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The number of IVT injections, diagnoses, visual acuity and safety profiles are shown in Figures 10.1 and 10.2 and in Tables 10.1 and 10.2.

Among the number of IVT injections performed from 2006 to 2012 at SNEC, Avastin* (bevacizumab) injections were most widely used.

Of the 1,085 anti-VEGF injections administered, the most common diagnosis treated was AMD.

Three months after treatment, one out of three patients demonstrated a gain of ≥ 15 letters in their visual acuity (Cheung et al., 2014)

Table 10.1 Visual acuity at 3 and 12 months post-treatment
	All (N = 113)	AMD-CNV (N = 43)	PCV (N = 70)	P value*
Baseline, mean (SD)	0.82 (0.57)	0.79 (0.53)	0.83 (0.59)	0.89
3 months, mean (SD)	0.68 (0.65) (n = 75)	0.76 (0.79) (n = 25)	0.64 (0.57) (n = 50)	0.94
12 months, mean (SD)	0.68 (0.6)	0.7 (0.64)	0.67 (0.57)	0.94
Patients with gain ≥ 15 letters at 3 months, N (%)	25 (33.3)	9 (36.0)	16 (32.0)	0.73
Patients with gain ≥ 15 letters at 12 months, N (%)	38 (34.2)	14 (34.1)	24 (34.3)	0.99

*P value based on the Wilcoxon rank-sum test or the chi-square test.

AMD, age-related macular degeneration; CNV, choroidal neovascularisation; PCV, polypoidal choroidal vasculopathy; SD, standard deviation.

Anti-VEGF injections performed in 1,182 patients demonstrated a good safety profile, with the majority of patients receiving Avastin* (bevacizumab) (n = 1,011) (Ng et al., 2015).

Table 10.2. Incidence of myocardial infarction, stroke and mortality with anti-VEGF injections
	Incidence (SNEC)	Age adjusted incidence rate	Weighted incidence rates (of Singapore population)
Myocardial infarction	19	350.2 (per 100,000 persons)	427.1 (per 100,000 persons)
Stroke	16	299.3 (per 100,000 persons)	340.4 (per 100,000 persons)
Mortality	43	778.9 (per 100,000 persons)	921.3 (per 100,000 persons)

VEGF, vascular endothelial growth factor.

Endophthalmitis from IVT injections

From January 2005 to September 2013, 16, 304 IVT injections were performed. Only one case of endophthalmitis (culture positive) was reported for an overall incidence of 0.006%.

Benchmark of success

SNEC’s patient cohort achieved a significant improvement in visual acuity after one year of treatment; however, there was no significant difference in the mean visual acuity change when outcomes were analysed by diagnosis of AMD-choroidal neovascularisation versus PCV.

Table 10.3. Comparison of visual acuity following IVT injections at SNEC versus that in international studies using anti-VEGF injections
Study origin	Sample size	Mean baseline VA ETDRS letters (SD)	Mean VA at 1 year ETDRS letters (SD)	Mean number of injections at 1 year (SD)
USA (2008) (Curtis et al., 2013)	91.628	-	-	-
Germany (2008) (Finger Wiedemann, Blumhagen, Pohl, & Holz 2013; Holz et al., 2013)	3,470	48.8 (18.7)	48.0 (11.7)	-
UK (2007) (Pushpoth et al., 2012)	897 (pre-treated, N = 125)	50.4	53.1	6.2 (2.6)
UK (2007) (Pushpoth et al., 2012)	897 (no pre- treatment, n = 772)	54.1	57.9	5.2 (2.7)
Sweden (2007) (Hjelmqvist et al., 2011; Holz et al., 2013)	471	58.3 (12.2)	59.3 (16.2)	-
Belgium (2008) (Holz et al., 2013; Rakic et al., 2013)	253	56.3 (14.2)	58.8 (17.9)	-
Netherlands (2008) (Holz et al., 2013; Rakic et al., 2013)	243	45.1 (21.5)	50.7 (24.0)	-
France (2007) (Cohen et al., 2009)	122	56.2 (14.0)	56.9 (17.0)	-
Beirut (2005) (Bashshur et al., 2008)	60	45.7	53.1	-
Korea (2007) (Kang & Roh, 2011)	41	42.1	46.0	-
Singapore-SNEC (2010) (Cheung et al., 2014)	132 (AMD-CNV, n = 43)	45.5	50.0	4.51 (2.25)
Singapore-SNEC (2010) (Cheung et al., 2014)	132 (PCV, n = 87)	43.5	51.5	3.43 (1.73)

AMD, age-related macular degeneration; CNV, choroidal neovascularisation; ETDRS, Early Treatment Diabetic Retinopathy Study; IVT, intravitreal; PCV, polypoidal choroidal vasculopathy; SD, standard deviation,; VA, visual acuity; VEGF, vascular endothelial growth factor.

The pivotal Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) study, carried out in the USA in patients with AMD treated with 0.3 or 0.5mg Lucentis® (ranibizumab), demonstrated a mean increase in visual acuity of 6.5 letters in the 0.3mg group and 7.2 letters in the 0.5 mg group (Rosenfield et al., 2006).

Although not a direct comparison, improvement in vision from the SNEC cohort was +8 letters at three months and +6.5 letters at 12 months.

