Aim. To evaluate the efficacy and safety of bevacizumab monotherapy or bevacizumab combined with focal / grid laser compared with focal / grid laser alone for treatment of diabetic macular edema (DME). Methods. One hundred twelve eligible patients, aged? 18 years, with type 1 or 2 diabetes mellitus and best correctedvisual acuity (BCVA) in the study eye of 35 to 69 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 4 m (Snellenequivalent:? 6/60 or? 6/12), with visual impairment due to center-involved diabetic macular edema (DME). Patients wererandomized into three treatment groups: (I) intravitreal bevacizumab monotherapy (n = 42), (II) intravitreal bevacizumabcombined with laser (n = 35), (III) laser monotherapy (n = 35). Bevacizumab injections were given for 3 initial monthly dosesand then pro re nata (PRN) thereafter based on BCVA stability and DME progression. The primary efficacy endpoints werethe meanchange in BCVA and central retinal subfield thickness (CRST) from baseline to month 12. Results. Bevacizumab monotherapy or bevacizumab + laser were superior to laser monotherapy in improving the meanchange in BCVA letter score from baseline to month 12 (+8.3 and +11.3 vs +1.1 letters; both p<0.0001). At month 12, agreater proportion of patients gained? 10 and? 15 letters and with BCVA letter score >73 (Snellen equivalent: >6/12) withbevacizumab monotherapy (23.8% and 7.1% and 4.8%, respectively) and bevacizumab + laser (57.1% and 28.6% and 14.3%, respectively) versus laser monotherapy (0% and 0% and 0%). The mean central retinal subfield thickness was significantlyreduced from baseline to month 12 with bevacizumab (-124.4? M) and bevacizumab + laser (-129.0? m) versus laser (-62.0? m; both p = 0.002). Conjunctival hemorrhage was the most common ocular events. No endophthalmitis cases occurred. Conclusion. Bevacizumab monotherapy or bevacizumab + laser showed superior BCVA improvements over macularlaser treatment alone in Mongolian patients with visual impairment due to diabetic macular edema.

Анотація наукової статті за медичними технологіями, автор наукової роботи - Anaraa Toishubai, Uranchimeg Davaatseren, Baasankhuu Jamyanjav, Lim Sun Taek, Munkhzaya Tsengenbayar


Рандомізоване дослідження, що порівнює інтравітреального бевацизумаб і фокусну лазерну фотокоагуляцію при діабетичної макулопатіі

Мета: оцінити ефективність і безпеку монотерапії бевацизумабом або бевацизумабом в поєднанні з фокальним / сітковим лазером в порівнянні з терапією тільки фокальним / сітковим лазером для лікування діабетичної макулопатіі (ДМ). Матеріали та методи. 112 підходять для дослідження пацієнтів у віці? 18 років з цукровим діабетом 1 або 2 типу та максимально коригувати гостротою зору (МКОЗ) в досліджуваному оці від 35 до 69 букв на відстані 4 м відповідно до дослідження раннього лікування діабетичної ретинопатії (Etdrs) (еквівалент Снеллена:? 6/60 або? 6/12), з порушеннями зору через діабетичної макулопатіі із залученням центру макули (дм). Пацієнти були довільно розділені на три групи лікування: (I) інтравітреального монотерапія бевацизумабом (N = 42), (II) інтравітреального терапія бевацизумабом в поєднанні з лазером (n = 35), (III) лазерна монотерапія (n = 35). ін'єкцій бевацизумабу призначене за 3 початкових щомісячних дози, а потім у міру необходімостіна підставі стабільності мкоз і прогресування дм. кінцевими показниками первинної еффектівностібилі середня зміна МКОЗ і товщина центральної області сітківки (CRST) від вихідного етапу до 12-го місяця. Результати. монотерапія бевацизумабом або бевацизумаб + лазер перевершили лазерну монотерапию в підвищенні показників середнього зміни за кількістю букв при мкоз з вихідного рівня до 12 місяці (+ 8,3і +11,3 проти +1,1 букв; обидва р<0,0001). на 12-му місяці велика частина пацієнтів домоглася показника? 10 і? 15букв і показника при МКОЗ >73 (еквівалент Снеллена: >6/12) з монотерапією бевацизумабом (23,8%, 7,1% і 4,8% відповідно), з терапією бевацизумаб + лазер (57,1%, 28,6% і 14,3% відповідно) в порівнянні з лазерноймонотерапіей (0% і 0% і 0%). Середня товщина центральної області сітківки була значно зменшена отісходного рівня до 12 місяця на терапії бевацизумабом (-124,4 мкм) і терапії бевацизумаб + лазер (-129,0 мкм) в порівнянні з монотерапією лазером (-62,0 мкм; обидва р = 0,002). кон'юнктивальна крововилив було найбільш поширеним явищем. Випадків ендофтальміту не було. Висновок. результати монотерапії бевацизумабом або бевацизумаб+лазер перевершили лазерну монотерапию в поліпшенні МКОЗ у монгольських пацієнтів з порушеннями зору через діабетичної макулопатіі.


