Intravitreal Ranibizumab Therapy for Diabetic Macular Edema in Routine Practice: Two-Year Real-Life Data from a Non-interventional, Multicenter Study in Germany

Abstract

Introduction: The prospective, non-interventional OCEAN study examined the use of intravitreal ranibizumab injections for the treatment of diabetic macular oedema (DME) in a real-world setting in Germany.

Methods: Adults with DME receiving ≥ 1 ranibizumab (0.5 mg) injections were recruited by 250 ophthalmologists. Best-corrected visual acuity (VA) testing, imaging and treatments were performed according to the investigators' routine practice and documented over 24 months.

Results: The full analysis set included 1226 participants. Mean baseline VA was 60.6 [95% CI: 59.7; 61.5] Early Treatment Diabetic Retinopathy Study letters. VA improved by ≥ 15 letters in 21.5% and 23.5% of the participants at 12 months and 24 months, respectively. They received a mean number of 4.42 [95% CI: 4.30; 4.54] injections in the first year and 5.52 [95% CI: 5.32; 5.73] injections over 24 months, which was markedly lower than in clinical trials. Only 33.4% of the participants received an upload with four initial monthly injections as recommended by the German ophthalmologic societies. Time-to-event analyses that account for missing data inherent to a non-interventional study design demonstrated that participants receiving ≥ 7 injections in the first year had a faster response, but the duration of the response was shorter compared to the subgroups receiving 1-3 and 4-6 injections. Serious adverse events were reported for 143/1250 (11.4%) participants in the safety population.

Conclusion: Under-treatment is a major problem of DME anti- vascular endothelial growth factor therapy under real life conditions. Despite fewer injections given compared to randomised controlled trials with a consequently reduced overall mean visual gain, a profound functional improvement (≥ 15 letters) was achieved over 2 years in 23.5% of eyes with DME.

Trial registration number: NCT02194803, ClinicalTrials.gov.

Funding: Novartis Pharma GmbH, Nuremberg, Germany.

Keywords: Diabetic macular edema; Observational study; Ranibizumab; Treatment outcome; Vascular endothelial growth factor A.

Fig. 1

Flow chart of disposition of patients with diabetic macular edema (DME) in the OCEAN study. Asterisk refers to reasons for exclusion from the full analysis set: pre-treatment of study eye with intravitreal anti-vascular endothelial growth factor (VEGF) within the last 3 months and/or pre-treatment with intravitreal steroids in the past (n = 12); not documented that DME was present and that ranibizumab treatment was medically indicated and planned (n = 7); pre-treatment with ranibizumab within the last 3 months (n = 4); and major, unresolvable errors in the visit chronology (n = 1). Dagger denotes multiple responses possible. Double dagger denotes that documentation discontinued before month 24. Double S denotes ‘Other reason’ for premature discontinuation of documentation and was most frequently specified as change to ‘other anti-VEGF medication’ (n = 49), change to aflibercept (n = 25) or change to bevacizumab (n = 19). Hashtag denotes the 947 participants with a documented visit at month 12 and the 30 participants who did not have a visit at month 12 but did have a later documented visit. Degree symbol denotes participants with a documented visit at month 24

Fig. 2

Mean number of injections administered during the first 12 months and during the entire 24-month observational period of the OCEAN study compared to current German recommendations. Error bars depict confidence intervals. Asterisk denotes the expected number of injections is based on an initial upload of four injections at monthly intervals, followed by two additional monthly injections as needed and then by single monthly injections as needed, as recommended by German medical societies. According to these recommendations it is expected that on average seven to eight injections are given during the first year and fewer than four injections are given in the second year [2, 8, 30]

Fig. 3

Time intervals between the first five injections during the OCEAN study and the respective next injection. Number of patients are plotted against the respective category of time intervals (days)

Fig. 4

Mean change of best-corrected visual acuity (VA) from baseline in participants with DME by pre-treatment status (a), and the corresponding total number of patients who discontinued the study (b) during the 24-month observational period. ETDRS Early Treatment Diabetic Retinopathy Study, Boxes in a represent mean changes and error bars represent 95% confidence intervals (CI). Gray bars represent number of patients

Fig. 5

Time-to-discontinuation in all patients (full analysis set [FAS] n = 1226) (a) and by pre-treatment status (b). If the time of discontinuation was not documented, it was set to day 1. Estimators are based on the Kaplan–Meier (KM) product-limit methodology. BL Baseline, mo Months. The dashed line represents the 1 year time point

Fig. 6

Time-to-response (VA improvement of ≥ 15 ETDRS letters from baseline) in treatment-naïve (a) and pre-treated participants (b). Time-to-response was defined as the first time an improvement of ≥ 15 letters from baseline was reached. Participants who did not reach a response were censored at the last documented time point. If no visual acuity data were documented after baseline, the participant was censored on day 1. Estimators are based on the Kaplan–Meier product-limit methodology. See Fig. 5 caption for abbreviations

Fig. 7

Duration-of-response (time from first improvement of ≥ 15 ETDRS letters to first time point of losing this improvement) in treatment-naïve (a) and pre-treated participants (b). Duration-of-response was defined as the time from first improvement of ≥ 15 letters from baseline to the first time point of losing this improvement. Participants who did not lose the response were censored at the last documented time point where the response was still present. If no visual acuity data were documented after the response date, the participant was censored on day 1. Estimators are based on the Kaplan–Meier product-limit methodology. See Fig. 5 caption for abbreviations