The overall incidence rate of endophthalmitis post-IVT injection is very low at 0.018% (3/16,304), which is below the rate reported in a meta-analysis of 0.056% (Fileta, Scott, & Flynn, 2014).

References

Bashshur, Z. F., Haddad, Z. A., Schakal, A., Jaafar, R. F., Saab, M., & Noureddin, B. N. (2008). Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. American Journal of Ophthalmology, 145, 249-256.
Cackett, P., Yeo, I., Cheung, C. M., Vithana, E. N., Wong, D., Tay, W. T., … Wong, T. Y. (2011). Relationship of smoking and cardiovascular risk factors with polypoidal choroidal vasculopathy and age-related macular degeneration in Chines persons. Ophthalmology, 118, 846-852.
Cheung, C. M., Bhargava, M., Laude, A., Koh, A. C., Xiang, L., Wong, D.,… Wong, T. Y. (2012). Asian age-related macular degeneration phenotyping study: rationale, design and protocol of a prospective cohort study. Clinical & Experimental Ophthalmology, 40, 727-735.
Cheung, C. M., Laude, A., Yeo, I., Tan, S. P., Fan, Q., Mathur, R.,… Wong, T. Y. (2017). Systemic, ocular and genetic risk factors for age-related macular degeneration and polypoidal choroidal vasculatopathy in Singaporeans. Scientific Reports. Doi: 10,1038/srep41386
Cheung, C. M., Li, X., Mathur, R., Lee, S. Y., Chan, C. M., Yeo, I.,…Wong, T. Y. (2014). A prospective study of treatment patterns and 1-year outcome of Asian age-related macular degeneration and polypoidal choroidal vasculopathy. PLoS One, 9, e101057.
Cohen, S. Y., Dubois, L., Tadayoni, R., Fajnkuchen, F., Nghiem-Buffet, S., Delahaye-Mazza, C.,… Quentel, G. (2009). Results of one-year’s treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting. American Journal of Ophthalmology, 148, 409-413.
Curtis, L. H., Hammill, B. G., Qualls, L, G., DiMartino, L. D., Wang, F., Schulman, K. A., & Cousins, S. W. (2012). Treatment patterns for neovascular age-related macular degeneration: analysis of 284 380 medicare beneficiaries. American Journal of Ophthalmology, 153, 1116-1124.
Fileta, J. B., Scott, I. U., & Flynn, H. W. Jr. (2014). Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surgery, Lasers and Imaging Retina, 45, 143-149.
Finger, R. P., Wiedemann, P., Blumhagen, F., Pohl, K., & Holz, F.G. (2013). Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study – a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany. Acta Ophthalmologica, 91, 540-546.
Hjelmqvist, L., Lindberg, C., Kanulf, P., Dahlgren, H., Johansson, I., & Siewert, A. (2011). One-year outcomes using ranibizumab for neovascular age-related macular degeneration: results of a prospective and retrospective observational multicentre study. Journal of Ophthalmology. Doi: 10.1155/2011/405724
Holz, F. G., Bandello, F., Gillies, M., Mitchell, P., Osborne, A., Sheidown, T.,…Figueroa, M. S. (2013). Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme. British Journal of Ophthalmology, 97, 1161-1167.
Kang, S., & Roh, Y. J. (2011). Ranibizumab treatment administered as needed for occult and minimally classic neovascular membranes in age-related macular degeneration. Japanese Journal of Ophthalmology, 55, 123-127.
Ng, W. Y., Cheung, C. M., Mathur, R., Chan, C. M., Yeo, I. Y., Wong, E.,… Wong, T. Y. (2014). Trends in age-related macular degeneration management in Singapore. Optometry & Visual Science, 91, 872-877.
Ng, W. Y., Tan, G. S., Ong, P. G., Cheng, C. Y., Cheung, C. Y., Wong, D. W.,… Cheung, G. C. (2015). Incidence of myocardial infarction, stroke, and death in patients with age-related macular degeneration treatd with intravitrel anti-vascular endothelial growth factor therapy. American Journal of Ophthalmology, 159, 557-564.
Pushpoth, S., Sykakis, E., Merchant, K., Browning, A. C., Gupta, R., & Talks, S. J. (2012). Measuring the benefit of 4 years of intravitreal ranibizumab treatment for neovascular age-related macular degeneration. British Journal of Ophthalmology, 96, 1469 – 1473.
Rakic, J. M., Leys, A., Brie, H., Denhaerynck, K., Pacheco, C., Vancayzeele S.,…Abraham, I. (2013). Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study. Clinical Ophthalmology, 7, 1849-1858.
Rosefield, P. J., Brown, D. M., Heier, J. S., Boyer, D. S., Kaiser, P. K., Chung, C. Y.,… Kim, R. Y. (2006). Ranibizumab for neovascular age-related macular degeneration. The New England Journal of Medicine, 355, 1419-1431.
Ting, D. S., Ng. W. Y., Ng, S. R., Tan, S. P., Yeo, I. Y., Mathur, R.,…Cheung, C. M. (2016). Choroidal thickness changes in age-related macular degeneration and polypoidal choroidal vasculopathy: a 12-month prospective study. American Journal of Ophthalmology, 164, 128-136.

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