Область наук:
  • Медичні технології
  • Рік видавництва: 2019
    Журнал: Сибірський медичний журнал (Іркутськ)
    Наукова стаття на тему 'A RANDOMIZED TRIAL COMPARING INTRAVITREAL BEVACIZUMAB AND FOCAL LASER PHOTOCOAGULATION FOR DIABETIC MACULAR EDEMA'

    Текст наукової роботи на тему «A RANDOMIZED TRIAL COMPARING INTRAVITREAL BEVACIZUMAB AND FOCAL LASER PHOTOCOAGULATION FOR DIABETIC MACULAR EDEMA»

    ?© Анараїт тойшубай, уранчімег даваацерен, баасанхуу жамьянжай, сун таєк лим, мунхзайа ЦЕНГЕНБАЯР,

    МУНХХІШІГ БАТБІЛЕГ, ОЮНЗАЯА ЛУВСАНЦЕРЕН, УРАНГУА ЖАМЬЯНСУРЕН, ХУДЕРЧУЛУУН НАНЖІД, АЛТАНСАЙХАН ХАСАГ - 2019 УДК: 617.735-002-002 DOI: 10.34673 / ismu.2019.41.16.005

    рандомізоване дослідження, що порівнює інтравітреального бевацизумаб і фокусну лазерну фотокоагуляцію при діабетичної макулопатіі

    Анараїт Тойшубай1, Уранчімег Даваацерен2, Баасанхуу Жамьянжай2, Сун Таєк Лім3, Мунхзайа Ценгенбаяр1, Мунххішіг Батбілег1, Оюнзаяа Лувсанцерен1, Урангуа Жамьянсурен1, Худерчулуун Нанжід4, Алтансайхан Хасаг5 ( 'Очна клініка Сондра, Улан-Батор, Монголія; 2Кафедра офтальмології, Медичний факультет, МНМУ,

    Улан-Батор, Монголія; 3Глазная клініка Парансе, Кванджу, Південна Корея; ^ Department of Epidemiology and Biostatistics Кафедра епідеміології та біостатистики, Медичний факультет, МНМУ, Улан-Батор, Монголія;

    5Медіцінскій факультет, МНМУ, Улан-Батор, Монголія)

    Резюме. Мета: оцінити ефективність і безпеку монотерапії бевацизумабом або бевацизумабом в поєднанні з фокальним / сітковим лазером в порівнянні з терапією тільки фокальним / сітковим лазером для лікування діабетичної макулопатіі (ДМ).

    Матеріали та методи. 112 підходять для дослідження пацієнтів у віці >18 років з цукровим діабетом 1 або 2 типу та максимально коригувати гостротою зору (МКОЗ) в досліджуваному оці від 35 до 69 букв на відстані 4 м відповідно Дослідження раннього лікування діабетичної ретинопатії (ETDRS) (еквівалент Снеллена: >6/60 або <6/12), з порушеннями зору через діабетичної макулопатіі з залученням центру макули (ДМ). Пацієнти були довільно розділені на три групи лікування: (I) інтравітреального монотерапія бевацизумабом (n = 42), (II) інтравітреального терапія бевацизумабом в поєднанні з лазером (n = 35), (III) лазерна монотерапія (n = 35). Ін'єкцій бевацизумабу призначено по 3 початкових щомісячних дози, а потім у міру необхідності на підставі стабільності МКОЗ і прогресування ДМ. Кінцевими показниками первинної ефективності були середня зміна МКОЗ і товщина центральної області сітківки (CRST) від вихідного етапу до 12-го місяця.

    Результати. Монотерапія бевацизумабом або бевацизумаб + лазер перевершили лазерну монотерапию в підвищенні показників середнього зміни за кількістю букв при МКОЗ з вихідного рівня до 12 місяці (+8,3 і +11,3 проти +1,1 букв; обидва р<0,0001). На 12-му місяці велика частина пацієнтів домоглася показника >10 і >15 букв і показника при МКОЗ >73 (еквівалент Снеллена: >6/12) з монотерапією бевацизумабом (23,8%, 7,1% і 4,8% відповідно), з терапією бевацизумаб + лазер (57,1%, 28,6% і 14,3% відповідно) в порівнянні з лазерної монотерапией (0% і 0% і 0%). Середня товщина центральної області сітківки була значно зменшена від вихідного рівня до 12 місяця на терапії бевацизумабом (-124,4 мкм) і терапії бевацизумаб + лазер (-129,0 мкм) в порівнянні з монотерапією лазером (-62,0 мкм; обидва р = 0,002). Кон'юнктивальна крововилив було найбільш поширеним явищем. Випадків ендофтальміту не було.

    Висновок. Результати монотерапії бевацизумабом або бевацизумаб + лазер перевершили лазерну монотерапию в поліпшенні МКОЗ у монгольських пацієнтів з порушеннями зору через діабетичної макулопатіі.

    Ключові слова: діабетична макулопатія; діабетична ретинопатія; фактор росту судинного ендотелію; бевацизумаб.

    А RANDoMizED TRIAL coMpARiNG INTRAviTREAL BEvAGzuMAB AND FocAL LAsER pHoTocoAGuLATioN for diabetic macular edema

    Anaraa Toishubai1, Uranchimeg Davaatseren2, Baasankhuu Jamyanjav2, Sun Taek Lim3, Munkhzaya Tsengenbayar1, Munkhkhishig Batbileg1, Oyunzaya Luvsantseren1, Urangua Jamyansuren1, Khuderchuluun Nanjid4, Altaisaikhan Khasag5 OSondra Eye Clinic, Ulaanbaatar, Mongolia; ^ Department of Ophthalmology, School of Medicine, MNUMS, Ulaanbaatar, Mongolia; 3Paransae Eye Clinic, Gwangju, South Korea; 4Department of Epidemiology and Biostatistics, School of Medicine, MNUMS, Ulaanbaatar, Mongolia; 5School of Medicine, MNUMS, Ulaanbaatar, Mongolia)

    Summary. Aim: To evaluate the efficacy and safety of bevacizumab monotherapy or bevacizumab combined with focal / grid laser compared with focal / grid laser alone for treatment of diabetic macular edema (DME).

