Switching to ranibizumab in diabetic macular oedema refractory to bevacizumab treatment | Archivos de la Sociedad Española de Oftalmología (English Edition)

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Ashraf, A.A. Souka, M. Daich Varela, H. el Kayal, P.G. Schlottmann" "autores" => array:5 [ 0 => array:3 [ "nombre" => "M." "apellidos" => "Ashraf" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "A.A." "apellidos" => "Souka" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "M." "apellidos" => "Daich Varela" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "H." "apellidos" => "el Kayal" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:4 [ "nombre" => "P.G." "apellidos" => "Schlottmann" "email" => array:1 [ 0 => "schlottp@yahoo.com.ar" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Departamento de Oftalmología, Facultad de Medicina, Universidad de Alejandría, Alexandria, Egypt" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital Oftalmológico Santa Lucía, Buenos Aires, Argentina" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Oftalmología, Organización Médica de Investigación, Buenos Aires, Argentina" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Cambio a ranibizumab en edema macular diabético refractario al tratamiento con bevacizumab" ] ] "textoCompleto" => "IntroductionDiabetic retinopathy and particularly diabetic macular oedema (DME) are the main causes of visual impairment in the working age population the world over.<a class="elsevierStyleCrossRef" href="#bib0130">1</a> Recent studies established anti-angiogenic injections (anti-VEGF) as the first line treatment for DME.<a class="elsevierStyleCrossRefs" href="#bib0135">2–6</a> At present, three anti-VEGF are available in clinical practice: aflibercept (Eylea, Regeneron Pharmaceuticals, USA; Bayer, Leverkusen, Germany), bevacizumab (Avastin, Genentech, USA; Roche, Basel, Switzerland) and ranibizumab (Lucentis, Genentech, USA; Novartis, Basel, Switzerland). The efficacy of these medicaments was previously established in a range of individual studies, many of which completed extended phases.<a class="elsevierStyleCrossRefs" href="#bib0135">2,3,7,8</a> Aflibercept and ranibizumab were approved by the Food and Drug Administration for treating DME, whereas the use of bevacizumab remains off label.Bevacizumab is the medicament of choice in many developing countries due to its low cost. However, recent clinical trials such as the T Protocol compared the visual results in patients with DME randomly treated with three drugs and demonstrated that bevacizumab (compared to ranibizumab and aflibercept) is less effective at the anatomic level.<a class="elsevierStyleCrossRef" href="#bib0170">9</a> After 2 years, the number of patients with a central macular thickness <250μm was 41% with bevacizumab 1.25mg, 69% with ranibizumab 0.3mg and 71% with aflibercept 2mg for all visual acuities.<a class="elsevierStyleCrossRef" href="#bib0175">10</a> This would indicate that at least half of patients treated with bevacizumab exhibited residual fluid despite continuous and timely therapy.There is no clear consensus on the best therapeutic strategy for treating persistent DME. There are very few studies on the switch from bevacizumab to ranibizumab, one of the most important being the REEF study.<a class="elsevierStyleCrossRefs" href="#bib0180">11,12</a> Even though the initial results appeared to indicate that patients with refractory oedema respond to the therapy switch, the exact time to carry out the switch remains to be determined. In fact, it is not known when the therapy switch has any real beneficial effect or if the described anatomic and functional improvements are only related to the accumulation of injections and not to the switch in therapeutic agents.The T Protocol demonstrated that most patients needed at least 9 anti-VEGF injections during the first year.<a class="elsevierStyleCrossRef" href="#bib0170">9</a> Several analyses demonstrated the existence of a group of late responders that failed to exhibit initial response to the therapy but eventually obtained anatomic as well as visual improvements compared to those of the early responders.<a class="elsevierStyleCrossRefs" href="#bib0190">13–15</a> On the other hand, a recent I Protocol sub-analysis demonstrated that the residual oedema at 24 weeks had dried up at the end of 3 years in 60% of patients, while the remaining 40% still exhibited residual fluid. A different analysis showed that, in the I Protocol, patients with significant early response (≥10 letters by week 12) maintained this intense response throughout time, and that patients with limited improvements (<5 gained letters) maintained a limited response after three injections throughout the three years of the study.