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Treat and extend protocol outcomes in diabetic macular edema: A narrative review
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How to cite this article: Bhatter P, Bheemidi A, Muste JC, Wu SZ, Snider MJ, Valentim CC, et al. Treat and extend protocol outcomes in diabetic macular edema: A narrative review. Am J Ophthalmic Clin Trails 2022;5:2.
Abstract
The objective of this study was to pool available data on change in visual acuity, number of injections, and change in central subfield thickness as reported by treat and extend (T&E) regimens for diabetic macular edema (DME) compared to monthly and pro re nata (PRN) regimens. PubMed, ScienceDirect, and EMBASE databases were queried for studies that met the following criteria: Retrospective or prospective design, T&E regimen reported in comparison to a monthly or PRN regimen for the treatment of DME, and a 12-month follow-up period. Eighty candidate publications were screened. Sixteen studies were included in the qualitative synthesis, 11 of which were rejected due to their observational methods. Five studies were included in the final analysis. T&E protocols for DME have been shown to be as effective as PRN or monthly treatment protocols with the added benefit of fewer office visits and minimized injection frequency.
Keywords
Diabetic macular edema
Diabetic retinopathy
Treat and extend
INTRODUCTION
Diabetic retinopathy and its sequelae, diabetic macular edema (DME), remain the leading cause of vision impairment among working-age adults globally.[1-3] Diabetes-related vision impairment is predicted to triple by the year 2050, reaching 3.4 million persons in the United States.[4] Many different treatment options for DME exist. Laser photocoagulation, once considered the gold standard, has largely been replaced by intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents.[5]
In RIDE and RISE, patients with DME receiving monthly ranibizumab injections were reported to have larger gains in visual acuity (VA) at 24 months compared to the placebo group.[6] VIVID and VISTA, which compared aflibercept injections to laser control, found similar efficacy for both monthly and bimonthly injection regimens, and greater gains in best-corrected visual acuity (BCVA) compared to laser after 148 weeks.[7]
In the aforementioned Phase III trials, patients received monthly injections for a finite time period. However, in real-world clinical settings, a comparable regimen is difficult to realistically attain. Attempts to do so often result in undertreatment of disease or a high burden of care on the patient, caregiver, and provider.[8-11] To counteract burden of treatment, pro re nata (PRN) injection schemes, where patients are evaluated every month but not necessarily injected, have also frequently been studied. The RESTORE protocol is one such study that showed that VA-guided PRN injections can maintain vision in patients with DME.[12]
More flexible, personalized dosing regimens, such as treat-and-extend (T&E), have the potential for fewer total injections over a given time frame with similar VA outcomes. TREX-DME followed 150 eyes randomized to monthly injections or one of two T&E regimens. Eyes assigned to T&E regimens had similar VA outcomes compared to those assigned to regular monthly injections after 12 and 24 months.[13] Despite the promise of T&E trials, examination of real-world clinical patterns has found suboptimal vision outcomes for patients receiving less frequent anti-VEGF injections.[14] The balance between strict monthly regimens, PRN regimens, and more flexible ones such as T&E remains elusive. To date, no high-level summary of this work has been undertaken. This review article explores clinical trials that have compared T&E regimens to monthly or PRN regimens.
MATERIAL AND METHODS
Preclinical studies, case reports, case series, observational studies, and randomized controlled trials were considered for inclusion. PubMed was queried with the following search query (“Treat and Extend” OR “T&E”) AND (“diabetic retinopathy” OR “diabetic macular edema” OR “DME”). Additional articles were identified from a manual search of reference lists within included articles.
Studies were considered and classified dichotomously. Inclusion criteria were as follows: English language, prospective or retrospective design, and T&E regimen after a PRN or monthly regimen or head-to-head comparison. Exclusion criteria were as follows: Failure to address T&E for DME specifically, absent methodology, and observational studies. The full text of each article was reviewed by PB, JM, and AB. The final articles were extracted.
