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Treat-and-extend-protokolla kostean AMD:n hoidossa

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Jorma Komulainen

Ns. Treat-and-extend-hoitoprotokollan vaikuttavuudesta verrattuna säännöllisiin VEGF-estäjähoitoihin ei ole tehty satunnaistettuja kontrolloituja tutkimuksia. Havainnoivien prospektiivisten ja retrospektiivisten tutkimusten perusteella näyttää kuitenkin siltä, että treat-and-extend-protokollalla voidaan saada PRN- ja fixed-protokollan kanssa vastaavia useita vuosia säilyviä tuloksia näön paranemisen ja säilymisen suhteen. Kansainvälisen asiantuntijaryhmän konsensussuosituksen mukaan OCT-seurannan perusteella ohjattu treat-and-extend-protokolla on käyttökelpoinen kostean AMD:n VEGF-estäjähoidon yksilöllisessä toteutuksessa.

A recent observational study, based on the Fight Retinal Blindness observational registry, reports the24-month outcomes of anti-vascular endothelial growth factor (VEGF) therapy for treatment-naive eyes with neovascular age-related macular degeneration (nAMD) using a treat and extend treatment regimen in routine clinical practice «Arnold JJ, Campain A, Barthelmes D ym. Two-year ou...»1. A cohort of eyes treated by practitioners using exclusively a treat and extend regimen was extracted from the registry. Data from 1198 eyes from 1011 patients receiving anti-VEGF therapy using a treat and extend regimen for treatment-naive nAMD between January 2007 and December 2012 and with 24-month follow-up were included in the analysis. Mean VA increased by +5.3 logarithm of the minimum angle of resolution letters from 56.5 letters (20/80+1) at initial visit to 61.8 (20/60+2) letters at 24 months. Mean VA gains improved and number of injections increased with successive years from +2.7 letters for eyes commencing in 2007 after a mean of 9.7 injections in 2 years, to +7.8 letters for eyes commencing in 2012 after a mean of 14.2 injections over 2 years. The proportion of eyes with VA >20/40 increased from 27% when starting treatment to 45% after 24 months; the proportion with vision of /=15 letters. There was an overall mean of 13.0 injections over the 24 months, 7.5 injections in the first year and 5.5 in the second year, with a mean of 14.8 clinic visits.

A randomized multicenter study compared the efficacy and safety of bevacizumab versus ranibizumab when administered according to a treat-and-extend protocol for the treatment of neovascular AMD «Berg K, Pedersen TR, Sandvik L ym. Comparison of r...»2. Altogether 441 patients aged 50 years or more with previously untreated neovascular AMD in 1 eye and best-corrected visual acuity (BCVA) between 20/25 and 20/320 were included and randomized to receive either bevacizumab 1.25 mg or ranibizumab 0.5 mg. Monthly injections were given until inactive disease was achieved. The patients were then followed with a gradual extension of treatment interval by 2 weeks at a time up to a maximum of 12 weeks. If signs of recurrent disease appeared, the treatment interval was shortened by 2 weeks at a time. The 1-year visit was completed by 371 patients. In the per protocol analysis at 1 year, bevacizumab was equivalent to ranibizumab, with 7.9 and 8.2 mean letters gained, respectively (95% confidence interval [CI] of mean difference, -2.4 to 2.9; P = 0.845). The intention-to-treat analysis was concordant. There was a statistically significant difference (P = 0.001) between the drugs regarding the number of treatments: 8.9 for bevacizumab and 8.0 for ranibizumab. There were fewer arteriothrombotic events in the bevacizumab group (1.4%) than in the ranibizumab group (4.5%) (P = 0.050) and significantly more cardiac events in the ranibizumab group (P = 0.036). However, patients treated with ranibizumab more often had a history of myocardial infarction (P = 0.021).