<a class="elsevierStyleCrossRef" href="#bib0205">16</a> Accordingly, early switch supporters proposed the inclusion of a strategy to identify slow responders at an early stage in order to allow these patients to achieve better visual outcomes within an adequate period of time. This proposal was set aside for a long time in due to the inability to determine whether early-switch patients responded to due to the effect of the new drug or a delayed response to the previous one.Materials and methodsPatients treated with bevacizumab for DME were assessed, while those who did not exhibit adequate improvement in their anatomy were switched to ranibizumab. If the latter exhibited improvements, they were switched again to bevacizumab. The hypothesis is that if the patient that initially responded to a switch did not exhibit improvement or worsened after inverting the switch, this would indicate that these patients were initially non-respondent to bevacizumab and therefore would respond to ranibizumab. In addition, if this were the case, the early identification of these patients could avoid the application of ineffective therapy.A prospective, single centre, open, without control group study was performed with patients treated for DME. The study complied with the principles of the Helsinki declaration and was approved by the institutional Review Committee of the Medical College of Alexandria University (Egypt). All study participants provided an informed consent in writing before the switch to ranibizumab and the switch back to bevacizumab. The selection of patients began in September 2015 and continued during 12 months.Eligible patients should have a DME diagnosed by means of optical coherence tomography (OCT) and previous treatment with at least three monthly injections (± one per week) of bevacizumab with unsuccessful response. Unsuccessful response was defined as a <10% reduction in central subfield thickness (CST) or CST increase after at least three injections. The authors chose to use anatomic parameters as main factors in order to increase the objectivity of the study, taking into account that both doctor and patient were aware of the therapy switch. Exclusion criteria included signs of ocular infection and antecedents involving cerebrovascular accident or myocardium infarct.Injection protocolAll patients underwent a complete ocular examination, comprising best corrected visual acuity (BCVA) using classic Snellen cards or decimal visual acuity subsequently converted to logMAR and its equivalent in EDTRS letters, anterior and posterior segment tonometry and biomicroscopy with slit lamp. All patients underwent fluorescein angiography as well as spectral domain OCT (Spectralis, Heidelberg, Germany) to determine central macular thickness.Patients exhibiting unsuccessful response after at least 3 monthly injections (±once a week) of intravitreal bevacizumab 1.25mg were administered 0.05mL (0.5mg) of intravitreal ranibizumab. Three injections would determine the aggregate effect of bevacizumab. One month after the switch, visual acuity and OCT measurements were repeated, drawing up a comparative map to identify central thickness changes. The assessment was performed after one month because it was expected that the effect of the switch to a new drug would be faster. If the patient exhibited successful response (>10% reduction in CST), the reversion to bevacizumab was carried out and the patient was administered 0.05mL (1.25mg) of said drug. If the patient did not show any satisfactory response (<10% reduction in CST), the switch was not reversed and a second dose of ranibizumab was administered.Statistical analysisData were analysed using the IBM SPSS software package version 20.0 (IBM Corp, Armonk, NY, USA). The Kolmogorov–Smirnov test was applied for assessing normality in distribution of variables. The range test with the Wilcoxon sign was applied to compare abnormally distributed quantitative variables of two related groups. The t for Student test was utilized for comparing normally distributed variables. Spearman's correlation was utilized for correlating the main changes in BCVA and post-switch CST with various anatomical and demographic parameters. Statistical significance of results was established at the level of 0.05%.ResultsThe study included 31 patients, with 43 eyes refractory to baseline DME treatment with bevacizumab. These 43 eyes of 31 patients were switched to ranibizumab. Of the 43 initialize, 34 exhibited improvement in CST > 10%, whereas in 9 eyes exhibited very little or no improvement. Of the 34 eyes that responded to the switch to ranibizumab, 25 agreed to switch back to bevacizumab. The nine remaining eyes did not switch back and received a second dose of ranibizumab. Of the 25 eyes that reversed the switch to bevacizumab, 4 were lost during the follow-up, leaving 21 eyes that underwent the switch and its reversal for statistical analysis.As for patient characteristics, mean age was 56.4 ± 7.1; 13 were males and 30 were females. Patients had previously received a mean of 4 ± 1.8 bevacizumab injections and the mean duration of oedema was 12 ± 10.5 months (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Patients who switched to ranibizumab exhibited statistically significant BCVA improvement of 0.67 ± 0.39 to 0.55 ± 0.36 logMAR (P < 0.05) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Overall, the patients exhibited statistically significant CST reduction having a mean value of 475.3 ± 122.8 to 417.3 ± 109.1 (P < 0.05).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>A search for correlations between BCVA changes and patient characteristics found that neither sex, age nor previous photocoagulation stage or number of previous injection and duration of oedema influenced patient results (<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a>). Similar results were obtained when correlating CST changes with demographic and clinical factors. However, it was observed that patients with neurosensory detachment (NSD) with or without intraretinal cysts (IRCs) exhibited a significantly higher anatomical improvement (118.69 ± 169.4μm) when compared to patients with only IRC (31.7 ± 65.7μm; P = 0.019). Similarly, when seeking a correlation between CST changes and baseline CST it was observed that patients with higher baseline CST exhibited more reduction than those with lower baseline CST (P < 0.05).