. Br J Ophthalmol 2010;94:292–296. 10. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 11. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012;119:1399–1411. 12. Ehlers JP. The MANTA 1-year results: the anti-VEGF debate continues. Br J Ophthalmol 2013;97:248–250. 13. Chang TS, Bressler NM, Fine JT, et al. Improved visionrelated function after ranibizumab treatment of neovascular age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 2007;125:1460–1469. 14. Bressler NM, Chang TS, Suner IJ, et al. Vision-related function after ranibizumab treatment by better- or worse-seeing eye: clinical trial results from MARINA and ANCHOR. Ophthalmology 2010;117:747–756.e4. 15. Gillies MC, Walton R, Liong J, et al. Efficient capture of highquality data on outcomes of treatment for macular dieases: the fight retinal blindness! project. Retina 2014;34:188–195. 16. Hjelmqvist L, Lindberg C, Kanulf P, et al. One-year outcomes using ranibizumab for neovascular age-related macular degeneration: results of a prospective and retrospective observational multicentre study. J Ophthalmol 2011;2011:405724. 17. Kruger Falk M, Kemp H, Sorensen TL. Four-year treatment results of neovascular age-related macular degeneration with ranibizumab and causes for discontinuation of treatment. Am J Ophthalmol 2013;155:89–95.
A
the two pivotal trials, MARINA2 and ANCHOR,3 demonstrated the efficacy of ranibizumab (Lucentis–Novartis) for wet AMD, regular intravitreal injections of ranibizumab have become the standard treatment for this condition. A detailed analysis of Phase 3 clinical trials has generated evidence-based guidelines for using ranibizumab for the treatment of neovascular AMD.4 Also, there have been numerous prospective5,6 and retrospective studies7–9 evaluating the optimal dosing regimen for anti-vascular endothelial growth factor (VEGF) treatment using individualized patient outcomes in routine clinical setting. Recently, there have been several studies comparing bevacizumab with ranibizumab in the treatment of neovascular AMD,10–12 which have shown that
ge-related macular degeneration (AMD) is the commonest cause of blindness in the developed world, with twice the prevalence of Alzheimer disease.1 It mainly affects people older than 50 years. Since
From the Save Sight Institute, University of Sydney, Sydney, Australia. Supported by grants from the RANZCO Eye Foundation, Sydney, and the National Health and Medical Research Council, Canberra. M. Gillies is a fellow in Sydney Medical School Foundation and is supported by an NHMRC Practitioner Fellowship. M. Gillies is listed as an inventor on a copyright of the FRB! Project software. The other authors have no conflict of interest to disclose. Reprint requests: Anagha Vaze, MBBS, DNB, Save Sight Institute, Sydney Eye Hospital, University of Sydney, Level 1, South Block, 8 Macquarie Street, Sydney, NSW 2000, Australia; e-mail: [email protected]
1774
DISCONTINUATION OF ANTI-VEGF TREATMENT VAZE ET AL
both drugs seem equally effective but require ongoing treatment. A positive effect of ranibizumab treatment on patients’ vision-related quality of life has also been reported by several studies.13,14 However, the ongoing nature of intravitreal therapy along with its financial implications places a strain on the patient, the health care system, and the treating physician. Thus, it is important to identify what issues affect the patients’ willingness and ability to undergo ongoing treatment, which will affect the long-term outcomes of intervention. Although patient compliance is clearly important for intravitreal therapy for AMD, few studies have specifically addressed it. The aim of our study was to give a detailed account of the reasons for discontinuation of anti-VEGF treatment in patients with neovascular AMD during a 6-year period from March 2006 to June 2012.
