Downloaded from http://bjo.bmj.com/ on April 27, 2015 - Published by group.bmj.com
BJO Online First, published on November 25, 2014 as 10.1136/bjophthalmol-2014-305684 Innovations
Dexamethasone intravitreal implant as adjunct therapy for patients with wet age-related macular degeneration with incomplete response to ranibizumab Pilar Calvo,1,2 Antonio Ferreras,1,2 Fadwa Al Adel,3 Yao Wang,4 Michael H Brent3,4 1
Department of Ophthalmology, Miguel Servet University Hospital, Zaragoza, Spain 2 University of Zaragoza, Zaragoza, Spain 3 Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada 4 Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Correspondence to Dr Michael Brent, Department of Ophthalmology, Toronto Western Hospital, UHN, 6E-423 399 Bathurst Street, Toronto, Ontario, Canada M5T2S8; [email protected] Received 15 June 2014 Revised 14 October 2014 Accepted 10 November 2014
ABSTRACT Purpose To evaluate the visual and anatomical outcomes of dexamethasone intravitreal implant (DXI; 700 μg, Ozurdex; Allergan, Irvine, California, USA) as adjunctive therapy for patients with refractory wet age-related macular degeneration (AMD). Methods Retrospective review of the medical records of seven patients (seven eyes) who initially responded well to intravitreal ranibizumab but subsequently developed persistent intra/sub-retinal fluid (IRF/SRF) and underwent a single injection of DXI, between May 2012 and May 2013. Two weeks after DXI, the patients continued with their monthly ranibizumab injections. Best corrected visual acuity (BCVA) logarithm of the minimum angle of resolution (logMAR) and central retinal thickness (CRT) were recorded at baseline, 2 weeks, 6 weeks, 3 months and 6 months after DXI injection. Complications were recorded too. Results All patients had at least 24 months of ranibizumab treatment. Mean age was 81.5±5.8 years. At baseline, mean BCVA was 0.53±0.13 logMAR (20/70 Snellen) and mean CRT was 273.14±50.94 μm. BCVA did not change significantly after DXI over the follow-up period. However, all eyes had lost fewer than 0.3 logMAR units. Complete resolution of the persistent IRF/SRF was achieved in five eyes (71.4%) at 6 weeks, and remained stable at 3 months. Two weeks after DXI injection, the mean CRT diminished compared with baseline (248.28±31.8 mm; p=0.03) and the greatest reduction was observed at 3 months after DXI injection (241.5±36.6 mm; p=0.04). Progression of lens opacity was detected in one case (50% of phakic eyes). Retreatment with DXI was performed in two eyes. Conclusions DXI appears to be effective in vision stabilisation, decreasing IRF/SRF and improvement of CRT in eyes with refractory wet AMD.
INTRODUCTION
To cite: Calvo P, Ferreras A, Al Adel F, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-305684
Since the introduction of anti-vascular endothelial growth factor (anti-VEGF) therapy for wet age-related macular degeneration (AMD), different treatment regimens have been developed. Multicentre studies such as MARINA and ANCHOR,1 2 have shown that monthly intravitreal injections of ranibizumab over a 2-year period not only maintained but improved best corrected visual acuity (BCVA), with a mean gain of 7.2 and 11.3 letters, respectively. However, there were still some patients with wet AMD (up to 10%) who had incomplete response with monthly ranibizumab treatment. Those patients lost >15 letters despite monthly ranibizumab injections.1 2 In these
incomplete responders, steroidal anti-inflammatory drugs (triamcinolone, dexamethasone) are well known for their positive effects on AMD.3–8 The complementary action of intravitreal steroid injection in neovascular AMD dates back to the combination of intravitreal triamcinolone acetonide and photodynamic therapy.9–11 Lately, a new sustainedrelease 700 mg dexamethasone intravitreal implant (DXI; Ozurdex; Allergan, Irvine, California, USA) has been approved for the treatment of patients with macular oedema following retinal vein occlusions (RVOs) or non-infectious uveitis.12 The purpose of this study was to evaluate the visual and anatomic outcomes after adding DXI therapy to patients with wet AMD and persistent intra/sub-retinal fluid (IRF/SRF). To our knowledge, this is the first study to evaluate DXI as an adjunctive therapy for patients with refractory wet AMD.