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Out of the 43 eyes that took part of the study, 21 were switched to ranibizumab and switched back again to bevacizumab. These patients exhibited significant CST reduction (P = 0.003) as well as important BCVA improvement (P = 0.001) after the switch to ranibizumab. However, when reversing the change to bevacizumab, the mean CST increased slightly from 374 ± 72μm (post-switch to ranibizumab) to a mean of 404.9 ± 106.3 post-switch back to bevacizumab (P = 0.197). A similar observation was made for BCVA: after the switch the mean was 0.3logMAR, and after reversing the switch a slight and nonsignificant worsening to 0.4logMAR (P = 0.266) was observed (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>DiscussionFew studies have analysed the effect of changing bevacizumab for other anti-VEGF in DME patients.<a class="elsevierStyleCrossRefs" href="#bib0180">11,12</a> This is in contrast with wet age-related macular degeneration where the effect of switching between anti-VEGF in refractory cases has been broadly studied.<a class="elsevierStyleCrossRefs" href="#bib0210">17–23</a> The switch to aflibercept or ranibizumab has been demonstrated in refractory cases and has generally shown variable degrees of visual and anatomic improvement, making this a reasonable option in selected wet age-related macular degeneration patients.Very few studies have investigated the effect of switching from bevacizumab to ranibizumab in patients with DME. The REEF study<a class="elsevierStyleCrossRef" href="#bib0180">11</a> was one of the longest studies researching this switch. The number of patients included in the said study was 43, who had received 4.7 bevacizumab injections before the switch. The patients were assessed after 3 injections of ranibizumab 0.5mg and, if exhibiting residual oedema, were switched to 3 injections of ranibizumab 2.0mg. Patients exhibited an improvement of +6.4 letters by the third month with central macular thickness reduction of 113μm. The present study produced similar results, with a significant improvement in visual acuity and anatomy of patients previously treated with bevacizumab. This study also analysed a subgroup to identify factors that could indicate improved response to the switch. It identified that age, sex, previous number of injections and duration of the oedema had no effect on the response obtained after the switch. It can be assumed that the previous number of injections is in some way related to the duration of oedema and that it does not influence the response to the switch.An interesting factor was the response based on OCT characteristics: it was found that cases with NSD, with or without IRC, exhibited a significantly higher response to the switch compared to cases with IRC only. Even though the exact reason is not clear, previous data of a subsequent RISE/RIDE analysis showed that patients with NSD exhibited a better anatomical response to ranibizumab.<a class="elsevierStyleCrossRef" href="#bib0245">24</a> However, recent data from the BOLT study, that researched the effects of bevacizumab in DME, demonstrated that 57% of nonresponders had baseline NSD and persistent oedema at 24 months.<a class="elsevierStyleCrossRef" href="#bib0190">13</a> It has not yet been determined whether patients with NSD tend to be more refractory to bevacizumab or if cases that are refractory to bevacizumab simply respond better to the switch. It has also been found that patients with higher baseline CST exhibited a more robust response to the switch. These data seem to match those of the T Protocol which demonstrated a significant anatomical superiority of ranibizumab compared to bevacizumab in DME cases.<a class="elsevierStyleCrossRef" href="#bib0170">9</a> Perhaps bevacizumab is not able to adequately treat patients with increased macular thickness and the switch enables enhanced anatomical improvements. It should be noted that this difference was not accompanied by visual acuity improvements in patients with increased CST, who did not exhibit better visual results.The second part of the study involved reversing the switch for patients who had responded to the initial switch back again to the original medicament, i.e., bevacizumab. The results indicated that, after reversing the switch, the patients did not exhibit anatomical or visual improvements. However, a slight and not statistically significant worsening of the subfoveal central thickness was evidenced. The concept of switching both medicaments has become controversial. Some authors recommend an early switch while others recommend a later switch in the course of treatment enabling the identification of late responders. Proponents of later switches affirm that patients showing poor early response actually respond later to continuous treatment. A post hoc analysis of BOLT, RISE/RIDE and the I Protocol identified a subgroup of patients defined as late responders who exhibited said belated response with successful final visual acuity.<a class="elsevierStyleCrossRefs" href="#bib0190">13–15</a> Likewise, a recent CATT analysis demonstrated that visual and anatomic gains reported in patients with age-related macular degeneration who switched from bevacizumab to aflibercept was similar to the gains obtained by CATT patients eligible for a switch at month 3 of treatment but were maintained with the same medicaments during one year. Said analysis concluded that these patients are part of a “slow responder” group that eventually respond to ongoing treatment.