Methods This was a retrospective single center study of patients with neovascular AMD who began treatment with ranibizumab from March 2006 to June 2012. Approval for data collection and analysis was obtained from the Human Research Ethics Committee of the Royal Prince Alfred Hospital, Sydney. The research adhered to the tenets set forth in the Declaration of Helsinki. The Fight Retinal Blindness! (FRB!) Project data tracking system was used to identify accurately all patients who discontinued treatment. The FRB! is a Web-based prospective audit system that anonymously tracks the outcomes of treatment of retinal disease, such as wet AMD, in large numbers of patients treated in routine retinal treatment centers. Baseline visit characteristics, such as lesion type and size, visual acuity (visual acuity in logarithm of the minimal angle of resolution letters), and treatments are recorded. The treatment outcomes (visual acuity and lesion activity status) and ocular adverse events are recorded at each follow-up visit, as well as treatment discontinuation along with its reason.15 Each patient had visual acuity measured at 4 m on a standard logarithm of the minimal angle of resolution chart, with their current spectacles if worn and pin hole. Whichever was better was entered. An ophthalmic examination included dilated fundoscopy and spectral domain optical coherence tomography (Spectralis HRAOCT; Heidelberg Engineering, Heidelberg, Germany). All patients underwent fluorescein angiography, indocyanine green angiography, or both before treatment to determine the type and size of the lesion. All patients with clinical signs of active subfoveal neovascularization were offered anti-VEGF treatment. Findings that
1775
were considered signs of lesion activity included fall in visual acuity from the previous visit, presence of macular hemorrhages, leakage on fluorescein angiography, and presence of subretinal or intraretinal fluid or both on optical coherence tomography examination. The reasons for discontinuation of the intravitreal anti-VEGF treatment for neovascular AMD during the 6-year period were ascertained from the FRB! database where available and hand searching the patient’s notes. Patients were not specifically contacted by the authors to explain their reasons for discontinuing the treatment. The FRB! fields for treatment discontinuation include the following possibilities: treatment being successful, further treatment being futile, patient goes to another doctor, patient declines, medically contraindicated, or deceased. Reasons for the doctor to discontinue the treatment were subdivided into lesion inactivity and further treatment futile; the latter including eyes that did not show improvement in the visual acuity and lesion activity or if the visual acuity deteriorated progressively despite receiving at least three to six injections. Other reasons for treatment discontinuation included treatment declined by the patient, transferring to another doctor, and death. Statistical analyses were performed using IBM SPSS software version 21. Differences among the groups were calculated using a one-way analysis of variance, differences between two groups were calculated using the independent samples t-test, and the changes over time were calculated using the paired-sample t-test. The chosen level of statistical significance was P , 0.05.
Results A total of 248 patients (284 eyes) began anti-VEGF treatment over the 6 years from March 2006 to June 2012. Of these 248, 105 (42.3%) patients (64 women, 101 whites, and 4 Asians; mean age, 81.5 [range, 56– 95] years) discontinued treatment permanently at this practice. The reasons for discontinuation were available for 102 of 105 (97.1%) patients. These were divided into three groups: treatment discontinued by the doctor, treatment declined by the patient, and other reasons. Eighty-three of the 105 patients (79.0%) were treatment-naive at baseline. Of the remaining 22 (21.0%) patients, 8 had pretreatment with laser, 13 were previously treated with photodynamic therapy, and 1 was previously treated with intravitreal triamcinolone. A summary of the clinical and demographic features of these patients is given in Table 1. In 9 of 248 (3.6%) patients, the doctor believed no further treatment was necessary because the lesion was
*Other reasons included death, patient seeing another doctor, one patient with bilateral disease who chose to continue treatment only in one eye because of poor general health, one patient experienced dysphasia and confusion 5 minutes after an injection. VA, visual acuity (number of letters read on the logarithm of the minimal angle of resolution chart).