To determine 3-year outcomes, a retrospective consecutive case series of 212 eyes from 196 patients diagnosed with treatment-naive neovascular AMD and treated with either ranibizumab or bevacizumab for a minimum of 1 year, using a treat-and-extend regimen was conducted «Rayess N, Houston SK 3rd, Gupta OP ym. Treatment o...»3. The mean follow-up period was 1.88 years (median, 2 years). At baseline, mean BCVA was 20/139; it improved to 20/79 (P < 0.001) after 1 year of treatment and was maintained at 20/69 and 20/64 at 2 and 3 years follow-up (P < 0.001), respectively. At baseline, mean central retinal thickness was 351 μm and significantly decreased to 285 μm, 275 μm and 276 μm at 1, 2 and 3 years of follow-up (P < 0.001), respectively. Patients received, on average, 7.6, 5.7 and 5.8 injections over years 1, 2 and 3 of treatment, respectively. At final follow-up, 94% of eyes had lost <3 lines BCVA, and 34.4% of eyes had gained ≥ 3 lines BCVA.

To evaluate 2-year visual acuity outcome of a treat-and-extend protocol of anti-vascular endothelial growth factor treatment in age-related macular degeneration, a prospective cohort study with 120 age-related macular degeneration patients with choroidal neovascularization was contucted «Abedi F, Wickremasinghe S, Islam AF ym. Anti-VEGF ...»4. Patients received 3 initial monthly ranibizumab or bevacizumab injections; monthly injections were continued until there was no choroidal neovascularization activity (subretinal/intraretinal fluid, loss of >5 letters, or persistent/recurrent retinal hemorrhage). When there was no choroidal neovascularization activity, the interval to the next visit/injection was extended by 2 weeks to a maximum of 12 weeks. In the presence of choroidal neovascularization activity, this interval was shortened by 2 weeks. Mean baseline visual acuity was 51.2 +/- 12.1 Early Treatment Diabetic Retinopathy Study scores. Mean visual acuity change from baseline was +9.5 +/- 10.9 and +8.0 +/- 12.9 letters after 12 months and 24 months, respectively, with, on average, 8.6 +/- 1.1 visits/injections in the first year and 5.6 +/- 2.0 in the second year. After 12 months and 24 months, 97.5% and 95.0% of patients, respectively, lost <15 letters.

An international group of specialists reviewed the literature and suggested consensus recommendations for treat-and-extend regimens (TERs) with anti-VEGF agents in retinal diseases «Freund KB, Korobelnik JF, Devenyi R ym. TREAT-AND-...»5. According to them, TER is defined as an individualized proactive dosing regimen usually initiated by monthly injections until a maximal clinical response is observed (frequently determined by optical coherence tomography), followed by increasing intervals between injections (and evaluations) depending on disease activity. The TER regimen has emerged as an effective approach to tailoring the dosing regimen and for reducing treatment burden (visits and injections) compared with fixed monthly dosing or monthly visits with optical coherence tomography-guided regimens (as-needed or pro re nata). It is also considered a suitable approach in many retinal diseases managed with intravitreal anti-vascular endothelial growth factor therapy, given that all eyes differ in the need for repeat injections.


  1. Arnold JJ, Campain A, Barthelmes D ym. Two-year outcomes of "treat and extend" intravitreal therapy for neovascular age-related macular degeneration. Ophthalmology 2015;122:1212-9 «PMID: 25846847»PubMed
  2. Berg K, Pedersen TR, Sandvik L ym. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology 2015;122:146-52 «PMID: 25227499»PubMed
  3. Rayess N, Houston SK 3rd, Gupta OP ym. Treatment outcomes after 3 years in neovascular age-related macular degeneration using a treat-and-extend regimen. Am J Ophthalmol 2015;159:3-8.e1 «PMID: 25217859»PubMed
  4. Abedi F, Wickremasinghe S, Islam AF ym. Anti-VEGF treatment in neovascular age-related macular degeneration: a treat-and-extend protocol over 2 years. Retina 2014;34:1531-8 «PMID: 24637667»PubMed
  5. Freund KB, Korobelnik JF, Devenyi R ym. TREAT-AND-EXTEND REGIMENS WITH ANTI-VEGF AGENTS IN RETINAL DISEASES: A Literature Review and Consensus Recommendations. Retina 2015;35:1489-506 «PMID: 26076215»PubMed