<a class="elsevierStyleCrossRef" href="#bib0250">25</a> On the other hand, recent data of a Protocol I analysis carried out by Dugel demonstrated that patients with robust early response (≥10 letters by week 12) maintained this significant response in time and in turn patients with limited response after three injections (<5 letter gain) demonstrated small improvement throughout the 3-year-long study.<a class="elsevierStyleCrossRef" href="#bib0205">16</a>In any debate related to switching medicaments, the crux of the matter is always whether patients who switched the drug improved due to being slow responders or to the switch itself. In the present study, the fact that patients who demonstrated initial response to ranibizumab halted their improvement seems to indicate that it was due to the effect of the new drug. If it would have been due to a slow response, the majority would have continued after reversing the switch. This study was designed to obtain a specific answer to that question but not to address long-term treatment results. It is still not known whether in the long term, after several ranibizumab injections, patients will evolve better or worse than those who continued with bevacizumab. In any case, the data of the last two years of the T Protocol have demonstrated that patients treated with bevacizumab, aflibercept or ranibizumab exhibited improvements with similar visual acuity and that the main difference between them is anatomical.<a class="elsevierStyleCrossRef" href="#bib0175">10</a> If these anatomical differences change in the course of a five-year treatment is yet to be determined.A limitation of the present study was the relatively small number of patients, the absence of randomization and a control group maintaining the same treatment without switches. However, the anatomical inclusion criteria reduced bias and was prospective.In conclusion, switching from bevacizumab to ranibizumab could influence the short-term results in patients with refractory DME regardless of age, sex or treatment length. At any rate, it appears that patients with thicker baseline CST and NSD exhibited the best response when switching from bevacizumab to ranibizumab.Conflict of interestPatricio Schlottman: speaker for Bayer, Novartis and Genentech; consultant of Novartis and Roche.Mohammed Ashraf, Ahmed Souka, Hassan El Kayal, Malena Daich Varela: These authors declare no conflict of interests." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1099729" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Aim" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1040912" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1099730" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1040911" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Injection protocol" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-11-04" "fechaAceptado" => "2018-04-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1040912" "palabras" => array:7 [ 0 => "Retina" 1 => "Macula" 2 => "Diabetic macular oedema" 3 => "Refractory" 4 => "Ranibizumab" 5 => "Bevacizumab" 6 => "Switch" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1040911" "palabras" => array:7 [ 0 => "Retina" 1 => "Mácula" 2 => "Edema macular diabético" 3 => "Refractario" 4 => "Ranibizumab" 5 => "Bevacizumab" 6 => "Cambio" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "AimTo determine the efficacy of switching to ranibizumab in patients with diabetic macular oedema refractory to treatment with bevacizumab, and to evaluate the outcomes when switching back to bevacizumab. MethodsA prospective study was conducted that included 43 eyes of 31 patients refractory to previous bevacizumab treatment. The patients were switched to ranibizumab, and optical coherence tomography was performed one month post-injection. Patients showing improvement (>10% reduction in central sub-field thickness) were switched back to bevacizumab, and optical coherence tomography was performed one month post-switch back. ResultsThe 34 eyes switched to ranibizumab showed a statistically significant improvement in mean best corrected visual acuity from 0.67±0.39 logMAR to a mean of 0.55±0.36 logMAR (P<0.05). In addition, there was a statistically significant decrease in central subfield thickness (CST) from a mean of 475.3±122.8 to a mean of 417.3±109.1 (P<0.05). In the 21 eyes that were switched back to bevacizumab, there was no significant difference either in the change in CST or in the change in best corrected visual acuity post-switch back. ConclusionSwitching to ranibizumab in patients improves both the best corrected visual acuity and CST in diabetic patients refractory to previous bevacizumab treatment. This effect is pronounced in patients with increased CST prior to the switch. Switching back to bevacizumab adds no further improvement." