Introduction
Diabetic macular edema (DME) currently affects approximately 20 million people worldwide [
1]. At the present time intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care [
1‐
6]. A network meta-analysis that included 24 clinical studies with 6007 participants confirmed that anti-VEGF therapy offers greater improvement in visual acuity (VA) than does laser photocoagulation, with an acceptable safety profile [
4]. These improvements usually occur within 1 year and can be sustained for up to 5 years [
2,
3,
7].
For the treatment of visual impairment due to DME, German medical societies [
8] recommend an initial upload of four anti-VEGF injections at monthly intervals, followed by two injections monthly and then by a single monthly injection if further treatment is needed. Monthly assessments of retinal thickness by optical coherence tomography (OCT) and VA should guide re-treatment (Electronic Supplementary Material [ESM] Fig. S1). These societies also recommend performing fluorescein angiography (FA) and OCT before initiating anti-VEGF therapy to confirm DME as the treatment indication and to detect ischemic maculopathy or permanent damage to the retina, both of which predict poor response to treatment [
8].
In the clinical trials reported to date, an average of 7–12 injections were administered in the first year and three to six injections in the second year [
2,
3,
9,
10]. Adhering to this schedule can be difficult outside of clinical trials, which may lead to under-treatment [
4]. Moreover, older patients and a higher frequency of comorbidities in a real-world setting may further reduce adherence to monitoring and therapy and impair the effectiveness of ranibizumab for the management of DME [
11,
12]. The effects of these factors merit evaluation, but such evaluations have so far been largely undocumented or restricted to retrospective data [
13‐
15].
Therefore, we have prospectively examined the effectiveness, treatment, monitoring and safety of ranibizumab (0.5 mg) injections in individuals with DME in Germany in the real-world, non-interventional OCEAN (Observation of treatment patterns with LuCEntis and real-life ophthalmic monitoring, including optional OCT in Approved iNdications) study.
Discussion
The real-world treatment of visual impairment due to DME with intravitreal ranibizumab suggests insufficient monitoring and potential under-treatment in Germany. Similar problems have been described in neovascular age-related macular degeneration (nAMD) [
19,
20], but only retrospective data are available on DME [
13,
14,
21‐
24]. Even though the mean number of injections and OCT examinations in our study did not meet current German recommendations, VA gains of ≥ 15 ETDRS letters were reported for over 20% of the participants. Improvements occurred largely within 3 months and were sustained up to month 24. The participants receiving the most (≥ 7) injections in the first year responded the fastest, but their response was less sustained than that of participants receiving fewer injections.
With a mean of 4.42 and 5.52 ranibizumab injections administered over 12 and 24 months, respectively, OCEAN participants with DME received notably fewer than the 7–12 and three to six injections administered in the first and second year, respectively, in previous clinical trials [
2,
3,
9,
10]. A complete four-injection upload as recommended for DME [
8] was documented only in one-third of the participants. These low re-injection rates observed in the study were obtained under conditions of a phase 4 study; as such, they may indicate an even worse re-treatment rate in the “unobserved” routine real-life setting.
Under-treatment with anti-VEGF injections was also observed in retrospective chart reviews of DME. A median of six injections in year 1 and one to two injections in year 2 were documented for 333 individuals with DME at a single German center [
14]. Similarly, a recently published German chart review study with 235 patients documented an average of 5.7 injections in the first year of DME treatment [
24]. This is below the recommendations but still slightly higher than the number of injections in OCEAN, potentially due to a selection bias, as only individuals with ≥ 1 year of follow-up and still actively followed in the clinic were included. OCEAN participants with DME were recruited from 250 centers, including 49 general ophthalmology practices, where monitoring and treatment were documented, but patients were referred to a retina specialist for the injections. Such referrals have been shown to delay treatment start [
16] and may also affect further treatment [
25,
26].
Based on retrospective data from the U.S. IRIS
® Registry, a comprehensive eye disease and condition registry, only 47% of people with DME were treated within 1 year of diagnosis. Those given anti-VEGF in the first year received on average 4.2 injections, similar to the number of injections received by participants in OCEAN [
27]. In another USA-based retrospective multicenter study, 156 individuals with DME received on average 5.8 injections in year 1 and 5.0 injections in year 2 [
13], while a third retrospective real-world study in the USA found that patients only received 3.1 injections in the first year of DME treatment [
28]. A Danish retrospective cohort study including 566 patients found that on average 6.1 intravitreal anti-VEGF injections were received in year 1 and 3.0 in year 2 [
29]. Discrepancies between these studies and OCEAN in terms of the number of injections may be due to selection bias or different clinical practice and reimbursement in the USA.
The low number of ranibizumab injections in OCEAN may be due to insufficient OCT monitoring, which is not routinely provided in Germany [
20]. On average, only 3.7 and 5.9 OCT examinations were reported over 12 and 24 months. Very similar figures for Germany were described in another European study (POLARIS), which supports the meaningfulness of the OCEAN data [
30]: the rare use of OCT was also evident in the POLARIS study from the high number of VA examinations. One possible reason for the lower use of OCT may be that OCT examinations in Germany are not reimbursed by the national health insurance and is therefore only included in individual selective contracts or offered as a self-payer service. Some of the OCEAN centers did not even have an OCT device at the start of the study despite the importance of the morphological re-treatment criteria. Many German ophthalmologists refrained from OCT controls during the follow-up. Another finding reported by the authors of the POLARIS study enables comparison between European countries: in Germany treatment often stops or is delayed after the first three injections; in comparison, the higher rate of OCT examinations in the UK was also associated with a considerably higher number of ranibizumab injections [
30].
