Glucocorticosteroid Intravitreal Implants in Posterior Retina Diseases

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; REY-ARES, L.; CESARONI, S

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 30

1668-2793

Glucocorticosteroids (GC) are used for the treatment of several conditions accompanied by swelling and/or edema of the posterior and intermediate segments of the eye, including diabetic retinopathy (DR), non-infectious posterior uveitis (NIPU) and retinal vein occlusion (RVO). Since systemic treatments do not reach the required concentrations to have effect in the eye and topical application is not effective in the posterior and intermediate retina, they should be directly administered to the vitreous humor by injections, surgical incisions or using devices.It is stated that the use of a GC slow-release intravitreal implant would allow to increase the length of the effect when compared with other choices. Its application by means of a device would avoid the need for sutures and therefore, the trauma related to implant insertion. Both the injection and the applicator require a surgery room or room prepared for minor surgeries.TechnologyThe main extended release implants used are dexamethasone and the fluocinolone acetonide (FA) implants. The former contains 0.7 mg dexamethasone, may be inserted in the vitreous body by means of a surgical incision or using an applicator and its effects is up to 180-day long. The latter contains 0.59 mg FA, is surgically implanted and may control inflammation for up to 3 years.PurposeTo assess the available evidence on the efficacy, safety and issues related coverage policies for the use of dexamethasone and fluocinolone intravitreal implants.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsSix clinical trials, 3 case series, one recommendation from the British NICE and 3 coverage policies were selected. No RCTs directly comparing the use of both intravitreal GC have been found. The selected evidence for the different clinical conditions is described below:Macula edema (ME) secondary to diabetic retinopathy (DR):In 2011, one clinical trial on 196 eyes with refractory DR randomized to a 0.59 mg FA implant or standard treatment (laser or observation) was published; the rate of eyes which improved their visual acuity in ≥3 lines was significantly higher in the group receiving the implant compared to the group receiving standard treatment after 6 months (16.8% vs. 1.4%; P≤0.01) and after 2 years (31.8 vs. 9.3%; P ≤ 0.01) being this difference non significant after 3 years. The reported adverse effects included increased intraocular pressure (IOP) (61.4%) and cataracts (91%). In 2010, one subgroup analysis of 57 patients with DR randomized to 0.7mg, 0,.5mg dexamethasone or no treatment was published. Statistically significant differences were found in the rate of eyes achieving a visual acuity ≥ 10 letters, in favor of the group receiving treatment with 0.7 mg versus no treatment at Day 60 (26% vs. 9%; P: 0.01) and 90 (33% vs. 12%; P: 0.007) but not at Day 180 while in the group receiving a 0.35 mg implant, the significant difference in favor of the treatment was observed only at Day 60 (23% vs. 9%; P: 0.04).Macular edema secondary to retinal vein occlusion (RVO):In 2010, one Phase III study including 1,267 patients with ME secondary to RVO was published. Patients were randomized to sham treatment or 0.35 or 0.7 mg dexamethasone implant. The time required to achieve a ≥15-letter improvement in visual acuity was significantly lower in the groups receiving implants, the rate of eyes achieving a ≥ 15-letter improvement compared with baseline was significantly higher in both groups using 0.35 mg or 0.7 mg dexamethasone implants compared with those not receiving treatment at Day 30 (21%, 18% and 8%), 60 (29% versus 11%) and 90 (22%, 23% and 13%) and non significant at Day 180. The significantly more common effects in both groups receiving implants included pain (6%) and ocular hypertension (4%) later, a selected group of patients were implanted with 0.7mg dexamethasone implant and showed a higher rate of cataracts after 12 months, in patients receiving 2 implants (29.8% vs. 5.7%).Non-infectious posterior uveitis:In 2011, one clinical trial randomized 229 patients with NIPU to 0.7 mg, 0.35 mg dexamethasone implants or sham procedure, was published. The rate of eyes presenting inflammation after 8 weeks was statistically different in the groups receiving 0.7mg, 0.35mg implants or sham procedure (47%, 36% and 12%; P≤ 0.01) and the rate of eyes which gained ≥ 15 letter was two to six times higher than in the groups receiving implants. In 2010, one clinical trial including 146 patients with NIPU randomized to a 0.59 mg intravitreal FA implant or standard treatment, was published. It showed a lower rate of uveitis recurrence in patients receiving the implant when compared with those receiving standard treatment with oral GC or immunosuppressive agents (18.2% vs. 63.5%; P≤ 0.01). The most common adverse effects observed in the group receiving implants were increased IOP (55.4%) and cataract which required resection (87.8%).The three case series that evaluated the rate of recurrence of NIPU before and after treatment with FA showed a statistically significant reduction in the rate of recurrence.Studies that evaluated the use of GC implants in different diseases:In 2009, one study conducted on 30 subjects with ME of diverse etiology, who were randomized to 0.7 mg dexamethasone by means of an applicator or incision, was published. No statistically significant differences were observed in the adverse effects or improvement in visual acuity. In 2007, one clinical trial conducted on 315 patients with persistent ME who were randomized to 0.7 mg, 0.35 mg dexamethasone or observation, was published. It showed a higher rate of eyes achieving a statistically significant improvement in visual acuity of 10 letters at Day 90, in the groups receiving 0.7 mg (35%) and 0.35 mg (22%) implants compared with those not receiving implants (13%) and an improvement ≥ 15 letters in favor of the group using the 0.7 mg dexamethasone implant at Day 90 (18%) and 180 (18%). The cost of the Ozurdex® application is USD 1,200 dollars.Coverage Policies and GuidelinesThe United Kingdom technology assessment NICE recommends the use of the intravitreal dexamethasone implant as a first-line choice for the treatment of patients with ME secondary to retinal central vein occlusion (RCVO).As regards the use of an dexamethasone intravitreal implant using an applicator (Ozurdex®) the US health sponsor Aetna and HUMANA consider that it may be used for the treatment of ME secondary to central retinal vein occlusion (CRVO)RCVO, to branch retinal vein occlusion (BRVO) and in NUPI. In relation to the FA intravitreal implant, Aetna considers it is a choice for the treatment of patients with NUPI not responding or not tolerating conventional treatment and experimental in patients with intermediate uveitis and ME secondary to RCVO.ConclusionsStudies of good methodological quality have been identified on the use of dexamethasone implants in patients with VRO and NUPI, in which different doses of dexamethasone implants were compared versus placebo and showing a statistically significant improvement in visual acuity in patients with VRO who received implants at Days 30, 60 and 90 after implantation but not at Day 180 and a higher rate of eyes without inflammation in patients with NUPI. The selected RCTs conducted on the use of fluocinolone in patients with NUPI or DR showed a high rate of adverse effects (increased IOP and cataracts). No good methodological quality studies have been identified on the use of FA implants in patients with VRO. One study was identified and included just 30 patients and compared the administration of dexamethasone implants using an applicator or by means of an incision, which showed not significant differences. No RCTs directly comparing the different types of intravitreal GC or on the efficacy and safety of using more than two implants successively have been identified. No evidence was found on the use of Ozurdex® in patients with relapsed ME. Although intravitreal triamcinolone is currently used, no RCTs comparing this intervention with GC implants have been identified. In summary, there is adequate information to support the use of GC intravitreal implants in posterior retina diseases, especially about dexamethasone, but the effectiveness against the triamcinolone injections has not been reported. Also, the advantage of using the applicator has not been evaluated either.