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Aim" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoDeterminar la eficacia del cambio a ranibizumab en pacientes con edema macular diabético refractario a bevacizumab y, posteriormente, evaluar los resultados tras volver al tratamiento inicial con bevacizumab. MétodosSe llevó a cabo un estudio prospectivo que incluyó 43 ojos de 31 pacientes refractarios al tratamiento previo con bevacizumab. Se realizó el cambio a ranibizumab y se controló mediante tomografía óptica de coherencia un mes después de la inyección. A aquellos que mostraron mejoría (reducción >10% en el espesor macular central) se les realizó una reversión del cambio a bevacizumab y fueron evaluados con tomografía óptica de coherencia un mes después de este cambio. ResultadosLos pacientes tratados con el cambio a ranibizumab mostraron una mejoría estadísticamente significativa en su mejor agudeza visual corregida, con una media de 0,67±0,39 a 0,55±0,36 logMAR (P<0,05). Asimismo, hubo una disminución estadísticamente significativa en el espesor macular con una media de 475,3±122,8 a 417,3±109,1 (P<0,05). A 21 ojos se les realizó una reversión del cambio a bevacizumab. No hubo una diferencia significativa en el espesor del subcampo central (ESC) ni en la mejor agudeza visual corregida tras este cambio. ConclusiónEl cambio a ranibizumab mejoró tanto la agudeza visual como el ESC en pacientes diabéticos refractarios al tratamiento previo con bevacizumab. Este efecto fue más marcado en pacientes con aumento del ESC antes del cambio a ranibizumab. Volver al tratamiento con bevacizumab no supuso ninguna mejoría." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Ashraf M, Souka AA, Daich Varela M, el Kayal H, Schlottmann PG. Cambio a ranibizumab en edema macular diabético refractario al tratamiento con bevacizumab. Arch Soc Esp Oftalmol. 2018;93:523–529." ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "SD: standard deviation; NSD: neurosensory detachment; OCT: optical coherence tomography; PFC: retinal panphotocoagulation; IRC: intra-retinal cysts." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Mean±SD or number of cases \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age in years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">56.4±7.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sex (male/female) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7/24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Previous injections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4±1.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Duration of oedema prior to switch \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12±10.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">OCT characteristics (NSD/IRC) (43 eyes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13/30 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PFC/no PFC (43 eyes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15/28 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1880911.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Demographic data of patients before switching to ranibizumab (43 eyes of 31 patients)." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CST: central subfield thickness (central macular thickness); SD: standard deviation; BCVA: best corrected visual acuity." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Prior to switch \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Post-switch \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Significance test \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">P \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">BCVA (LogMar)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mean±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.67±0.39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.55±0.36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">t=4.37<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a></td><td class="td" title="table-entry " rowspan="2" align="left" valign="top"><0.05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Median \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.39 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">CST (μm)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mean±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">475.3±122.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">417.3±109.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Z=−3.7<a class="elsevierStyleCrossRef" href="#tblfn0010">**</a></td><td class="td" title="table-entry " rowspan="2" align="left" valign="top"><0.05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Median \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">462 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">396 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1880910.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "Paired t-test." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "**" "nota" => "Range test with Wilcoxon sign of obtained results was 5%." ] ] ] "descripcion" => array:1 [ "en" => "Comparison between the baseline and post-switch best corrected visual acuity and macular thickness." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CST: central subfield thickness (central macular thickness); NSD: neurosensory detachment; BCVA: best corrected visual acuity; PFC: retinal panphotocoagulation; IRC: intraretinal cysts; OCT: optical coherence tomography." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Changes in BCVA (Log MAR) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Sig. test (t-test) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">P \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Changes in CST (μm) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Sig. test (t-test) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">P \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Sex</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.10±0.14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.103 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54.7±52.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.92 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.123±0.18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">59.4±131.