METHODS The design of the study followed the tenets of the Declaration of Helsinki and the protocol was approved by the Institutional Research Ethics Board at the University Health Network, Toronto, Canada. We retrospectively reviewed the medical records of seven patients with choroidal neovascularisation due to AMD diagnosed by clinical exam, spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography, between May 2012 and May 2013 at the Toronto Western Hospital, who had initially shown a successful response to ranibizumab (defined as complete resolution of IRF/SRF on OCT) but finally developed an incomplete response to the treatment (defined as presence of IRF or SRF on OCT despite a minimum of three consecutive monthly injections). Those patients received DXI injection as an adjunctive treatment to help with the resistant IRF/SRF. All patients continued receiving monthly ranibizumab injections. We excluded patients with coexisting retinopathy other than AMD or any patient who had undergone a previous vitrectomy. A standard protocol was followed for the intravitreal injection of DXI, according to the manufacturer’s instructions. Subconjunctival anaesthesia was administered by injecting 2% xylocaine into the inferior conjunctiva, the eyelid was prepped with 5% povidone-iodine solution, a lid speculum was inserted, 5% povidone-iodine drop was installed at the site of injection and DXI was inserted into the vitreous cavity through the pars plana using a single use 22-gauge applicator device
Calvo P, et al. Br J Ophthalmol 2014;0:1–4. doi:10.1136/bjophthalmol-2014-305684
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://bjo.bmj.com/ on April 27, 2015 - Published by group.bmj.com
Innovations Table 1 Demographics and clinical findings of the study patients Case
Eye
Sex
Age (years)
BCVA logMAR (Snellen) baseline
BCVA logMAR (Snellen) 6 weeks
BCVA logMAR (Snellen) 3 months
BCVA logMAR (Snellen) 6 months
1 2 3 4 5 6 7
OD OD OS OD OD OD OL
F M M M F F M
78 84 89 74 90 80 76
0.69 0.3 0.69 0.6 0.54 0.39 0.54
0.47 (20/60) 0.3 (20/40) 1 (20/200) 0.39 (20/50) 0.54 (20/70) 0.47 (20/60) 0.3 (20/40)
0.39 0.17 0.87 0.39 0.47 0.47 0.39
0.69 (20/100) 0.17 (20/30) 0.87 (20/150) 0.39 (20/50) 0.47 (20/60) 0.6 (20/80) 0.47 (20/60)
(20/100) (20/40) (20/100) (20/80) (20/70) (20/50) (20/70)
(20/50) (20/30) (20/150) (20/50) (20/60) (20/60) (20/50)
Baseline, before dexamethasone intravitreal injection; BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; OD, right eye; OS, left eye.