2.7 (2.0–3.0) 7.3 (2.0–18.0) 7.4 (2.0–21.0) 3.7 (2.0–6.0) 7.3 (2.0–30.0)
8.9 (2.0–30.0)
8.3 (7.0–10.1) 66.8 (4.0–270.0) 62.7 (4.0–258.1) 14.4 (4.1 to 36.0) 62.1 (4.0–304.0)
74.6 (4.0–304.0)
47.3 (37–62) 54.0 (36–80) 55.7 (32–78) 55.6 (5–81) 53.4 (31–82) 53.3 (4–82) 53.3 (32–79) 62.5 (34–83) 52.9 (31–82) 49.6 (4–83)
48.2 (31–69) 31.5 (4–78)
3 69.0 (56–90) 1/2 3/0 3/0 40 82.0 (57–95) 25/15 37/3 32/8 26 83.2 (64–94) 16/10 26/0 20/6 27 81.2 (63–93) 16/11 26/1 20/7 9 79 (70–89) 6/3 7/2 8/1 105 81.5 (56–95) 64/41 101/4 83/22
No. of patients Age, mean (range), years Gender (female/male) Race (white/Asian) No. of patients with pretreatment at baseline (no/yes) Baseline VA letters, mean (range) VA at the time of last injection, mean (range) Time to treatment discontinuation, mean (range), weeks Total no. of injections, mean (range)
Missing (Patients Lost to Follow-up) Other Reasons* Treatment Declined by the Patient Treatment Stopped by the Doctor as Further Treatment Futile Treatment Stopped by the Doctor Because of Inactive Lesion Total No. of Patients Who Discontinued Treatment
Table 1. Summary of Demographic and Clinical Findings in Patients With Neovascular Age-Related Macular Degeneration Who Discontinued the Anti-VEGF Treatment Permanently
1776 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 9
inactive. In 27 (10.9%) patients, further treatment was thought to be futile. Twenty-six (10.5%) patients declined further treatment because of various reasons. These included pain/ discomfort (3 [1.2%]), too frequent visits (2 [0.8%]), difficulty in attending the practice (2 [0.8%]), treatment not being perceived to be beneficial (6 [2.4%]), treatment perceived to be too expensive (2 [0.8%]), and other medical condition that were more severe (11 [4.4%]). In 40 (16.1%) patients, the treatment was discontinued because of various other reasons, which included patients being referred to another doctor locally for ongoing management (27 [10.9%]) and death (11 [4.4%]). Of the remaining 2 (0.8%) patients, the treatment was discontinued in one after the patient experienced an episode of dysphasia and confusion 5 minutes after an injection, and the other patient experienced giddiness after the injection, and the treatment was discontinued in the view of her poor general health. In patients where treatment was discontinued because of the choroidal neovascularization becoming inactive, the mean visual acuity before the first injection was 53.3 (range, 32–79) letters improving to 62.5 (34–83) letters at the visit of the final injection (P = 0.013, paired-sample t-test). In the patients who themselves declined further treatment, there was no change in the mean visual acuity from presentation to time of their last injection (53.4 [31–82] letters on presentation and 53.3 [94–82] letters at the time of the last injection [P = 0.98]). The mean baseline visual acuity in patients of the further treatment futile group was 48.2 letters (range, 31–69 letters), which was lower than the other groups; however, the differences were not statistically significant (P = 0.28 and 0.13, respectively, t-test). The mean visual acuity at the time of the last injection in the group of patients in which further treatment was eventually deemed futile was 31.5 (4–78) letters, a highly significant decrease from their mean baseline visual acuity (P , 0.001, paired-sample t-test). In the 143 (56.4%) patients who did not discontinue treatment, the mean visual acuity before the first injection was higher, at 63.3 (35–85) letters with a significant improvement to 67.7 (20–85) letters (P , 0.001, paired-sample t-test) at their most recent visit. There was a significant difference among the 3 groups regarding the mean time to treatment discontinuation and mean total number of injections (P = 0.03 and 0.02, respectively, analysis of variance). The mean time to treatment discontinuation in patients whose lesions became inactive was 14.4 (range, 4.1– 36.0) weeks, which was significantly less than that of the patients with further treatment futile and in the patients who declined the treatment, which was 74.6 (4.0–304.0) weeks and 62.7 (4.0–258.1) weeks,
DISCONTINUATION OF ANTI-VEGF TREATMENT VAZE ET AL
respectively (P , 0.001 for both comparisons). Similarly, the mean total number of injections in the group whose lesions became inactive was 3.7 (range, 2.0– 6.0), which was significantly less than that of the patients in further treatment futile group and the patients who declined further treatment (8.9 [2.0–30.0] and 7.4 [2.0–21.0], respectively [P , 0.001 for both]). However, the difference in the time to treatment discontinuation and the total number of injections was not statistically significant between the further treatment futile group and the group that declined further treatment (P = 0.47 and 0.28, respectively). Eight (88.9%) of the 9 patients in the lesion inactive group, 20 (74.1%) of the 27 patients in the further treatment futile group, and 20 (76.9%) of the 26 patients in the treatment declined by the patient group had not had any previous treatments at baseline. Of the seven patients who had received previous treatment in the further treatment futile group, four were treated with photodynamic therapy, two with laser, and one with intravitreal triamcinolone. In the group of patients who declined further treatment, four of six had been previously treated with laser and two with photodynamic therapy.