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Characteristics in OCT</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">NSD±IRC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.166±0.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.224 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">118.69±169.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.019<a class="elsevierStyleCrossRef" href="#tblfn0015">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">IRC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.095±0.15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31.7±65.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">PFC</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PFC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.13±0.15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52.1±117.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.214 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.64 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">No PFC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.092±0.19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">69.0±106.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1880914.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "*" "nota" => "Statistically significant." ] ] ] "descripcion" => array:1 [ "en" => "Ratio between BCVA and CST changes post-switch to ranibizumab and sex, PFC status and characteristics in OCT." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "The significance of obtained results was 5%.CST: central subfield thickness (central macular thickness); BCVA: best corrected visual acuity." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Change in BCVA (Log MAR) r \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">P \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Change in el CST (μm) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">P \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r=0.297 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r=0.006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oedema duration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r=0.029 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r=0.28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Number of previous injections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r=0.062 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r=0.209 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.197 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Baseline CST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r=0.019 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">r=0.57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><0.0001<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1880912.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "*" "nota" => "Statistically significant." ] ] ] "descripcion" => array:1 [ "en" => "Ratio between age, oedema duration, number of injections and baseline CST and post-switch BCVA and CST changes utilizing Spearman's correlation (r)." ] ] 4 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "The significance of obtained results was 0.0125% (Bonferroni correction)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Mean±SD (number of eyes 21) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Significance (paired t-test) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Central macular thickness (μm)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pre-switch \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">474.5±138.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Post-switch \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">374.6±72.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P=0.003<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Post-reversion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">404.9±106.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P=0.197<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Best corrected visual acuity (logmar)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pre-switch \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.71±0.35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Post-switch \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.301±0.065 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P=0.001<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Post-reversion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.40±0.08 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P=0.266<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1880913.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "P-value of pre-switch data with post-switch data." ] 1 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "b" "nota" => "P-value of post-switch data with post-switch reversion data. * Statistically significant." ] ] ] "descripcion" => array:1 [ "en" => "Comparison between best corrected visual acuity (logMAR) and central macular thickness espesor macular pre-switch, post-switch to ranibizumab and post-switch reversion to bevacizumab." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:25 [ 0 => array:3 [ "identificador" => "bib0130" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "T.A. 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Switching to ranibizumab in diabetic macular oedema refractory to bevacizumab treatment

Cambio a ranibizumab en edema macular diabético refractario al tratamiento con bevacizumab

M. Ashrafa, A.A. Soukaa, M. Daich Varelab, H. el Kayala, P.G. Schlottmannc,

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schlottp@yahoo.com.ar

Corresponding author.