in a scleral tunnel approach. No topical ophthalmic antibiotics were used before or after the procedure. BCVA, intraocular pressure (IOP) (measured by Goldmann applanation tonometry) and central retinal thickness (CRT) were retrospectively recorded at baseline, 2 weeks, 6 weeks, 3 months and 6 months after the DXI injection. All patients continued receiving monthly ranibizumab injections. Snellen visual acuity was measured by a certified ophthalmic technician. The Snellen value was recalculated to determine the corresponding logarithm of the minimum angle of resolution (logMAR) value.13 CRT was determined using SD-OCT Cirrus (Carl Zeiss Meditec, Dublin, California, USA). The scanning was performed with the 512×128 scan pattern. Only good-quality examinations with a signal strength of 6/10 or better were retained. The statistical analysis was performed using IBM’s statistical software (SPSS V.22.0; IBM Corporation, Somers, New York, USA). Descriptive findings are displayed as mean±SD. All study variables had a normal distribution as verified with the Kolmogorov–Smirnov test (K-S of 1 sample) except BCVA at 3 months. Differences between normally distributed variables were calculated by paired-sample t test, while the Wilcoxon signed-rank test was used for comparisons involving the BCVA at 3 months; p
BJO Online First, published on November 25, 2014 as 10.1136/bjophthalmol-2014-305684 Innovations
Dexamethasone intravitreal implant as adjunct therapy for patients with wet age-related macular degeneration with incomplete response to ranibizumab Pilar Calvo,1,2 Antonio Ferreras,1,2 Fadwa Al Adel,3 Yao Wang,4 Michael H Brent3,4 1
Department of Ophthalmology, Miguel Servet University Hospital, Zaragoza, Spain 2 University of Zaragoza, Zaragoza, Spain 3 Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada 4 Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Correspondence to Dr Michael Brent, Department of Ophthalmology, Toronto Western Hospital, UHN, 6E-423 399 Bathurst Street, Toronto, Ontario, Canada M5T2S8; [email protected] Received 15 June 2014 Revised 14 October 2014 Accepted 10 November 2014
ABSTRACT Purpose To evaluate the visual and anatomical outcomes of dexamethasone intravitreal implant (DXI; 700 μg, Ozurdex; Allergan, Irvine, California, USA) as adjunctive therapy for patients with refractory wet age-related macular degeneration (AMD). Methods Retrospective review of the medical records of seven patients (seven eyes) who initially responded well to intravitreal ranibizumab but subsequently developed persistent intra/sub-retinal fluid (IRF/SRF) and underwent a single injection of DXI, between May 2012 and May 2013. Two weeks after DXI, the patients continued with their monthly ranibizumab injections. Best corrected visual acuity (BCVA) logarithm of the minimum angle of resolution (logMAR) and central retinal thickness (CRT) were recorded at baseline, 2 weeks, 6 weeks, 3 months and 6 months after DXI injection. Complications were recorded too. Results All patients had at least 24 months of ranibizumab treatment. Mean age was 81.5±5.8 years. At baseline, mean BCVA was 0.53±0.13 logMAR (20/70 Snellen) and mean CRT was 273.14±50.94 μm. BCVA did not change significantly after DXI over the follow-up period. However, all eyes had lost fewer than 0.3 logMAR units. Complete resolution of the persistent IRF/SRF was achieved in five eyes (71.4%) at 6 weeks, and remained stable at 3 months. Two weeks after DXI injection, the mean CRT diminished compared with baseline (248.28±31.8 mm; p=0.03) and the greatest reduction was observed at 3 months after DXI injection (241.5±36.6 mm; p=0.04). Progression of lens opacity was detected in one case (50% of phakic eyes). Retreatment with DXI was performed in two eyes. Conclusions DXI appears to be effective in vision stabilisation, decreasing IRF/SRF and improvement of CRT in eyes with refractory wet AMD.
INTRODUCTION
To cite: Calvo P, Ferreras A, Al Adel F, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-305684
Since the introduction of anti-vascular endothelial growth factor (anti-VEGF) therapy for wet age-related macular degeneration (AMD), different treatment regimens have been developed. Multicentre studies such as MARINA and ANCHOR,1 2 have shown that monthly intravitreal injections of ranibizumab over a 2-year period not only maintained but improved best corrected visual acuity (BCVA), with a mean gain of 7.2 and 11.3 letters, respectively. However, there were still some patients with wet AMD (up to 10%) who had incomplete response with monthly ranibizumab treatment. Those patients lost >15 letters despite monthly ranibizumab injections.1 2 In these
incomplete responders, steroidal anti-inflammatory drugs (triamcinolone, dexamethasone) are well known for their positive effects on AMD.3–8 The complementary action of intravitreal steroid injection in neovascular AMD dates back to the combination of intravitreal triamcinolone acetonide and photodynamic therapy.9–11 Lately, a new sustainedrelease 700 mg dexamethasone intravitreal implant (DXI; Ozurdex; Allergan, Irvine, California, USA) has been approved for the treatment of patients with macular oedema following retinal vein occlusions (RVOs) or non-infectious uveitis.12 The purpose of this study was to evaluate the visual and anatomic outcomes after adding DXI therapy to patients with wet AMD and persistent intra/sub-retinal fluid (IRF/SRF). To our knowledge, this is the first study to evaluate DXI as an adjunctive therapy for patients with refractory wet AMD.
