Intravitreal triamcinolone acetonide for exudative age related macular degeneration

J B Jonas; I Kreissig; P Hugger; G Sauder; S Panda-Jonas; R Degenring

doi:10.1136/bjo.87.4.462

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Intravitreal triamcinolone acetonide for exudative age related macular degeneration

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Authors' reply to Wong et al.
Jost B. Jonas
Published on: 9 July 2003
Author's reply to Bhatt
Jost B. Jonas
Published on: 9 July 2003
Are we overlooking the side-effects of the drugs in our zeal to conquer ARMD?
Uday K Bhatt
Published on: 21 May 2003
Re: Intravitreal triamcinolone acetonide for exudative age-related macular degeneration
David Wong
Published on: 21 May 2003

Published on: 9 July 2003
Authors' reply to Wong et al.
- Jost B. Jonas
Dear Editor
We thank Dr Wong and colleagues very much for their interest in our study,[1] we agree with them that comparing a single preoperative measurement with the best out of a series of postoperative measurements gives a tendency towards a falsely high increase in visual acuity after the triamcinolone acetonide injection. That there was an increase in visual acuity after the injection in some patients, howeve...
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Dear Editor
We thank Dr Wong and colleagues very much for their interest in our study,[1] we agree with them that comparing a single preoperative measurement with the best out of a series of postoperative measurements gives a tendency towards a falsely high increase in visual acuity after the triamcinolone acetonide injection. That there was an increase in visual acuity after the injection in some patients, however, may have been demonstrated in Table 1 giving the visual acuity measurements prior to, and after, the application of triamcinolone acetonide. At 1 and 2 months, the difference to the preoperative values was significant with a p-values of 0.04. Unfortunately, the values are described as non significant what is a typographical error in the manuscript. I regret this fault. The authors agree with Dr Wong and colleagues, that the effect of triamcinolone acetonide is temporary, and that repeated injections may be necessary. In some patients, repeated intravitreal injections of triamcinolone acetonide were associated with repeated re-increase in visual acuity.[2]
We also agree with Dr Wong and coworkers, that comparing the preoperative intraocular pressure measurement with the highest value during the follow-up again falsely increased the number of ocular hypertensive subjects after the injection. In this matter, however, it was not in favour of the treatment modality since it artificially increased the number of patients with unwanted side-effects. Concerning the number of patients with very high intraocular pressure values after the injection, a preliminary analysis shows that about 1% of the eyes injected will need filtering surgery (own data).
The authors would like to thank Dr Wong and colleagues for constructively commenting on the study and pointing out, as did the authors, that the intravitreal injection of triamcinolone acetonide as treatment of exudative macular degeneration is still in clinical evaluation and that its therapeutic effect has not been proved so far. This may be even more important, as a recent randomised study using 4 mg of triamcinolone acetonide did not demonstrate an effect on the risk of loss of visual acuity during the first year of the study in eyes with classic choroidal neovascularization.[3] A significant antiangiogenic effect, however, was found 3 months after treatment. In view of the anti- angiogenic, anti-inflammatory and anti-oedematous effect of intravitreal triamcinolone, it may show that further randomised trials using different dosages of triamcinolone acetonide in eyes with different types of subfoveal neovascularization may be warranted.
References
(1) Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol 2003;87:24-7.
(2) Jonas JB, Kreissig I, Degenring RF. Repeated intravitreal injections of triamcinolone acetonide as treatment of progressive exudative age-related macular degeneration. Graef Arch Clin Exp Ophthalmol 2002;240:873-4.
(3) Gillies MC, Simpson JM, Luo W, et al. A randomised clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: one-year results. Arch Ophthalmol 2003;121:667-73.
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Conflict of Interest:
None declared.
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Published on: 9 July 2003
Author's reply to Bhatt
- Jost B. Jonas
Dear Editor
We thank Dr Bhatt for his letter and his interest in our study.[1]
1. We completely agree with him that the steroid induced rise in intraocular pressure as the one of the most frequently encountered side- effects of intravitreal triamcinolone acetonide can be of major concern. In a recent study, an increase intraocular pressure after an intravitreal injection of 25 mg triamcinolone acetonide...
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Dear Editor
We thank Dr Bhatt for his letter and his interest in our study.[1]
1. We completely agree with him that the steroid induced rise in intraocular pressure as the one of the most frequently encountered side- effects of intravitreal triamcinolone acetonide can be of major concern. In a recent study, an increase intraocular pressure after an intravitreal injection of 25 mg triamcinolone acetonide was found in about 50% of the eyes injected.[2] In the majority of them, intraocular pressure could be normalized by topical antiglaucomatous medication without development of glaucomatous changes of the optic nerve head. About 1% of the eyes, however, had to undergo filtering surgery since intraocular pressure was elevated to values higher than 40 mm Hg despite maximal medical treatment. It has remained unclear yet, whether frequency and amount of the rise in intraocular pressure are dependent on the dosage of triamcinolone injected. It may be a topic of future studies.