RESULTS
After screening 80 candidate publications, a total of five studies were included. Sixteen studies were included in the qualitative synthesis, but 11 were rejected as they were observational in nature. The five studies included in the final analysis are shown in [Table 1].
| Basic information | T&E | PRN or monthly | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Author | Prospective or retrospective | Design | Treatment drug | Average age (years) | Number of eyes | N | Mean number of injections | Mean VA Improvement (ETDRS letters) | Mean CRT Improvement (µm) | N | Mean Number of Injections | Mean VA Improvement (ETDRS letters) | Mean CRT Improvement (µm) |
| Eichenbaum et al. | Prospective | Controlled, randomized | Ranibizumab | 62.5 | 20 | 10 | 10.7 | 7 | −124.3 | 10 | 10.9 | 8.2 | −154.6 |
| Prünte et al. | Prospective | Controlled, randomized | Ranibizumab | 63.7 | 359 | 128 | 24-month data only | 6.8 | −24.35% | 123 | 24-month data only | 7.4 | −23.16% |
| Ebneter et al. | Retrospective | Comparative case series | Ranibizumab | 63 | 46 | 22 | 8.9 | 9.3 | −117.6 | 24 | 5.9 | 9 | −68.1 |
| Ehlers et al. | Prospective | Double arm, randomized | Ranibizumab | 63.1 | 27 | 12 | 9.6 | 8.4 | −120.1 | 15 | 10.9 | 2.7 | −83.1 |
| Payne et al. | Prospective | Double arm, randomized | Ranibizumab | 59 | 150 | 60 | 10.7 | 9.6 | 146 | 30 | 13.1 | 8.6 | −123 |
VA: Visual acuity, ETDRS: Early treatment diabetic retinopathy study, CRT: Central retinal thickness
T&E versus monthly
The TREX-DME study was the first prospective, randomized, and controlled trial to evaluate ranibizumab dosing in a T&E algorithm with and without laser photocoagulation as compared to a monthly injection scheme.[13] This study did not specify between treatment-naïve and treatment-resistant patients, and divided the patients into three cohorts: Monthly (n = 30), T&E (n = 60), and T&E with laser (n = 60). Patients in all three cohorts received four monthly injections in the loading phase, and those in the monthly cohort continued to receive monthly injections for 2 years. Once a baseline central retinal thickness (CRT) < 325 μm had been established over three visits, the T&E period was extended 2 weeks if there was no more than a 10% increase in CRT thickness from baseline. If there was a 10–20% increase in thickness compared to baseline CRT, the interval was maintained, and if <20% increase compared to baseline, the interval was reduced by 3 weeks. The maximum length of T&E interval was set at 12 weeks. Eyes in the laser T&E cohort received laser treatment at week 4 and again were eligible to receive it every 3 months.
The primary 1-year outcome of improvement in BCVA showed no significant difference between the three groups (P = 0.80). Similarly, the improvement in CRT also showed no significant difference between groups (P = 0.47). The number of injections was significantly higher for the monthly group compared to the T&E group (P < 0.001) as well as between the monthly compared to the T&E with laser (P < 0.001). There was no significant difference between the T&E compared to the T&E with laser group (P = 0.25) in regard to the number of injections. In the 2-year data, there was also a significant difference in the number of injections, with significantly fewer number of injections in the T&E (18.9) and T&E with laser groups (17.5) compared to monthly treatment group (24.7) (P < 0.001).[15]
Eichenbaum et al. were another single-center, prospective, and randomized study that included 20 eyes of 20 different subjects.[16] This study did not specify between treatment-naïve and treatment-resistant patients, and divided patients into monthly (n = 10) or T&E (n = 10) cohorts. The T&E group in this study received monthly injections till a CRT < 325 μm had been established or there was a stable CRT with no more than ±15 μm fluctuation and no change in BCVA of ±3 letters over 3 months of follow-up. Following this period, as long the CRT did not increase by more than 325 μm or the BCVA drop by more than 5 letters, the interval was extended by 2 weeks. The maximum interval length was 12 weeks.
The mean change from baseline BCVA was not significant between the monthly and T&E groups for both the 1-year (P = 0.136) and 2-year (P = 0.082) data. The mean improvement in CRT was found to not be statistically different between the monthly and T&E groups for both 1-year (P = 0.542) and 2-year (P = 0.477) data. The mean number of injections was also reported to not be significant between the monthly and T&E groups for 1 year (P = 0.582) and 2 years (P = 0.287).
The REACT study was the first prospective and randomized trial to look at treatment-resistant patients and included 27 eyes.[17] Patients with persistent foveal-involving DME that had failed bevacizumab (at least six injections within the past 12 months) were enrolled in either a monthly (n = 15) or T&E (n = 12) study protocol. Patients in both cohorts received 4 monthly ranibizumab injections in the loading phase, and those in the monthly cohort continued to receive monthly injections for 1 year. In the T&E arm, if CRT decreased to <300 μm or there was no intraretinal or subretinal fluid (SRF) in the macular cube, the follow-up interval was increased by 2 weeks to a maximum of 12 weeks. If these conditions were not met, the interval was reduced by 2 weeks. The time frame for the REACT study was 12 months.
