Primary Study Objective and Outcome
In the current study, the dispensing patterns of ranibizumab and aflibercept were analyzed and compared using data recorded and deposited by Australian pharmacies in the IMS® AUS LRx 09/2015 database. The primary objective of this study was to investigate the dispensing patterns of ranibizumab and aflibercept for the treatment of nAMD on the basis of the number of units dispensed of each anti-VEGF agent 6 and 12 months after the index date. Our analysis showed that the numbers of ranibizumab and aflibercept units dispensed were comparable, as the 95% CI limits of the adjusted mean difference between cohorts did not exceed 1.00 unit at either time point. We therefore conclude that ranibizumab and aflibercept are dispensed similarly by Australian pharmacies in the first year of treatment.
The dispensing frequencies reported here for ranibizumab and aflibercept in the first year of treatment are similar to the injection frequencies reported for both agents in previous studies investigating the use of Australian PBS-listed therapies for nAMD. A report published by the Australian Drug Utilisation Sub Committee (DUSC) in 2015 showed that patients who started treatment between December 2012 and November 2013 with 12-month follow-up received a mean of 9.3 ranibizumab injections and 8.3 aflibercept injections . Although the DUSC study reported a lower mean difference of 1.0 injection for aflibercept-treated patients compared with ranibizumab-treated patients, the identification period for this study began upon PBS-listing of aflibercept, and thus may not reflect more recently established patterns of nAMD treatment in clinical settings. In addition, Gillies et al.  showed the mean number of injections did not significantly differ between the ranibizumab cohort (8.1) and the aflibercept cohort (8.0) for treatment-naive nAMD eyes in patients who completed 12 months of anti-VEGF therapy, while a recent analysis of data from Australian EMR databases yielded a mean number of 9.3 ranibizumab injections in T&E-treated eyes in the first year of treatment . Our findings show that the 12-month dispensing patterns for ranibizumab and aflibercept are consistent with real-world injection frequency data and support the use of dispensing data as a proxy for injection data when these are unavailable. Furthermore, the mean number of ranibizumab units dispensed during the first year of treatment was lower than the expected 13 ranibizumab doses under a monthly regimen as per the product label and further supports the adoption of the T&E protocol in Australian clinics for the treatment of nAMD .
Of note, the mean numbers of dispensed units/injections of ranibizumab and aflibercept reported here and by others in the first year of nAMD treatment for Australian patients [7, 14, 17] exceed those reported by studies that used US and European EMR databases. US nAMD patients were reported to receive a mean of 6.1–6.9 ranibizumab injections  and European patients were reported to receive a mean of 4.3–6.0 ranibizumab injections [30,31,32] in the first year of treatment. A recent analysis of US physician-level medical claims data also showed that in the first year of treatment the mean numbers of ranibizumab (4.9) and aflibercept (5.2) injections for nAMD patients were comparable despite differences in the labels between the two agents . It is possible that “as needed” (pro re nata) treatment regimens may account, in part, for the lower anti-VEGF injection frequencies reported for Europe and the USA compared with Australia. However, despite differences in injection frequencies between geographical regions, the use of ranibizumab and aflibercept in the first year of treatment is comparable within countries, suggesting that the results of these studies may be generalized across populations.
Secondary Study Outcomes
No clinically meaningful differences were observed at month 6 or month 12 with regard to dispensing intervals between ranibizumab and aflibercept. Notably, the mean dispensing interval at month 12 for aflibercept (41.6 days) is consistent with the approximately 45 day mean injection interval expected under the recommended 8-week dosing schedule in the first year of treatment (i.e., 360 days/8 injections). In contrast, the mean dispensing interval for ranibizumab (41.2 days) is longer than the approximately 28 day mean interval expected under a monthly dosing regimen (i.e., 360 days/13 injections) in the first year of treatment. These results suggest that Australian ophthalmologists administer ranibizumab at intervals that differ from those recommended on the label, and give further credence to the common adoption of a T&E regimen in Australia.