The question of the best dosage of intravitreal triamcinolone acetonide as treatment of exudative age-related macular degeneration has not been answered, yet, let alone the question whether intravitreal triamcinolone acetonide is at all helpful for therapy of exudative age- related macular degeneration. Recently, Gillies and colleagues published the one-year results of their randomised clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration.[3] Using a dosage of 4 mg triamcinolone acetonide, they found that a single dose of intravitreal triamcinolone had no effect on the risk of loss of visual acuity during the first year of the study in eyes with classic choroidal neovascularization, despite a significant antiangiogenic effect found 3 months after treatment. The experiences of Gillies and coworkers may be reason to use a higher dosage of triamcinolone acetonide in a treatment trial of exudative age-related macular degeneration.
2. Without doubt, intravitreal steroids increase cataract formation and lead to earlier cataract surgery. The possible phototoxicity of ultraviolet radiation after cataract surgery, however, may not be reason not to inject triamcinolone acetonide intravitreally since phototoxicity may take a relatively long time to develop, and because some intraocular lenses can provide some protection against phototoxicity by filtering the ultraviolet radiation.
3. The authors completely agree with Dr Bhatt, that one of the mechanisms by which intravitreal triamcinolone may possibly be helpful in the treatment of exudative age-related macular degeneration is its anti- inflammatory effect. Another reason could be a direct anti- angioproliferative effect which has been found in in-vitro studies on bovine retinal endothelial cells (own data). The authors also agree with Dr. Bhatt that repetitive injections of triamcinolone acetonide may be necessary as has been suggested.[4]
References
(1) Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol 2003;87:24-7.
(2) Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol 2003;87:24-7.
(3) Gillies MC, Simpson JM, Luo W, et al. A randomised clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: one-year results. Arch Ophthalmol 2003; 121:667-73.
(4) Jonas JB, Kreissig I, Degenring RF. Repeated intravitreal injections of triamcinolone acetonide as treatment of progressive exudative age-related macular degeneration. Graef Arch Clin Exp Ophthalmol 2002;240:873-4.
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Conflict of Interest:
None declared.
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Published on: 21 May 2003
Are we overlooking the side-effects of the drugs in our zeal to conquer ARMD?
- Uday K Bhatt, Senior House Officer - Ophthalmology
Dear Editor
First of all let me congratulate the authors for their work on exudative ARMD. But there are still some issues which need to be brought into account:
1. Some published studies show that even 4.0 mg of intravitreal triamcinolone has significant side effects in terms of increased IOP and more so for eyes which needed the second dose of the triamcinolone, with a few of them even needing a filtratio...
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Dear Editor
First of all let me congratulate the authors for their work on exudative ARMD. But there are still some issues which need to be brought into account:
1. Some published studies show that even 4.0 mg of intravitreal triamcinolone has significant side effects in terms of increased IOP and more so for eyes which needed the second dose of the triamcinolone, with a few of them even needing a filtration surgery. In this particular study however 25mg of Triamcinolone has been used which may cause even more increased elevation of IOP. This issue is an important one as many of our ARMD patients have co-existing chronic open angle glaucoma with a compromised blood supply of the optic nerve head. With the intravitreal steroids induced rise in IOP, we may tilt the balance on the wrong side thereby taking their peripheral vision along-with the central loss due to the ARMD. [1,2,5]
2. The effect of intravitreal steroids in the progression of cataract is not very much emphasized in various studies. If earlier cataract surgery in treated ARMD patients is required, this has theoretical implications in terms of ultraviolet light exposure, one of the environmental factors implicated in ARMD. If there is no long term benefit for preventing the progression of ARMD with the steroids then why should we increase the chances of cataract in these patients thereby rendering their retinas more vulnerable to damage caused by the UV radiation?[2]
3. Various in-vitro studies suggest that down-regulation of inflammatory markers and changes in the endothelial cell permeability are probably the modes of action of triamcinolone in exudative ARMD, but all these actions are probably only for the duration when the steroids are in high concentration in the vicinity. To maintain high concentrations triamcinolone should be injected repeatedly and probably that is the reason the improvement fades with time in many patients. Moreover none of the studies published so far have been long enough to actually give a fair idea about the long term outcome. The longest duration for which the follow up has been done is 18 months. [3,4]