Discussion In this study, we have examined the various reasons for discontinuation of intravitreal therapy because these will obviously influence the long-term outcomes of intervention. Treatment was discontinued in 42.3% of patients in the practice studied over a 6-year period. Of these, the treatment was discontinued in 14.5% by the doctor, in 10.5% by the patient, and in 16.1% because of other reasons. In 1.2% of patients, the reason was not found. The visual acuity of the group in which treatment was eventually deemed futile fell significantly, whereas in those in whom further treatment was believed unnecessary because of inactivity improved. The ongoing nature of intravitreal therapy has prompted studies into the ways to reduce the treatment load and optimize the treatment outcomes.4–12 Two other studies have recently examined the rates and reasons for discontinuing intravitreal therapy for wet AMD. Hjelmqvist et al16 evaluated 1-year outcomes of ranibizumab for neovascular AMD, reporting that a total of 101 of 471 patients (24.1%) discontinued the treatment within 1 year of starting the treatment. In approximately one third of these cases (n = 34), this was due to the physician’s decision that no further follow-up was required, although the exact reason for this was not reported. Forty-three patients discontinued for “other reasons” that included poor vision (n = 17), lack of visual improvement (n = 3), nonattendance at follow-
1777
up visits (n = 7), change in therapy (n = 6), death (n = 5), and other reasons (n = 5). Six patients declined further injections, two patients withdrew consent, one had a serious adverse event, seven were referred for treatment elsewhere, and the reason was unknown in eight patients. This study did not provide more detailed account of the reasons and had a very short follow-up period of only 12 months, whereas the treatment for wet AMD can be lifelong. Kruger Falk et al17 reported the reasons for treatment discontinuation over a 4-year period. In 21% of patients, the treatment was discontinued because the lesions were believed to be inactive; only 4% of patients declined further treatment. By contrast, in this study, we found that the treatment was discontinued because of inactivity of the lesion only in 3.6% patients and the patient declined the treatment in 10.5%. The proportion of patients in which further treatment was believed to be futile was similar between our study and the study by Kruger Falk et al.17 We found that such patients had a lower baseline visual acuity compared with the patients with inactive lesions. Although the difference was not statistically significant, this suggests that low vision at baseline, which might be due to preexisting structural foveal damage or other confounding ocular disease, might have a less favorable prognosis in the long-term. We found a highly significant decrease in the mean visual acuity of these patients from the beginning of treatment to the time of the last injection, which is consistent with a poor response to treatment. There was a significant increase in the mean visual acuity in the patients in the lesion inactive group, whereas there was no change in the mean visual acuity in the group of patients who eventually declined the treatment. Thus, patients who lost vision tended to discontinue treatment; however, the doctor and not the patient mainly made this decision. The analysis of time to treatment discontinuation and total number of injections received by the above three groups showed that the patients in the group with inactive lesions were good responders to the treatment requiring fewer injections and shorter treatment duration. The patients in the further treatment futile group were poor responders who failed to show improvement despite receiving more injections over a longer period of time. Patients who declined treatment tended to do so later during the treatment, which apparently was not on the basis of the response to the treatment but because of various other reasons. Only 2.8% of patients declined treatment because they did not perceive that it was beneficial. The proportion of treatment-naive patients at baseline was 79.0%. The large majority (88.9%) of patients, in whom treatment was discontinued because the lesion was inactive and no further treatment was
1778 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