    Methods. One hundred twelve eligible patients, aged >18 years, with type 1 or 2 diabetes mellitus and best corrected visual acuity (BCVA) in the study eye of 35 to 69 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 4 m (Snellen equivalent: >6/60 or <6/12), with visual impairment due to center-involved diabetic macular edema (DME). Patients were randomized into three treatment groups: (I) intravitreal bevacizumab monotherapy (n = 42), (II) intravitreal bevacizumab combined with laser (n = 35), (III) laser monotherapy (n = 35). Bevacizumab injections were given for 3 initial monthly doses and then pro re nata (PRN) thereafter based on BCVA stability and DME progression. The primary efficacy endpoints were the meanchange in BCVA and central retinal subfield thickness (CRST) from baseline to month 12.

    Results. Bevacizumab monotherapy or bevacizumab + laser were superior to laser monotherapy in improving the mean change in BCVA letter score from baseline to month 12 (+8.3 and +11.3 vs +1.1 letters; both p<0.0001). At month 12, a greater proportion of patients gained >10 and >15 letters and with BCVA letter score >73 (Snellen equivalent: >6/12) with bevacizumab monotherapy (23.8% and 7.1% and 4.8%, respectively) and bevacizumab + laser (57.1% and 28.6% and 14.3%, respectively) versus laser monotherapy (0% and 0% and 0%). The mean central retinal subfield thickness was significantly reduced from baseline to month 12 with bevacizumab (-124.4 | im) and bevacizumab + laser (-129.0 | im) versus laser (-62.0 | im; both p = 0.002). Conjunctival hemorrhage was the most common ocular events. No endophthalmitis cases occurred.

    Conclusion. Bevacizumab monotherapy or bevacizumab + laser showed superior BCVA improvements over macular laser treatment alone in Mongolian patients with visual impairment due to diabetic macular edema.

    Key words: diabetic macular edema; diabetic retinopathy; vascular endothelial growth factor; bevacizumab.

    Diabetic retinopathy is the most common microvascular complication of diabetes mellitus and the leading cause of blindness in working-age adults in the United States, Europe, and increasingly worldwide [1]. Diabetic macular edema is a major cause of the vision loss (DME visual impairment) associated with diabetic retinopathy [2]. In 2010 of an estimated 92.6 million adults with diabetic retinopathy worldwide, 20.6 million were estimated to have DME [3]. The increasing prevalence of diabetes worldwide highlights the importance of diabetic macular edema as a global health issue [4].

    The Early Treatment Diabetic Retinopathy Study (ETDRS) established the role of laser in preventing up to 15 letters (ETDRS scale) loss of best-corrected visual acuity (BCVA) with prompt therapy [5]. Although laser photocoagulation has been the standard treatment for DME for nearly 3 decades, there is increasing evidence that superior outcomes can be achieved with anti-vascular endothelial growth factor (anti-VEGF) therapy [6-12]. Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of DME [13]. A decade of clinical trials demonstrated anti-VEGF drugs that bind soluble VEGF restore the integrity of the blood-retinal barrier, resolve macular edema, and improve vision in most patients with DME [14-19]. In 2007, the DRCR.net reported results from a phase two randomized clinical trial that suggested intravitreal bevacizumab treatment had an effect on the reduction of DME in some eyes (Protocol H) [20]. The Pan-American Collaborative Retina Group (PACORES) also reported an apparent benefit of bevacizumab treatment for DME [21]. A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT) study randomized 80 participants to intravitreal bevacizumab or macular laser treatment and found that whereas the bevacizumab group gained a median of eight letters in visual acuity over 12 months , the laser group lost a median of 0.5 letters over the same time period [22, 23]. Three commonly used intravitreous VEGF inhibitors: Ranibizumab (Lucentis, Genentech), Bevacizumab (Avastin, Genentech), and Aflibercept (Eylea, Regeneron Pharmaceuticals) have been shown to be beneficial and relatively safe for the treatment of diabetic macular edema. Bevacizumab is a full-length recombinant humanized monoclonal antibody that, in contrast to pegaptanib's isoform-specific actions, blocks all isoforms of VEGF-A. It shares a similar molecular structure with ranibizumab, which was designed as a monoclonal antibody fragment from the same parent murine antibody [24]. In 2015 року, the Diabetic Retinopathy Clinical Research Network published the results of Protocol T study [25]. In this comparative-effectiveness, randomized clinical trial of center-involved DME causing decreased visual acuity, treatment with intravitreous aflibercept, bevacizumab, or ranibizumab was associated with a substantial improvement in mean visual acuity by 1 month, with the improvement sustained through 1 year.

