The total number of injections within 6 months was significantly lower in the patients treated with aflibercept compared with those treated with ranibizumab (2.8 vs 3.0; p < 0.01). There were no significant differences observed in improvement of RPED, final CMT, difference in CMT, BCVA and improvement in BCVA 4 and 6 months after the initial therapy, between patients treated with ranibizumab or aflibercept (Table 4).
Treatment of wet AMD with anti-VEGF medications can improve or stabilize vision in a large proportion of patients who would otherwise progress to blindness within 1 to 2 years.2,14,15 Differences in disease management strategies are likely to be associated with the healthcare system, and include reimbursement, selection of patients for treatment, and the number of permitted injections.16 However, little is known about the prioritization and selection of anti-VEGF agents and their treatment patterns and clinical outcomes in a real-world setting, under restrictions set by health insurance programs. Moreover, due to the offer of full reimbursement, the cost of anti-VEGF agents is not a confounding factor. The current study was conducted to better understand the real-world treatment strategy of wet AMD under the NHI Program in Taiwan.
Following the analysis of factors influencing decision making, it was found that initial BCVA and CMT were not major considerations when choosing the therapy. Although there were consistently more applications for aflibercept, there were a notably increased number of applications for ranibizumab in patients who were older or had a history of hypertension, coronary artery disease, or cerebral vascular accidents. This suggests that systemic safety is an important consideration, as anti-VEGF injections can increase the risk of systemic thrombotic cardiovascular events. The terminal elimination half-life of free aflibercept in plasma has been reported to be approximately 5 to 6 days after intravitreal administration (Eylea [package insert], Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; 2011). In comparison, ranibizumab has been reported to have a short systemic half-life of 0.09 days after intravitreal injection.9 However, no significant differences in systemic or ocular safety were noted in the VIEW 1 and VIEW 2 randomized trials, which compared the efficacy of aflibercept and ranibizumab for the treatment of AMD.11 Therefore, there is still no consensus on differences in systemic exposure or side effects following the intravitreal injection of these two drugs.
In the current study, patients who had a history of AMD in the other eye were more likely to choose aflibercept than ranibizumab to treat AMD. Since aflibercept was not approved for reimbursement in Taiwan until August 2014, it is possible that the other eyes of most of these patients were treated with either ranibizumab or bevacizumab, or a different treatment option. Even though no significant difference in efficacy has been reported between aflibercept and ranibizumab, previous studies have shown some improvements in anatomical and even functional outcomes, when aflibercept was used to treat patients who did not respond well to ranibizumab.4–6,17–23 The authors hypothesize that one of the reasons for this finding may be because some patients and ophthalmologists choose to treat the newly affected eye with aflibercept if the response was not satisfying following treatment with ranibizumab in the other eye.
The pathophysiology of the association between RPED and AMD is unclear. A previous study reported that RPED is an important predictive factor of vision loss in patients with AMD.24 In addition, Pepple et al reported that about half of all patients with AMD and newly diagnosed RPED experienced an average vision loss of >3 lines over a 1-year follow-up period.25 Previous large randomized trials reported that patients treated with aflibercept had higher rates of RPED flattening compared with those receiving ranibizumab over 52 weeks of follow-up.3,10,11 Furthermore, other studies have shown a good response in the height, size, and total regression of RPED in patients treated with aflibercept.3–6 This may be the main reason why there were a higher proportion of applications for aflibercept compared with ranibizumab in patients presenting with RPED in their affected eyes. However, selection bias could also explain the finding of no difference in RPED improvement between the two groups.
Only 34% to 46% of the patients received three loading doses of anti-VEGF injections, even though receiving an initial loading dose has been reported to result in greater improvements in visual acuity.16 However, due to treatment burden and the limited number of approved doses, the results show that ophthalmologists in Taiwan favor a pro re nata strategy to minimize the number of injections made under the reimbursement policy. No significant differences were found in the clinical outcomes between patients with or without the three loading doses. Furthermore, a previous study reported that the use of a loading dose was important to maximize the initial gain in vision, but that it did not seem to influence the rate of decline in visual acuity during 2 years of follow-up.16 This may further explain why >50% of the eyes with AMD had their approved medication injected under the pro re nata strategy.
With regard to clinical outcomes, significantly fewer injections were found in patients receiving aflibercept compared with those receiving ranibizumab within a 6-month period. Although the VIEW 1 and VIEW 2 trials demonstrated a longer duration of efficacy using aflibercept, several other clinical observational studies reported no difference in the number of injections between the two drugs.12,13 No other differences in clinical outcomes were identified between the two drugs, including improvements in BCVA or CMT at 4 or 6 months after treatment.
There were some limitations to the present study. First, as the study was retrospective, selection bias could exist. For example, although the initial visual acuity and CMT were not different between the two groups, the height and amount of subretinal fluid might influence the decision of the patients and clinicians, and these factors may also affect the final outcome. Second, the treatment strategy used in the current study was restricted due to the role of the NHI in Taiwan. Therefore, it was not possible to analyze the effectiveness of shifting from one agent to the other, or combination therapy with other medications, such as steroid or photodynamic therapy. Finally, the insurance program only reimbursed up to seven injections, under treatment definitely occurred in patients who required more frequent injections, which could have led to the relatively poor outcomes observed in the patients.
In conclusion, the results indicate that age, laterality, presence of RPED, and history of cardiovascular disease were key concerns for patients and ophthalmologists when choosing their anti-VEGF drug. Under the restrictive insurance program in Taiwan, more patients and ophthalmologists tend to choose aflibercept for the treatment of wet AMD, due to the presumed superior efficacy of this agent. However, in clinical practice, no significant difference in efficacy of clinical outcomes was found between patients treated with ranibizumab and aflibercept. However, fewer injections were administered to patients treated with aflibercept. Large, prospective studies may be needed to investigate the long-term treatment efficacy and safety of these two drugs to reduce the trade-off between treatment burden and clinical outcomes.
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