The mean number of overall ranibizumab injections between the T&E and monthly injection groups was reported to be statistically insignificant (P = 0.21). While the statistical significance of vision change comparing the T&E and monthly groups was not reported, across all subjects, BCVA improved by 2.7 letters (P = 0.28) in the monthly group and 8.4 letters (P < 0.05) in the T&E group. Similarly, mean CRT changes were not compared between groups but across all subjects. CRT in the monthly group improved by 83.1 μm (P = 0.10) at month 12 while subjects under the T&E group improved by 120.2 μm (P < 0.01).
T&E versus PRN
Ebneter et al. are the first retrospective, comparative case series on 46 treatment-naïve patients comparing PRN (n = 24) dosing versus a T&E regimen (n = 22).[18] In the PRN dosing group, patients received 3 monthly injections of ranibizumab in the loading phase and then placed on a PRN protocol, only receiving further injections at monthly visits if BCVA fell by more than 5 letters. Patients in the T&E group received monthly injections until a stable CRT was reached, though numerically what this represented was not specified in the study. The treatment intervals were prolonged by 2 weeks as long as the CRT remained stable or shortened by 1 week each visit till intraretinal or SRF resolved. It is important to note that if the interval needed to be shortened, the patient was maintained on the shortened interval after resolution of subretinal or intraretinal fluid for 6 months. In addition, this T&E arm had no specific loading interval or max. interval specified.
The mean improvement in BCVA was not statistically significant (P = 0.3) between the T&E and PRN groups. The mean decrease in CRT thickness was not statistically significant (P = 0.2) between the T&E and PRN groups either. The mean number of ranibizumab injections was significantly higher (P < 0.001) in the T&E group compared to the PRN group. There was also a significantly higher (P < 0.05) mean number of clinic visits for the T&E group as compared to the PRN group. However, the mean number of clinic visits was 10 for the PRN group, while study protocol dictated that every member of the PRN group should have 13 total visits.
The RETAIN study was the first prospective, randomized, and controlled trial to evaluate ranibizumab dosing in a T&E algorithm with and without laser photocoagulation as compared to a PRN injection scheme.[19] This study did not specifically include treatment-naïve or treatment-resistant patients and divided the patients into three cohorts: PRN (n = 123), T&E (n = 128), and T&E with laser (n = 121). Patients in all three cohorts received 4 monthly injections in the loading phase, and those in the PRN cohort continued to be evaluated monthly while those in the T&E arm and T&E with laser arm had intervals extended by 4 weeks at a time to a maximum interval of 12 weeks if the patient’s BCVA was stable. If the patient’s BCVA worsened, the interval was reduced by 1 month. It is important to note that BCVA stability was at the discretion of the assessing clinician with no standardized criteria in place. Eyes in the T&E with laser cohort received laser treatment at the discretion of the clinician as well with a minimum 3-week treatment window.
The mean improvement in BCVA for both the T&E and T&E with laser groups was found to be non-inferior to PRN after 1 year (P < 0.0001). There was no significant difference between T&E (P = 0.51) and T&E with laser (P = 0.69) groups compared to PRN following 2 years of treatment. Regarding anatomical outcomes, the mean improvement in CRT for both the T&E (P = 0.74) and T&E with laser groups (P = 0.22) compared to PRN was found to be non-significant after 1 year. In addition, following 2 years of treatment, there was a significant difference between T&E with laser when compared to PRN (P < 0.05) but not with T&E compared to PRN (P = 0.936) groups. Although the statistical significance of mean difference in number of injections across 24 months was not reported, the mean number of injections for the T&E with laser, T&E, and PRN was 12.4, 12.8, and 10.7, respectively.
DISCUSSION
T&E dosing has been shown to be an effective strategy for the treatment of DME, although T&E has not been submitted to the FDA for any of the anti-VEGF drugs, we currently have in practice.[20] Reported advantages seen from a T&E regimen include comparable vision gains to monthly and PRN regimens with fewer patient visits, fewer injections, and improved patient expectations at each visit.[21]
While initial studies such as the RISE and RIDE trials evaluated monthly injection protocols, there has not been the equivalent of the CATT study in DME, which evaluated PRN versus monthly anti-VEGF therapy in age-related macular degeneration.[22] Despite this, PRN treatment strategies are widely accepted and used in clinical trials such as DRCR.net Protocol T, which compared various anti-VEGF medication and their effect on BCVA.[23] Given that there has been no study to date focused on comparing PRN and monthly regimens exclusively, both treatment regimens were chosen to be compared in this review.