    Diabetes is becoming major public health concern in Mongolia. Most recent report from the Mongolian STEPS Survey on the Prevalence of Noncommunicable Disease and Injury Risk Factors 2009 estimated the prevalence of diabetes was 6.5% (95% CI 4.5-8.4) in the study population [26]. It has been reported that in 2010in Mongolia, the prevalence of any grade DR was 30.2%, DME 17.7% and sight threatening retinopathy was 6.4% and 96.3% of patients who needed laser or surgical treatment had not been treated [27]. This low treatment rate is explained by the lack of trained personnel, especially vitreo-retinal specialists, diagnostics and therapeutic instruments at that time. Nowadays, thanks to the introduction of the latest technology and equipment in our practice, we are able to diagnose and treat patients with diabetic retinopathy at a qualitatively new level. The purpose of this study was to treat and evaluate the clinical efficacy and safety of bevacizumab monotherapy and bevacizumab therapy combined with laser therapy versus laser monotherapy in Mongolian patients with visual impairment resulting from DME.

    Materials and Methods

    Study Design. The study was a prospective, randomized, laser-controlled, 12 month, single-center, clinical trial, and was undertaken at Infinity Eye Clinic, Ulaanbaatar, Mongolia. Patients were randomized into three treatment groups: (I) intravitreal bevacizumab monotherapy, (II) intravitreal bevacizumab combined with laser, (III) laser monotherapy. One eye was selected and treated as the study eye. If both eyes were eligible, the eye with the worse visual acuity (VA; assessed at visit 1) was selected for treatment, unless, based on medical reasons, the investigator deemed the other eye more appropriate to receive study treatment. The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Ethical Committee of the School of Medicine, Mongolian National University of Medical Sciences. All study participants provided written informed consent before entering the study.

    Patients. The study population consisted of 112 male and female patients >18 years of age with either type 1 or 2 diabetes mellitus, and visual impairment due to DME.

    The key inclusion criteria were: (1) patients of either gender aged >18 years; (2) diabetes mellitus (type 1 or 2);

    (3) best-corrected visual acuity (BCVA) in the study eye between 35 and 69 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 4 m (Snellen equivalent >6/60 or <6/12); (4) center-involving diabetic macular edema (DME) with central macular thickness (CMT) on optical coherence tomography (OCT) of >270 | im; (5) media clarity, pupillary dilation, and subject cooperation sufficient for adequate fundus imaging; (6) intraocular pressure (IOP) <30 mmHg; (7) ability to return for regular study visits. The key exclusion criteria were: (1) macular ischemia (foveal avascular zone [FAZ] >1000 | im greatest linear dimension (GLD) or severe perifoveal intercapillary loss on FFA; (2) macular edema due to a cause other than DME; (3) coexistent ocular disease;

    (4) history of an anti-VEGF treatment for DME in the past 12 months in the study eye; (5) any other treatment for DME in the past four months (such as focal / grid macular photocoagulation, intravitreal or peribulbar corticosteroids); (6) hemoglobin A1c (HbA1c) >12.0%; (7) BP > 160/100; (8) any stage of PDR; (9) medical history of chronic renal failure; (10) pregnancy (11) uncontrolled glaucoma.

    Baseline Evaluation. After informed consent, medical and ophthalmic history was recorded and ophthalmologic examination was performed, including BCVA, applanation tonometry, and anterior segment and dilated slit-lamp biomicroscopic examination. All subjects had standard ETDRS 7 field fundus photographs, FFA and OCT imaging.

    Efficacy and Safety Assessments

    Best Corrected Visual Acuity. At baseline and each follow-up visit, investigators assessed the BCVA using the ETDRS-like VA testing chart at a starting distance of 4 m. The primary efficacy end point was the mean change in BCVA letter score from baseline to month 12. Secondary efficacy end points included the proportion of patients with a BCVA letter score >73 (Snellen equivalent: >6/12), the proportion of patients who gained >10 and >15 ETDRS letters (improvement), the proportion of patients who lost <15 ETDRS letters (stabilization) at month 12.

    Optical Coherence Tomography. Optical coherence tomography was performed at every study visit using spectral-domain OCT (Cirrus ™, Carl Zeiss Meditec, Germany). Trials for diabetic retinopathy have defined CMT values >250 | im as significant for macular edema to qualify for various trials [6,7,22] .In order to control for any ceiling or floor effect, the 270 | im in CMT was considered as a eligible criteria. Retinal thickness was determined using individual A-scans along with each of 6 B-scans. Baseline and 1 year OCT scans were graded at the Infinity Eye Clinic by the investigators. The end points included the mean change in CRST and the proportion of patients with <250 | im ( "dry macula") from baseline over time.

    Stereoscopic Color Fundus Photography and Fluorescein Angiography Stereoscopic color fundus

    photography and fluorescein angiography (VX-10, Kowa Company, Ltd, Nagoya, Japan) were performed at baseline, month 4, month 8 and month 12. After pupil dilation and before fluorescein dye injection, red-free and ETDRS 7-field color photographic images of the retina of the study eye were taken.

    Safety Assessments. Safety was assessed by analysis of the incidence of adverse events (AEs) and serious adverse events (SAEs), by ophthalmic examinations, intraocular pressure measurements, and by changes in vital signs over the 12-month assessment period. All ocular and nonocular AEs and SAEs were recorded.

    Treatment

    Bevacizumab monotherapy. Bevacizumab injections were given for 3 initial monthly (every 4 weeks) doses and then pro re nata (PRN) thereafter based on BCVA stability and DME progression. Subjects were subsequently reviewed every 4 weeks. At each visit, a full history was taken, ETDRS BCVA was recorded by an investigator, and a complete ocular examination (including anterior chamber reaction, IOP and dilated fundoscopy) and OCT were performed.