A lower proportion of ranibizumab patients than aflibercept patients persisted with the index treatment at month 12, with the proportion of patients switching to the comparator agent higher for the ranibizumab cohort at both assessment time points. Aflibercept was first listed on the Australian PBS for the treatment of nAMD in December 2012, and it is possible that the availability of a new treatment option may have been appealing to clinicians after 2012, contributing to the higher level of switching to the comparator observed for the ranibizumab cohort compared with the aflibercept cohort [7, 25]. This hypothesis is further supported by the pattern of the Kaplan–Meier curves illustrated in Fig. 5. There are two important observations from the Kaplan–Meier curves for the time to discontinuation or switch of the index anti-VEGF treatment: (1) the gradual continuous reduction in persistence with the index drug over time in both cohorts and (2) divergence between the cohorts occurred only at 30–60 days after the index treatment and remained parallel thereafter. It is important to note that the data used in the current study were collected from regional pharmacies across Australia and that some patients may have: (1) switched from their original pharmacy during the identification period to a pharmacy that is not registered with the IMS® AUS LRx 09/2015 database; (2) switched to unlicensed bevacizumab for the treatment of nAMD during the identification period; or (3) switched between two or more pharmacies that are in the same geographical region during the identification period. Such patients may have been recorded in the IMS® AUS LRx 09/2015 database as having switched from or discontinued use of their index agent, thereby contributing to the appreciable proportion of patients who discontinued their index therapy (48.6% for ranibizumab and 45.8% for aflibercept) at month 12. This scenario may also account, in part, for the differences in the proportion of ranibizumab and aflibercept patients who switched to the comparator agent at both assessment time points together with the lower risk of discontinuation or switching for aflibercept relative to ranibizumab. The divergence in Kaplan–Meier curves between the two cohorts between 30 and 60 days after the index treatment and not beyond suggests that prescribing preference rather than a difference in treatment efficacy is the predominant driver of drug use discontinuation or switching. It should also be considered that statistically significant differences reported in this study are a consequence of the large number of patients included in the analysis and do not necessarily reflect meaningful differences in routine clinical settings.
Although no difference in the dispensing patterns of ranibizumab and aflibercept in the first year of treatment was concluded from our analysis, it is important to note the limitations of this study. First, the data used in this analysis were collected for healthcare transaction purposes rather than for research purposes, and it was assumed that patients with a recorded receipt for a given anti-VEGF agent were prescribed that agent for the treatment of nAMD. During the identification period, aflibercept was licensed for the treatment of nAMD only, while ranibizumab was licensed for several indications (i.e., nAMD, diabetic macular edema, and retinal vein occlusion) [7, 9, 10, 26, 27]. The inclusion of ranibizumab prescriptions for indications other than nAMD would conceivably result in an overestimation of the number of ranibizumab units dispensed in the final study cohort, thereby artificially increasing the mean number of ranibizumab units dispensed and lowering the mean dispensing interval. However, we believe that the impact of ranibizumab prescriptions for indications other than nAMD on the final dataset used here is likely to be negligible as the cost of ranibizumab was reimbursed only for the treatment of nAMD by the PBS during the identification period [9, 26]. Second, baseline patient characteristics such as age and sex were not well populated in the IMS® AUS LRx 09/2015 database and could not be used as covariates in the analyses presented here. Although baseline patient comorbidities (based on MBDBI scores) were comparable between the two cohorts, differences in baseline patient characteristics may influence the findings reported here. Third, information regarding the injection of ranibizumab or aflibercept (including the date of injection or the number of injections administered) is not captured in the database; hence, the number of units dispensed and the date of dispensation were used as a proxy for these data. Although our analysis supports the value of dispensing data as a proxy for injection data in Australia, our results may not reflect anti-VEGF use in other countries. Fourth, although the frequency of dispensing is suggestive of bilateral treatment, laterality is not consistently captured in the database and was not controlled for in this study. Fifth, regional differences in anti-VEGF treatment rates across Australia were not evaluated here despite treatment rates being higher for more densely populated states or territories (e.g., Australian Capital Territory, New South Wales, and Tasmania) than for less densely populated regions (e.g., Northern Territory) . In addition, only sites using the IMS® AUS LRx 09/2015 database were included in this study, which may result in a selection bias. This database has 31% coverage of all retail pharmacies; therefore, the generalizability of the study results may extend only to persons claiming prescribed medication from these pharmacies in Australia. Finally, the IMS® AUS LRx 09/2015 database does not contain information on outcomes of clinical interest, such as visual acuity or retinal anatomical features (e.g., retinal fluid, retinal atrophy, pigment epithelial detachment, and hemorrhage); thus, further data sources are required to explore the relationship between injection frequency and visual outcomes in routine clinical settings. It is important to note that all limitations of the IMS® AUS LRx 09/2015 database apply equally to both final study cohorts, and the results or interpretations of this study are not expected to be systematically biased in favor of either anti-VEGF agent.