Non-adherence to monitoring and treatment is a known problem in DME [
28]. In a German real-world study that included 136 individuals with DME receiving anti-VEGF only 35% adhered to the visit schedule [
12]. Another real-world study in Germany that included 134 individuals with DME receiving anti-VEGF found a non-adherence rate of 44%, which was mostly patient associated [
23]. Possible reasons for non-adherence include comorbidities, patient age [
12,
23] and/or the high visit burden, particularly since individuals with DME also require frequent diabetes monitoring. It has also been suggested that adherence may be hampered by reimbursement issues, mobility limitations, a lack of patient motivation and interference with work schedules [
28]. Even with appropriate monitoring, some physicians may use re-injection criteria that differ from the recommendations. It is also possible that recommendations were followed but that participants were not treated because they met success or stop criteria or refused treatment; while this last possibility cannot be discerned from the data, but it is unlikely.
Despite under-treatment, VA notably improved in OCEAN participants with DME after 12 months (+ 4.0 ETDRS letters) and 24 months (+ 5.2 letters). Participants with low baseline VA (< 55 letters) and those receiving ≥ 7 injections in year 1 showed the highest gains. The VA improved less than in patients with DME in randomized controlled trials such as. RESTORE [
7], Protocol I [
31] and Protocol T [
2] where participants given ranibizumab with or without laser photocoagulation gained between + 7 and + 12 ETDRS letters. Clinical trials have strict treatment and follow-up schedules and inclusion/exclusion criteria, which may lead to better outcomes.
The VA improvements in patients in the prospective OCEAN study were also slightly lower than improvements reported in retrospective chart reviews. Two UK-based studies showed improvements of + 5 ETDRS letters [
22] and + 6.6 letters [
21] at 12 months. The latter study selected individuals receiving a ≥ 3-injection upload who may be expected to have better results. In a German retrospective study [
14], the maximum improvement for DME within 12 months was + 6.2 ETDRS letters, but the change from baseline to month 12 was − 1.3 letters. This VA loss may be due to bias, as only patients still under treatment were included, preferentially selecting individuals with chronically active disease [
14]. A second German chart review study documented VA gains of + 5.6 ETDRS letters in the first year of ranibizumab treatment [
24]. A small retrospective study from Taiwan found average improvement of + 4.9 ETDRS letters at 12 months with a mean injection load of 4.3 injections [
32].
About 60% of the participants completed the OCEAN study, which is comparable with other non-interventional studies, such as the AURA study on ranibizumab treatment for nAMD, where 53% completed 2 years [
33]. Time-to-event analyses have the advantage of including participants irrespective of the length of their individual observational period and missing data. The discontinuation rate among the participants in the OCEAN study was quite constant, suggesting that no specific factor triggered discontinuation at a particular time point. Participants receiving one to three injections during year 1 were documented for a shorter period than participants with more injections. It cannot be determined whether participants leaving the study early continued treatment outside the study.
Over 20% of the OCEAN participants with DME showed a relevant VA improvement (≥ 15 ETDRS letters) at months 12 and 24. Most participants responded within 3 months, consistent with the fast responses shown in clinical trials [
2,
7]. The response rate was higher in individuals receiving ≥ 7 injections in year 1, suggesting that more injections, potentially due to better adherence, increase VA gains. However, as a considerable proportion of participants discontinued the study early, and the group with ≥ 7 injections was small, this finding may not be transferrable to the general DME population.
By contrast, the duration-of-response was shortest in participants receiving the most injections. This could mean that participants receiving more injections do so because they respond to treatment but require additional ranibizumab injections to maintain the beneficial effects, such as due to higher disease activity.
Participants with the lowest baseline VA (< 55 ETDRS letters) showed the highest VA gain (‘floor effect’), and the response was faster and lasted longer than that in the subgroups with higher VA, demonstrating that individuals with DME and significantly impaired VA achieve sustainable improvements with ranibizumab. Participants with baseline VA of > 68 ETDRS letters gained less (‘ceiling effect’) but maintained higher VA than that of the other subgroups, supporting the need for prompt monitoring and treatment to prevent vision loss from DME [
34].
No new safety findings were identified in this population. The documented incidence of AEs (20.5%) and SAEs (11.4%) over 2 years was lower than those reported in randomized trials [
2,
31], potentially due to under-reporting in this non-interventional setting.
The non-interventional design is a strength of this study, as it describes the use of ranibizumab therapy for DME in routine clinical practice, in patients who are older and have more comorbidities than those in clinical trials [
11,
15] and who may also have more difficulties adhering to the treatment schedule. Seeing a beneficial effect of ranibizumab with a well-characterized safety profile in this setting is encouraging.
Non-interventional studies harbor a number of important limitations, including non-standardized diagnostics, high discontinuation rates, under-reporting, artificial patient selection and selective reporting; all of these have to be kept in mind when interpreting the results. Although even randomized controlled trials reported a loss of follow-up of between 23.4% (NCT00473382) and 42.1% (NCT00168389) of DME patients over 3 years, the group of discontinued documentation and treatment in the daily routine is more strongly associated with a distortion potential and thus does likely not reflect the actual distribution of the functional response. In this study, we have tried to describe this window of uncertainty and take account the limited tracking through a transparent and robust methodology.
Acknowledgements
We would like to thank all study participants for their time and good cooperation. The authors would also like to thank the collaborators for the ORCA study group, Teresa Barth (University Eye Hospital, Regensburg) and Chris P. Lohmann (Klinikum Rechts der Isar, Munich).
The Participants of the OCEAN Group are listed in the Supplementary Materials.