    Retreatment Criteria. As of month 3, one injection per month was continued if stable VA was not reached. The stable vision was defined as a change of fewer than 15 letters in an ETDRS chart. Patients were treated at monthly intervals until stable vision was achieved, that is, no further BCVA improvement attributable to treatment was observed compared with the 2 previous consecutive visits according to the investigator. After suspension, injections were resumed PRN, if there was a decrease in BCVA due to DME progression and CSMT was greater than 270 | im on OCT.

    Intravitreal Bevacizumab Injection Technique. Intravitreal bevacizumab (Avastin, Genentech) injections (1.25 mg in 0.05 ml) were performed in the operating theatre of the Infinity Eye Clinic by the investigators. Bevacizumab injections were done under sterile conditions, using topical anesthesia and povidone-iodine 5% into the conjunctival sac and onto the lid margins, and following application of a drape and insertion of a lid speculum. The injections were undertaken with a 30-gauge needle through the supra- or infratemporal quadrant, with a drop of gatifloxacin placed in the fornix at the end of the procedure. Patency of the central retinal artery was determined by indirect ophthalmoscopy and VA of hand movements. The IOP was checked 30 minutes after the injection. After the injection, topical gatifloxacin was instilled 4 times per day for 5 days.

    Laser Treatment. All patients in the intravitreal bevacizumab combined with laser and laser monotherapy groups underwent modified ETDRS macular laser therapy (MLT) at their baseline visit or within 7 days of randomization. ETDRS MLT was performed using the VISULAS * 532s (Carl Zeiss, Germany). Subjects were subsequently reviewed every 4 months. Re-treatments were performed if clinically indicated by ETDRS guidelines [28]. In the ETDRS, initial treatment for macular edema was usually done in one sitting. Four months after the initial treatment and at 4-month intervals thereafter, if clinically significant macular edema and treatable lesions were present, additional treatment was given to these lesions. Repeat fluorescein angiography was usually necessary to assess whether treatable lesions were present. 29Modified ETDRS MLT used a 50 | im argon laser spot size and the laser was applied only more than 500 | im from the edge of the foveal avascular zone (FAZ), with focal treatment aiming

    to cause mild blanching of the retinal pigment epithelium and not darkening / whitening of microaneurysms. Areas of diffuse leakage or non-perfusion were similarly treated in a grid pattern. At each visit, a full history was taken and a complete ocular examination was performed (including IOP and dilated fundoscopy); ETDRS BCVA was recorded by the investigators; and 7-field color fundus photography, FFA, and OCT were undertaken.

    Statistical Analysis. All statistical analyses were carried out using IBM SPSS version 20.0 (IBM Corp., Armonk, NY, USA) software for Windows. P-values ​​of less than 0.05 were taken as significant. One-way ANOVA was used to compare baseline BCVA. The mean change BCVA and CRST at 12 month were compared using multiple comparisons Tukey HSD test.

    Results and discussion

    A total of 112 participants were randomized to receive bevacizumab (n = 42), bevacizumab combined with laser (n = 35), or laser (n = 35). The mean age of the participants was 54.5 ± 10 years and 55.4% were women. A total of 94.6% of the participants had type 2 diabetes, and the mean duration of diabetes was 8.5 ± 4.6 years. The mean visual acuity letter score at baseline was 55.7 ± 8.9, and the mean central retinal subfield thickness was 399.4 ± 114.36 | im. The baseline characteristics of each treatment group are summarized in Table 1. Overall, baseline demographics and diabetes or ocular characteristics were comparable across the 3 treatment groups. The patients received an average of 8 bevacizumab intravitreal injections in the bevacizumab group, 7.5 in the bevacizumab + laser group.

    Efficacy

    Best-Corrected Visual Acuity. The mean change ± SD in the BCVA letter score from baseline to month 12 improved significantly with bevacizumab and bevacizumab + laser treatment versus laser monotherapy (8.3 ± 3.2 letters and 11.3 ± 4.5 letters vs 1.1 ± 3.7 letters), hence the primary end point was achieved (Table 2) (Figure 1). There was a significant difference between the mean ETDRS BCVA at 12 months in the bevacizumab and laser monotherapy group (mean difference 7.2; p<0.0001); bevacizumab + laser and laser monotherapy group (mean difference 10.2; p<0.0001) (Table 2). In the laser group, mean BCVA stabilized around baseline level at month 12. At month 12, 4.8% of patients in the bevacizumab group and 14.3% of patients in the bevacizumab + laser group had a BCVA letter score >73 (Snellen equivalent: >6/12).

    The mean number of bevacizumab injections administered was 8.07 in the bevacizumab group, 7.51 in the bevacizumab + laser treatment group. The percentages of eyes with a change in the letter score of 10 or more and 15 or more are provided in Table 3.