The two studies with the largest number of subjects enrolled in this review are the TREX-DME and RETAIN studies. Both studies compare T&E with and without laser, with TREX-DME including a monthly cohort, and RETAIN a PRN cohort. The RETAIN study, which was published first, showed no significant difference between all three groups when it came to BCVA between the 1- and 2-year follow-up period. In addition, the RETAIN study T&E interval extension was 4 weeks when BCVA was maintained, which is less conservative than the other four studies included in this review. The RETAIN protocol also established the need for interval extension or reduction based on the patient having stable vision per investigator discretion, which is unlike any of the other studies in this review. Although the 2-year data did not specify if there was a significant difference in the mean number of injections, the RETAIN study may be interpreted as a non-inferiority study demonstrating T&E without laser is just as effective as T&E with laser or PRN treatment with a minimally conservative protocol design.
The TREX-DME study was designed as a monthly versus T&E study based on the RIDE and RISE clinical trials. BCVA and CRT were found to be equivalent across all three treatment cohorts at 2 years. Although this study had a more conservative treatment regimen, with strict anatomical parameters for T&E intervals extension and reduction, the number of injections was found to be significantly lower in the T&E and T&E with laser cohorts. Notably, this was found to be true in the 2-year follow-up period as well, even with patients who were not considered treatment naïve. These findings have tremendous real-world implications including fewer office visits, injections, imaging, and other patient- and healthcare-related costs. In addition, as compared to PRN protocols, where patients are unsure if they will be receiving an injection, T&E protocols mandate injections at office visits. Thus, patients can better prepare knowing that they will be receiving treatment.
Ebneter et al. were the only included study to review treatment-naïve patients. Subgroup analysis in the study showed that patients with poor baseline BCVA (<56 letters) experienced significantly more improvement in their BCVA compared to those with better baseline BCVA in both the PRN and T&E groups. However, patients in both subgroups experienced significant visual improvement in both arms of the studies. It is important to note that in this study, approximately 30% of the patients did not have a resolution of SRF despite a stable BCVA, which was relatively the same across the other studies in this review. This is consistent with the VIVID and VISTA trials as there were patients who still had macular edema at the end of both trials.[7] Although SRF is often tolerated with injections and not associated with worsening VA, it follows that a T&E protocol dictated by CRT thickness for interval extension or shortening would also view SRF negatively.[24] Thus, many of the T&E protocols in this study were probably more conservative than needed, though this specific population of patients with persistent SRF needs to be further investigated. Regardless, there always will be a select percentage of patients with treatment-resistant edema due to mechanisms such as tolerance and tachyphylaxis, thus switching between anti-VEGF drugs may be an option. The REACT study, although with a small sample size, demonstrated that even bevacizumab-resistant patients treated with ranibizumab had significant improvement in their BCVA and CRT on a T&E protocol. This mirrors the results seen in the ROTATE study, which looked at monthly and PRN regimens of ranibizumab for bevacizumab-resistant DME.[25] However, this systematic review was not designed to offer commentary on efficacy after switching anti-VEGF drugs.
This systematic review includes data from four prospective and one retrospective study examining visual and anatomical outcomes of T&E with and without laser compared to monthly and PRN regimens of anti-VEGF agents for DME. Due to heterogeneous methods, it was not possible to conduct direct comparisons between studies. Other limitations include a relatively small sample size of studies, the inability to comment on treatment regimens alternating between anti-VEGF agents, and the inability to assess real-world outcomes.
CONCLUSION
With regard to VA and CRT improvement, T&E protocols DME has been shown to be just as effective as PRN or monthly treatment protocols. T&E protocols, especially over longer periods of follow-up (>2 years), can reduce office visits and injection frequency with no change in visual outcomes, even in treatment-resistant patients. Ebtner et al. were the only study to show more office visits for the T&E group versus the PRN group, though this was attributed to poor follow-up for the PRN group given that they were expected to have one visit per month for 13 total visits per study design, but only averaged 10 visits. The rest of the four studies in this review showed either fewer visits or an equivocal number compared to PRN or monthly protocols. Even though T&E seems to be an effective regimen for many patients, further real-world clinical studies may examine dosing, switching between anti-VEGF medications, and monitoring long-term follow-up for T&E.
Declaration of patient consent
Patients’ consent not required as patients’ identity is not disclosed or compromised.
Financial support and sponsorship
Rishi P Singh reports personal fees from Genentech/Roche, personal fees from Alcon/Novartis, grants from Apellis and Graybug, personal fees from Zeiss, personal fees from Bausch + Lomb, personal fees from Regeneron Pharmaceuticals, Inc., and personal fees from Gyroscope and Asceplix. All other authors report no disclosures.
Conflicts of interest
Dr. Rishi P. Singh is the Editor in Chief of this journal.
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