a Departamento de Oftalmología, Facultad de Medicina, Universidad de Alejandría, Alexandria, Egypt

b Hospital Oftalmológico Santa Lucía, Buenos Aires, Argentina

c Departamento de Oftalmología, Organización Médica de Investigación, Buenos Aires, Argentina

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and ranibizumab &#40;Lucentis&#44; Genentech&#44; USA&#59; Novartis&#44; Basel&#44; Switzerland&#41;&#46; The efficacy of these medicaments was previously established in a range of individual studies&#44; many of which completed extended phases&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">2&#44;3&#44;7&#44;8</span></a> Aflibercept and ranibizumab were approved by the Food and Drug Administration for treating DME&#44; whereas the use of bevacizumab remains off label&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Bevacizumab is the medicament of choice in many developing countries due to its low cost&#46; However&#44; recent clinical trials such as the T Protocol compared the visual results in patients with DME randomly treated with three drugs and demonstrated that bevacizumab &#40;compared to ranibizumab and aflibercept&#41; is less effective at the anatomic level&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> After 2 years&#44; the number of patients with a central macular thickness &#60;250<span class="elsevierStyleHsp" style=""></span>&#956;m was 41&#37; with bevacizumab 1&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#44; 69&#37; with ranibizumab 0&#46;3<span class="elsevierStyleHsp" style=""></span>mg and 71&#37; with aflibercept 2<span class="elsevierStyleHsp" style=""></span>mg for all visual acuities&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> This would indicate that at least half of patients treated with bevacizumab exhibited residual fluid despite continuous and timely therapy&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">There is no clear consensus on the best therapeutic strategy for treating persistent DME&#46; There are very few studies on the switch from bevacizumab to ranibizumab&#44; one of the most important being the REEF study&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">11&#44;12</span></a> Even though the initial results appeared to indicate that patients with refractory oedema respond to the therapy switch&#44; the exact time to carry out the switch remains to be determined&#46; In fact&#44; it is not known when the therapy switch has any real beneficial effect or if the described anatomic and functional improvements are only related to the accumulation of injections and not to the switch in therapeutic agents&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The T Protocol demonstrated that most patients needed at least 9 anti-VEGF injections during the first year&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> Several analyses demonstrated the existence of a group of late responders that failed to exhibit initial response to the therapy but eventually obtained anatomic as well as visual improvements compared to those of the early responders&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">13&#8211;15</span></a> On the other hand&#44; a recent I Protocol sub-analysis demonstrated that the residual oedema at 24 weeks had dried up at the end of 3 years in 60&#37; of patients&#44; while the remaining 40&#37; still exhibited residual fluid&#46; A different analysis showed that&#44; in the I Protocol&#44; patients with significant early response &#40;&#8805;10 letters by week 12&#41; maintained this intense response throughout time&#44; and that patients with limited improvements &#40;&#60;5 gained letters&#41; maintained a limited response after three injections throughout the three years of the study&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a> Accordingly&#44; early switch supporters proposed the inclusion of a strategy to identify slow responders at an early stage in order to allow these patients to achieve better visual outcomes within an adequate period of time&#46; This proposal was set aside for a long time in due to the inability to determine whether early-switch patients responded to due to the effect of the new drug or a delayed response to the previous one&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">Patients treated with bevacizumab for DME were assessed&#44; while