    Table 1

    Key Baseline Demographics, Diabetes, and Ocular Characteristics

    Variable Total Treatment groups P value

    Bevacizumab Bevacizumab + laser Laser

    n / mean% / SD n / mean% / SD n / mean% / SD n / mean% / SD

    Number of patients 112 42 35 35

    Age 54.54 10.14 54.36 9.76 54.03 12.24 55.26 8.38 0.872a

    Gender 0.139b

    Male 50 44.6% 20 47.6% 11 31.4% 19 54.3%

    Female 62 55.4% 22 52.4% 24 68.6% 16 45.7%

    Diabetes type 0.703b

    Type 1 6 5.4% 3 7.1% 2 5.7% 1 2.9%

    Type 2 106 94.6% 39 92.9% 33 94.3% 34 97.1%

    HbAlc (%) 10.17 3.14 9.85 3.08 10.8 3.26 9.92 3.07 0.357a

    Duration of DM 8.47 4.19 8.12 3.61 8.6 4.73 8.77 5.52 0.812a

    Baseline BCVA 55.72 8.95 56.59 8.87 54.94 8.59 55.46 9.54 0.710a

    Baseline CRST (| im) 399.41 114.36 397.33 114.76 410.14 116.9 391.2 113.8 0.781a

    BCVA = best-corrected visual acuity; CRST = central retinal subfield thickness; DM = diabetes mellitus; HbAlc = glycosylated hemoglobin A1c; SD = standart deviation; aANOVA; b x2 test.

    Efficacy Outcome Measures in the Three Treatment groups

    Efficacy Outcome Measure Total Treatment groups P value

    Bevacizumab (n = 42) Bevacizumab + laser (n = 35) Laser (n = 35)

    Baseline BCVA 0.710

    | Mean (SD) 55.72 (8.95) 56.59 (8.87) 54.94 (8.59) 55.46 (9.54)

    BCVA at 12 month <0.0001

    | Mean (SD) 62.40 (9.72) 64.9 (8.6) 66.3 (6.6) 56.0 (10.1)

    Change in BCVAa <0.0001

    | Mean (SD) 7.17 (5.58) +8.3 (3.2) + 11.3 (4.5) + 1.1 (3.7)

    Baseline CRST (| m) 0.781

    | Mean (SD) 399.41 (114.36) 397.33 (114.76) 410.14 (116.9) 391.2 (113.8)

    CRST at 12 month (| m) 0.003

    | Mean (SD) 293.07 (77.07) 272.9 (51.6) 281.1 (52.9) 329.2 (106.7)

    Change in CRST (| m) b 0.002

    | Mean (SD) -106.35 (84.39) -124.4 (82.4) -129.0 (74.6) -62.0 (80.8)

    BCVA = best-corrected visual acuity; CRST = central retinal subfield thickness; SD = standart deviation; "Difference between Bevacizumab and Laser (Multiple Comparisons, Tukey HSD); Difference between Bevacizumab combined with laser and Laser (Multiple Comparisons, Tukey HSD); b Difference between Bevacizumab and Laser (Multiple Comparisons, Tukey HSD); Difference between Bevacizumab combined with laser and Laser (Multiple Comparisons, Tukey HSD)

    Central Retinal Subfield Thickness. The mean change in CRST from baseline to month 12 decreased significantly for

    Table 2 Safety

    Serious Adverse Events.

    There were no ocular and nonocular SAEs reported in any of the treatment arms. No endophthalmitis cases occurred.

    Adverse Events.

    Conjunctival hemorrhage was themostcommonocularevents. Bevacizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.

    This prospective,

    randomized clinical trial has demonstrated that treatment with bevacizumab as monotherapy or combined with laser treatment is superior to laser treatment alone in improving and sustaining visual acuity in Mongolian

    Figure 1. Mean change in BCVA from baseline to month 12 (ETDRS letter score).

    bevacizumab (124.4 | im; p<0.002) and bevacizumab + laser (129.0 | im; p<0.002) compared with laser (62.0 | im). There

    Categorized BCVA letter score and CRST outcomes at month 12

    Efficacy Outcome Measure Bevacizumab (n = 42) Bevacizumab + Laser (n = 35) Laser (n = 35) P value

    n% n% n%

    Proportion w th final VA>73 2 4.8 5 14.3 0 0.0 0.044a

    Proportion w th <10 letter gain 32 76.2 15 42.9 23 100.0 0.0001b

    Proportion w th >10 letter gain 10 23.8 20 57.1 0 0.0

    Proportion w th <15 letter gain 39 92.9 25 71.4 23 100.0 0.002a

    Proportion w th >15 letter gain 3 7.1 10 28.6 0 0.0

    Proportion w th <30 letter gain 42 100.0 35 100.0 23 100.0

    Proportion w th >30 letter gain 0 0.0 0 0.0 0 0.0

    Proportion w th <10 letter loss 0 0.0 0 0.0 10 83.3

    Proportion w th >10 letter loss 0 0.0 0 0.0 2 16.7

    Proportion w th <15 letter loss 0 0.0 0 0.0 12 100.0

    Proportion w th >15 letter loss 0 0.0 0 0.0 0 0.0

    Proportion w th <30 letter loss 0 0.0 0 0.0 12 100.0

    Proportion w th >30 letter loss 0 0.0 0 0.0 0 0.0

    Proportion w th final CRST <250 17 40.5 10 28.6 5 14.3 0.040b

    BCVA = best-corrected visual acuity; CRST = central retinal subfield thickness; VA visual acuity; BOLD = significant p<0.05; aFisher's Exact test; bx2 test.

    was no difference detected between the two bevacizumab treatment groups.At month 12, the proportion of patients with CRST < 250 | im was greater in the bevacizumab monotherapy group (40.5%) and the bevacizumab + laser group (28.6%) compared with the laser group (14.3%).