METHODS The design of the study followed the tenets of the Declaration of Helsinki and the protocol was approved by the Institutional Research Ethics Board at the University Health Network, Toronto, Canada. We retrospectively reviewed the medical records of seven patients with choroidal neovascularisation due to AMD diagnosed by clinical exam, spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography, between May 2012 and May 2013 at the Toronto Western Hospital, who had initially shown a successful response to ranibizumab (defined as complete resolution of IRF/SRF on OCT) but finally developed an incomplete response to the treatment (defined as presence of IRF or SRF on OCT despite a minimum of three consecutive monthly injections). Those patients received DXI injection as an adjunctive treatment to help with the resistant IRF/SRF. All patients continued receiving monthly ranibizumab injections. We excluded patients with coexisting retinopathy other than AMD or any patient who had undergone a previous vitrectomy. A standard protocol was followed for the intravitreal injection of DXI, according to the manufacturer’s instructions. Subconjunctival anaesthesia was administered by injecting 2% xylocaine into the inferior conjunctiva, the eyelid was prepped with 5% povidone-iodine solution, a lid speculum was inserted, 5% povidone-iodine drop was installed at the site of injection and DXI was inserted into the vitreous cavity through the pars plana using a single use 22-gauge applicator device
Calvo P, et al. Br J Ophthalmol 2014;0:1–4. doi:10.1136/bjophthalmol-2014-305684
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://bjo.bmj.com/ on April 27, 2015 - Published by group.bmj.com
Innovations Table 1 Demographics and clinical findings of the study patients Case
Eye
Sex
Age (years)
BCVA logMAR (Snellen) baseline
BCVA logMAR (Snellen) 6 weeks
BCVA logMAR (Snellen) 3 months
BCVA logMAR (Snellen) 6 months
1 2 3 4 5 6 7
OD OD OS OD OD OD OL
F M M M F F M
78 84 89 74 90 80 76
0.69 0.3 0.69 0.6 0.54 0.39 0.54
0.47 (20/60) 0.3 (20/40) 1 (20/200) 0.39 (20/50) 0.54 (20/70) 0.47 (20/60) 0.3 (20/40)
0.39 0.17 0.87 0.39 0.47 0.47 0.39
0.69 (20/100) 0.17 (20/30) 0.87 (20/150) 0.39 (20/50) 0.47 (20/60) 0.6 (20/80) 0.47 (20/60)
(20/100) (20/40) (20/100) (20/80) (20/70) (20/50) (20/70)
(20/50) (20/30) (20/150) (20/50) (20/60) (20/60) (20/50)
Baseline, before dexamethasone intravitreal injection; BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; OD, right eye; OS, left eye.
in a scleral tunnel approach. No topical ophthalmic antibiotics were used before or after the procedure. BCVA, intraocular pressure (IOP) (measured by Goldmann applanation tonometry) and central retinal thickness (CRT) were retrospectively recorded at baseline, 2 weeks, 6 weeks, 3 months and 6 months after the DXI injection. All patients continued receiving monthly ranibizumab injections. Snellen visual acuity was measured by a certified ophthalmic technician. The Snellen value was recalculated to determine the corresponding logarithm of the minimum angle of resolution (logMAR) value.13 CRT was determined using SD-OCT Cirrus (Carl Zeiss Meditec, Dublin, California, USA). The scanning was performed with the 512×128 scan pattern. Only good-quality examinations with a signal strength of 6/10 or better were retained. The statistical analysis was performed using IBM’s statistical software (SPSS V.22.0; IBM Corporation, Somers, New York, USA). Descriptive findings are displayed as mean±SD. All study variables had a normal distribution as verified with the Kolmogorov–Smirnov test (K-S of 1 sample) except BCVA at 3 months. Differences between normally distributed variables were calculated by paired-sample t test, while the Wilcoxon signed-rank test was used for comparisons involving the BCVA at 3 months; p
