gain of only 1.3 letters over 1 year [81]. On the other hand, a prospective ‘as needed’ study using bevacizumab, demonstrated impressive VA retention [77, 82]. This study had the poorest mean commencing VA, suggesting the possibility of a potentially high ‘ceiling’, and VA was not best corrected, so that baseline VA may have been underestimated.

Flexible Dosing Regimens: ‘Treat-and-Extend’ Approach

Most applications of the ‘treat-and-extend’ approach generally also use three consecutive monthly ‘loading’ doses of ranibizumab, or treat with monthly injections until there are no signs of macular haemorrhage on slit lamp biomicroscopy, and no intraor sub-retinal fluid is observed on OCT [78]. Treatment intervals are then sequentially lengthened by around 2 weeks at each visit, if there are no signs of recurrent exudation, to a maximum of 10 [83] or 12 [78] weeks. The follow-up period is then shortened by 2 weeks if any sign of exudation or new macular haemorrhage is observed [78]. Using this regimen, Gupta et al. demonstrated similar outcomes to the ANCHOR and MARINA trials with relative VA stability at both 1 and 2 years [78], although the number of patients who completed a 2-year follow-up was low. Other small case series have described somewhat similar outcomes [83].

15.2.5What Are the Long-Term Considerations in Anti-VEGF Therapy of NV-AMD?

Participants in the MARINA and ANCHOR trials were followed for an additional 2 years into the HORIZON extension study. Over 60% of these patients needed additional treatments in the third year, and many also needed treatment into the fourth year. Overall, better visual and anatomical outcomes at 2 years predicted longer time to re-treatment during this period. Nevertheless, significant loss of the VA gain occurred, which was presumably due to under-treatment during the extension period, or to chronic signs such as increasing atrophy or fibrosis [33]. There are no clear data yet available to determine which of these parameters accounts for most of this decline. This information will be important to develop.

Summary for the Clinician

›OCT detects VEGF-induced hyperpermeability, and can be used to detect, localize, classify and quantify intraretinal, sub-retinal, and sub-RPE fluid. OCT, particularly spectral domain instrumentation, is therefore recommended to identify active leak before and particularly during followup of anti-VEGF therapy. RCTs have invariably shown resolution of fluid and reduced CRT on OCT after intravitreal ranibizumab or bevacizumab, with accompanying improved VA.

›In the major, pivotal RCTs, monthly ranibizumab intravitreal injections have documented the best and sustained VA outcomes (level I evidence).

›However, monthly injections over long periods are not feasible in many patients. Flexible dosing strategies have therefore been developed, and appear feasible, particularly with close monitoring, though benefits could be less (Level III evidence). The month 4 to month 5 period, after three consecutive monthly injections, and institution of an ‘as needed’ regimen, appears to be very useful as a marker of anti-VEGF therapy need.

›Studies with <5 injections in the first 12 months generally showed the weakest efficacy benefits, although the results were variable. The small PrONTO and larger SUSTAIN Studies showed that monthly monitoring was required to maintain efficacy benefits, compared with the SAILOR cohort 1, which had mandatory quarterly follow-up visits, although more frequent follow-up was possible and performed for many patients [33].

›Close monitoring aims to detect the persistence or recurrence of ‘active’ disease using history, VA changes, slit-lamp biomicroscopic examination of the macula and OCT. If active disease is still present or has recurred, additional treatment should be initiated quickly to improve the likelihood of maintaining or restoring the best functional outcome. However, if the disease is inactive,re-treatmentisnotnecessary.Continued monthly follow-up (with an injection if required) is recommended, particularly during the first 12 months, in order to detect active disease (level III evidence).

›However, if the clinical signs remain quiescent for periods, extending follow-up intervals appear then to be justified. This approach, termed ‘treat-and-extend’ and popularized by Spaide has gained considerable acceptance by clinicians. Evidence from a recent series indicates generally better VA results than with ‘as needed’ regimens, but with a somewhat higher injection frequency (level III evidence). Apart from these better outcomes, this approach also provides greater certainty for patients when they attend. Treating according to individual patient’s needs while retaining good visual outcomes is the important goal.

›Re-treatment is indicated when any persistent or recurrent fluid is seen on OCT, VA falls, a fresh haemorrhage is observed, new or persistent distortion is described or other clinical features indicate continued disease activity (level III evidence).

›A critical issue is the extent of delay in diagnosis, referral and initiation of anti-VEGF treatment. For example, after only 1 month in the PIER trial, VA deteriorated in the untreated control group by a mean five letters. Delayed initiationoftreatmentinpatientswithnewlydiagnozed AMD is also associated with substantial VA loss. Smaller lesion size was a predictive factor for better VA outcomes in all of the major trials. Similarly, it is critical for any prolonged absences need to be avoided and warned about in advance. Finally, patient support strategies may be very helpful in helping them to achieve the best visual and functional outcomes.

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