    Bevacizumab Laser Bevacizumab + Laser

    Figure 2. Mean change in CRST from baseline to month 12.

    patients with DME visual impairment. A greater proportion of patients treated with bevacizumab gained >10, >15 BCVA letter scores and with BCVA letter score >73 Table 3 from baseline compared with the laser-treated patients. Bevacizumab treatment consistently improved B CVA across all subgroups regardless of baseline characteristics as compared with the laser treatment alone.

    The functional improvement in BCVA was accompanied by a significant improvement in anatomic end points, CRST on OCT, and resolution of leakage on fluorescein angiography. The mean change CRST from baseline to month 12 decreased significantly for bevacizumab and bevacizumab + laser (both; p = 0.002) compared with laser (Figure 2). At month 12, 40.5% (bevacizumab), 28.6% (bevacizumab + laser), and 14.3% (laser) patients had CRST <250 | im. This study showed that the bevacizumab monotherapy or bevacizumab therapy combined with the laser therapy were safe and well tolerated in DME visual impairment patients.

    The treatment efficacy reported in the bevacizumab studies to date is comparable to that described in this report (Table 5). The DRCR.net Protocol H study was uncontrolled with only two intravitreal injection protocol. 20The Pan-American Collaborative Retina Study (PACORES) was a nonrandomized, uncontrolled with only a 3 injection

    protocol for 6 months. 21The BOLT study was based on 6-week injection intervals, and was a 2-arm, randomized, controlled, masked clinical trial. The results of this study on bevacizumab replicate the observations made with ranibizumab in DME in larger randomized controlled trials, suggesting that pan-VEGF-A inhibitors appear to have similar effects on DME.22

    A recent prospective randomized 3-arm trial (1.25 mg intravitreal bevacizumab alone, intravitreal bevacizumab in combination with intravitreal triamcinolone acetonide, and MLT) in patients with clinically significant macular edema (CSME) reported positive visual outcomes similar to those of our trial. 30However, the findings were at the 36-week time point, ETDRS VA charts were not used, retreatments were performed at 12-week intervals, and a significant reduction of CRST from baseline was only observed at 6 weeks. Additionally, all of those studies use Stratus OCT, a time domain OCT which is subject to frequent artifacts and lower repeatability compared to spectral-domain Cirrus OCT which was used in our study. This study is different from other studies in that, all enrolled participants in this study were first time diagnosed with the DME and, importantly, they have never been received the MLT. The other studies, all enrolled patients with persistent DME who have received at least 1 prior MLT. Other differences were observed in the baseline characteristics of the participants in our study in comparison with other studies are that, they were comparatively young, more shorter duration of diabetes after the initial diagnosis and poor control of DM.

    Our study used initiation of treatment with 3 initial monthly (every 4 weeks) doses and then pro re nata (PRN) dosing regimen addressing individual patient needs with reduced treatment burden. Currently, monthly injections (RISE and RIDE [10,11]), pro re nata (PRN) approach (RESOLVE [9]), and treat-and-extend (RETAIN [31]) are the main strategies of treating DME with anti -VEGF agents. The PRN and treat-and-extend strategies are considered more

    література

    1. Bourne R.R., Jonas J.B., FlaxmanS.R., Et al. Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe: 1990-2010 // Br J Ophthalmol. 2014. Vol. 98. P.629-638.

    2. Boyer D.S., Hopkins J.J., Sorof J., Ehrlich J.S. Anti-vascular endothelial growth factor therapy for diabetic macular edema // Ther Adv Endocrinol Metab. 2013. Vol.4. P.151-169.

    3. International Diabetes Foundation. IDF Diabetes Atlas. Seventh Edition. 2015.

    4. Yau J.W., Rogers S.L., Kawasaki R., et al. Global prevalence and major risk factors of diabetic retinopathy // Diabetes Care. 2012. Vol. 35. P.556-564.

    5. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report number 9 // Ophthalmology. 1991. Vol. 98. P. 766-785.

    6. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema // Ophthalmology. 2010. Vol. 117. P. 1064-1077.

    7. Bressler S.B., Qin H., Beck R.W., Chalam K.V., Kim J.E., et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab // Arch Ophthalmol.2012. Vol. 130. P.1153-1161. DOI: 10.1001 / archophthalmol.2012.1107

    8. Nguyen Q.D., Shah S.M., Khwaja A.A., et al. Two-year outcomes of the Ranibizumab for Edema of the Macula in Diabetes (READ-2) study // Ophthalmology. 2010. Vol. 117. P.2146-2151.

    9. Massin P., Bandello F., Garweg J.G., et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study // Diabetes Care. 2010. Vol. 33. P.2399-2405.

    10. Nguyen Q.D., Brown D.M., Marcus D.M., et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE // Ophthalmology. 2012. Vol. 119. P.789-801.

    11. Brown D.M., Nguyen Q.D., Marcus D.M., et al. Long-term

    favorable compared with the monthly approach because of the reduced cost burden.

    The limitations of our clinical trial were small number of patients and relatively short follow-uptime course. Further large multicenter studies are required with longer follow-up (at least 3 years). Because of the chronic nature of the underlying disease process and the mechanism of action of anti-VEGF agents, monotherapy with anti-VEGF drugs is likely to be impractical, although the development of slow delivery systems may yet address this issue. Nevertheless, one would anticipate that treating patients with the clinically significant macular edema with the repeated intravitreal bevacizumab at an earlier time point, before irreversible structural damage has been sustained, will result in even better visual outcomes. Furthermore, more rapid reduction in macular edema compared with MLT may lead to a superior longer-term visual acuity. In conclusion, this study demonstrated the superiority of bevacizumab therapy with or without laser therapy over laser monotherapy in improving BCVA and reducing CRST in Mongolian patients with DME visual impairment.