believed necessary, was treatment-naive at baseline compared with 74.1% in the further treatment futile group, which indicates that some patients in the latter group might have had some structural damage at the fovea from the previous treatments. Our study gives a more detailed account of the reasons for which the patient declined the treatment. Surprisingly, expense, treatment frequency, difficulty attending the practice, pain and discomfort, or treatment not perceived beneficial were relatively uncommon causes of treatment discontinuation with a combined proportion of 6.0%. Ranibizumab has been available with prescription on the Pharmaceutical Benefits Scheme since August 2007 in Australia. Before this date, it cost the patient $2,000 per dose, now it costs a maximum of $30.70 on the Pharmaceutical Benefits Scheme or $4.90 for patients receiving social security support. This may explain the relatively low number of patients declining treatment because of expense (0.8%). Many (4.4% of the total) of the patients who chose to discontinue treatment themselves did so because of intercurrent medical conditions that might be expected in the patients of this age group. Many patients (10.9%) did not actually discontinue the treatment but were referred for treatment elsewhere for their greater convenience. The practice studied was in the central business district of a large city. The results of this study should be viewed with some qualifications. Some patients may have withheld the true reason for their decision to discontinue treatment if it related to a sensitive matter, such as the cost of treatment. There were no clear guidelines used for the treating doctor to discontinue treatment, and thus, these are likely to vary from one doctor to the next. Also, as the study involved a single center, the results need to be validated using larger data sets involving more centers. This study indicates that quality of life issues such as financial burden, frequent treatment visits, and pain and discomfort that are associated with the treatment have a lower influence on permanent treatment discontinuation than we had expected, given the heavy burden of ongoing intravitreal therapy for wet AMD. We also found that patients with low baseline visual acuity and previous treatment may be associated with less favorable prognosis. Many patients who lost vision eventually gave up treatment; however, it was the doctor rather than the patient who made this decision more often. Ongoing analyses of reasons for discontinuing treatment using data from larger data sets from disease registries, such as the FRB! project, will be useful to optimize patient outcomes. Key words: age-related macular degeneration, vascular endothelial growth factor inhibitors, treatment efficacy, patient acceptance, quality of life, patient outcomes, treatment discontinuation.
2014 VOLUME 34 NUMBER 9
References 1. Hampton T. Genetic research provides insights into age-related macular degeneration. JAMA 2010;304:1541–1543. 2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 3. 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. 4. Mitchell P, Korobelnik JF, Lanzetta P, et al. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol 2010;94:2–13. 5. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007;143:566–583. 6. Spielberg L, Leys A. Treatment of neovascular age-related macular degeneration with a variable ranibizumab dosing regimen and one-time reduced-fluence photodynamic therapy: the TORPEDO trial at 2 years. Graefes Arch Clin Exp Ophthalmol 2010;248:943–956. 7. Cohen SY, Dubois L, Tadayoni R, et al. Results of one-year’s treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting. Am J Ophthalmol 2009;148: 409–413. 8. Michalova K, Wickremasinghe SS, Tan TH, et al. Ranibizumab treatment for neovascular age-related macular degeneration: from randomized trials to clinical practice. Eye (Lond) 2009;23:1633–1640. 9. Querques G, Azrya S, Martinelli D, et al. Ranibizumab for exudative age-related macular degeneration: 24-month outcomes from a single-centre institutional setting. Br J Ophthalmol 2010;94:292–296. 10. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 11. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012;119:1399–1411. 12. Ehlers JP. The MANTA 1-year results: the anti-VEGF debate continues. Br J Ophthalmol 2013;97:248–250. 13. Chang TS, Bressler NM, Fine JT, et al. Improved visionrelated function after ranibizumab treatment of neovascular age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 2007;125:1460–1469. 14. Bressler NM, Chang TS, Suner IJ, et al. Vision-related function after ranibizumab treatment by better- or worse-seeing eye: clinical trial results from MARINA and ANCHOR. Ophthalmology 2010;117:747–756.e4. 15. Gillies MC, Walton R, Liong J, et al. Efficient capture of highquality data on outcomes of treatment for macular dieases: the fight retinal blindness! project. Retina 2014;34:188–195. 16. Hjelmqvist L, Lindberg C, Kanulf P, et al. One-year outcomes using ranibizumab for neovascular age-related macular degeneration: results of a prospective and retrospective observational multicentre study. J Ophthalmol 2011;2011:405724. 17. Kruger Falk M, Kemp H, Sorensen TL. Four-year treatment results of neovascular age-related macular degeneration with ranibizumab and causes for discontinuation of treatment. Am J Ophthalmol 2013;155:89–95.