We need data from multicenter, placebo-controlled trials on a much larger population with long-term follow-up to establish the efficacy of the drug and assess possible side effects and complications. Until then we should probably reserve this therapy for those cases where there is recurrence after laser treatment.[5]
References
(1) Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina 2000; 20(3):244-50.
(2) Challa JK, Gillies MC, Penfold PL, Gyory JF, Hunyor AB, Billson FA. Exudative macular degeneration and intravitreal triamcinolone: 18 month follow up. Aust N Z J Ophthalmol. 1998 Nov;26(4):277-81.
(3) Penfold PL, Gyory JF, Hunyor AB, Billson FA. Exudative macular degeneration and intravitreal triamcinolone. A pilot study. Aust N Z J Ophthalmol 1995 Nov;23(4):293-8.
(4) Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol 2003 Jan;87(1):24-7.
(5) Ranson NT, Danis RP, Ciulla TA, Pratt L. Intravitreal triamcinolone in subfoveal recurrence of choroidal neovascularisation after laser treatment in macular degeneration. Br J Ophthalmol 2002 May; 86(5):527-9.
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Conflict of Interest:
None declared.
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Published on: 21 May 2003
Re: Intravitreal triamcinolone acetonide for exudative age-related macular degeneration
- David Wong, Ophthalmologist
- Other Contributors:
  Ian Campbell, Carl Groenewald, Elizabeth Lancaster
Dear Editor
We read the article on intravitreal triamcinolone injections for exudative age-related macular degeneration with interest.[1] The paper stated that visual acuity increased significantly (p...
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Dear Editor
We read the article on intravitreal triamcinolone injections for exudative age-related macular degeneration with interest.[1] The paper stated that visual acuity increased significantly (p<_0.001 from="from" _0.16="_0.16" _0.11="_0.11" to="to" a="a" mean="mean" maximum="maximum" of="of" _0.23="_0.23" _0.17.="_0.17." the="the" authors="authors" therefore="therefore" picked="picked" best="best" one="one" up="up" _10="_10" postoperative="postoperative" visual="visual" acuity="acuity" measurements="measurements" and="and" compared="compared" it="it" with="with" single="single" preoperative="preoperative" measurement.="measurement." this="this" is="is" misleading="misleading" reader="reader" regarding="regarding" true="true" effectiveness="effectiveness" treatment.="treatment." p="p"/> The Macular Photocoagulation Study Group found that the differences in between two repeated tests was one line or more in 13% of cases and the differences were greatest in patients with visual acuity of 20/100 or worse.[2] By taking up to 10 postoperative measurements, Jonas et al. greatly increased the chances of a positive result. The difference between mean pre-injection 0.16 (20/125 or 6/36) and best mean postoperative 0.23 (20/87 or 6/26) was less than one line on the Snellen chart.
Table 1 gave the mean visual acuity pre-injection and at various time intervals post-injection. At 1 and 2 months, the p values were 0.04. It was unclear whether the p values were one or two tailed but both were described as not significant (NS) in table 1. Multiple significance testing at each of a number of time points is generally not recommended - if it is done, some kind of adjustment to the p values is needed.[3,4] Looking at the results presented table 1, the readers might conclude that triamcinolone had a transient and doubtful beneficial effect on the visual acuity.
The authors go on to further analyse the results into improvements of 3 and 6 or more lines. The vision was tested on a Snellen chart which has irregular steps. Three or 6 lines do not therefore represent a constant change in visual angle (as in a logMAR chart) and therefore the analysis was confusing.
Variations in intraocular pressure of 5 or 6 mmHg occur diurnally in normal individuals as well as glaucomatous patients.[5-7] Whilst there is little doubt that triamcinolone may affect the intraocular pressure, the comparison of the baseline with the highest (p<_0.001 was="was" misleading="misleading" as="as" the="the" comparison="comparison" of="of" highest="highest" with="with" that="that" at="at" _7="_7" months="months" p0.001.="p0.001." more="more" interest="interest" might="might" be="be" number="number" patients="patients" who="who" had="had" very="very" high="high" levels="levels" range="range" extended="extended" to="to" _64="_64" mmhg="mmhg" and="and" whether="whether" these="these" intraocular="intraocular" pressures="pressures" responded="responded" treatment.="treatment." p="p"/> The authors’ experience in using triamcinolone is well recognised. We congratulate them on an otherwise excellent piece of work.
References
(1) Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol 2003;87(1):24-7.
(2) Blackhurst DW, Maguire MG. Reproducibility of refraction and visual acuity measurement under a standard protocol. The Macular Photocoagulation Study Group. Retina 1989;9(3):163-9.
(3) Altman DG. Practical Statistics for Medical Research. London: Chapman and Hall, 1991.
(4) Matthews R. The numbers don't add up. New Scientist 2003;177(2385):28.
(5) Pointer JS. The diurnal variation of intraocular pressure in non- glaucomatous subjects: relevance in a clinical context. Ophthalmic Physiol Opt 1997;17(6):456-65.
(6) De_Vivero C, O_Brien C, Lanigan L, Hitchings R. Diurnal intraocular pressure variation in low-tension glaucoma. Eye 1994;8(Pt5):521-3.
(7) Smith J. Diurnal intraocular pressure. Correlation to automated perimetry. Ophthalmology 1985;92(7):858-61.
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Conflict of Interest:
None declared.
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