    Конфлікт інтересів. Автори заявляють про відсутність конфлікту інтересів.

    Прозорість дослідження. Це дослідження було підтримано Infinity Eye Clinic. Автори висловлюють подяку професору Lim Sun TaeИ всім членам дослідного товариства Mongolian Vitreo-Retinal Society. Дослідники несуть повну відповідальність за надання остаточної версії рукописи до друку.

    Декларація про фінансові та інших взаємодіях. Всі автори брали участь у розробці концепції та дизайну дослідження і в написанні рукопису. Остаточна версія рукописи була схвалена всіма авторами. Автори не отримували гонорар за дослідження.

    Матеріал надійшов до редакції: 17.12.2018 р.

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    Інформація про авторів:

    Анараїт Тойшубай - докторант, магістр медичних наук, директор очна клініка Сондра, Улан-Батор, Монголія, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0001-8485-2961; Уранчімег Даваацерен - доцент, к.м.н., завідувач кафедри офтальмології, Медичний Факультет, Монгольський національний університет імені Медичних Наук, Улан-Батор, Монголія, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., 0RCID: 0000-0002-5860- 1947; Баасанхуу Жамьяанжав - професор, к.м.н, директор очна лікарня Болор Мелмій, Улан-Батор, Монголія, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., 0RClD: 0000-0002-7062-5503; Лім Сун Тек - професор, к.м.н, директор очна лікарня Парансе, Кванджу, Південна Корея, e-mail: goodponds @ naver. com6, 0RCID: 0000-000l-6047-4177; Мунхзаяа Ценгенбаяр - лікар-офтальмолог, Очна клініка Сондра, Улан-Батор, Монголія, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0003-2427-7437; Мунххіші гБатбілег - докторант, магістр медичних наук, лікар-офтальмолог, Очна клініка Сондра, Улан-Батор, Монголія, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., 0RCID: 0000-0001-5101-649X; Оюунзаяа Лувсанцерен - лікар-офтальмолог, Очна клініка Сондра, Улан-Батор, Монголія,

    email: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0003-0299-2165; Урангуа Жамьяансурен - лікар-офтальмолог, Очна клініка Сондра, Улан-Батор, Монголія, email: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0002-5028-1889; Худерчулуун Нанжід - к.м.н, кафедрою громадського здоров'я та охорони здоров'я, Монгольський національний університет медичних наук, Улан-Батор, Монголія, email: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0001-7699-2649; Алтайсайхан Хасаг - професор, к.м.н, кафедри ендокринології, Медичний Факультет, Монгольський національний університет імені Медичних Наук, Улан-Батор, Монголія, email: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0002-7014-1883.

    Information About the Authors:

    Anaraa Toishubai - doctorant, Master of Medical Sciences (MMedSc), Director of Sondra Eye Clinic, Ulaanbaatar, Mongolia, e-mail:

    Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0001-8485-2961; Uranchimeg Davaatseren - PhD (Medicine), Associate professor, Head of the Department of Ophthalmology, School of Medicine, Mongolian National University of Medical Science, Ulaanbaatar, Mongolia, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0002 -5860-1947; Baasankhuu Jamyanjav - PhD (Medicine), Professor, Director of Bolor Melmii Eye Hospital, Ulaanbaatar, Mongolia, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її.б, ORCID: 0000-0002-7062-5503; Lim Sun Taek -PhD (Medicine), Professor, Director of Paransae Eye Hospital, Gwangju, South Korea, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 00000001-6047-4177; Munkhzaya Tsengenbayar - retina specialist of Sondra Eye Clinic, Ulaanbaatar, Mongolia, e-mail: tsmunkh_zaya @

    yahoo.com, ORCID: 0000-0003-2427-7437; Munkhkhishig Batbileg - doctorant, Master of Medical Sciences (MMedSc), retina specialist of Sondra Eye Clinic, Ulaanbaatar, Mongolia, e-mail: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0001-5101-649X; Oyunzaya Luvsantseren - retina specialist of Sondra Eye Clinic, Ulaanbaatar, Mongolia, email: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-00030299-2165; Urangua Jamyansuren - glaucoma specialist of Sondra Eye Clinic, Ulaanbaatar, Mongolia, email: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0002-5028-1889; Khuderchuluun Nanjid - PhD (Medicine), Scool of Public Health, Mongolian National University of Medical Science, Ulaanbaatar, Mongolia, email: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0001-7699-2649; Altaisaikhan Khasag -PhD (Medicine), Professor, Department of Endocrinology, School of Medicine, Mongolian National University of Medical Science, Ulaanbaatar, Mongolia, email: Ця електронна адреса захищена від спам-ботів. Вам потрібно увімкнути JavaScript, щоб побачити її., ORCID: 0000-0002-7014-1883.


    Ключові слова: ДІАБЕТИЧНА макулопатія / Діабетична ретинопатія / ФАКТОР ЗРОСТАННЯ СУДИННОГО ЕНДОТЕЛІЮ / бевацизумаб / DIABETIC MACULAR EDEMA / DIABETIC RETINOPATHY / VASCULAR ENDOTHELIAL GROWTH FACTOR / BEVACIZUMAB

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