those who did not exhibit adequate improvement in their anatomy were switched to ranibizumab&#46; If the latter exhibited improvements&#44; they were switched again to bevacizumab&#46; The hypothesis is that if the patient that initially responded to a switch did not exhibit improvement or worsened after inverting the switch&#44; this would indicate that these patients were initially non-respondent to bevacizumab and therefore would respond to ranibizumab&#46; In addition&#44; if this were the case&#44; the early identification of these patients could avoid the application of ineffective therapy&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">A prospective&#44; single centre&#44; open&#44; without control group study was performed with patients treated for DME&#46; The study complied with the principles of the Helsinki declaration and was approved by the institutional Review Committee of the Medical College of Alexandria University &#40;Egypt&#41;&#46; All study participants provided an informed consent in writing before the switch to ranibizumab and the switch back to bevacizumab&#46; The selection of patients began in September 2015 and continued during 12 months&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Eligible patients should have a DME diagnosed by means of optical coherence tomography &#40;OCT&#41; and previous treatment with at least three monthly injections &#40;&#177; one per week&#41; of bevacizumab with unsuccessful response&#46; Unsuccessful response was defined as a &#60;10&#37; reduction in central subfield thickness &#40;CST&#41; or CST increase after at least three injections&#46; The authors chose to use anatomic parameters as main factors in order to increase the objectivity of the study&#44; taking into account that both doctor and patient were aware of the therapy switch&#46; Exclusion criteria included signs of ocular infection and antecedents involving cerebrovascular accident or myocardium infarct&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Injection protocol</span><p id="par0040" class="elsevierStylePara elsevierViewall">All patients underwent a complete ocular examination&#44; 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drawing up a comparative map to identify central thickness changes&#46; The assessment was performed after one month because it was expected that the effect of the switch to a new drug would be faster&#46; If the patient exhibited successful response &#40;&#62;10&#37; reduction in CST&#41;&#44; the reversion to bevacizumab was carried out and the patient was administered 0&#46;05<span class="elsevierStyleHsp" style=""></span>mL &#40;1&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#41; of said drug&#46; If the patient did not show any satisfactory response &#40;&#60;10&#37; reduction in CST&#41;&#44; the switch was not reversed and a second dose of ranibizumab was administered&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Data were analysed using the IBM SPSS software package version 20&#46;0 &#40;IBM Corp&#44; Armonk&#44; NY&#44; USA&#41;&#46; The Kolmogorov&#8211;Smirnov test was applied for assessing normality in distribution of variables&#46; The range test with the Wilcoxon sign was applied to compare abnormally distributed quantitative variables of two related groups&#46; The <span class="elsevierStyleItalic">t</span> for Student test was utilized for comparing normally distributed variables&#46; Spearman&#39;s correlation was utilized for correlating the main changes in BCVA and post-switch CST with various anatomical and demographic parameters&#46; Statistical significance of results was established at the level of 0&#46;05&#37;&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">The study included 31 patients&#44; with 43 eyes refractory to baseline DME treatment with bevacizumab&#46; These 43 eyes of 31 patients were switched to ranibizumab&#46; Of the 43 initialize&#44; 34 exhibited improvement in CST&#160;&#62;&#160;10&#37;&#44; whereas in 9 eyes exhibited very little or no improvement&#46; Of the 34 eyes that responded to the switch to ranibizumab&#44; 25 agreed to switch back to bevacizumab&#46; The nine remaining eyes did not switch back and received a second dose of ranibizumab&#46; Of the 25 eyes that reversed the switch to bevacizumab&#44; 4 were lost during the follow-up&#44; leaving 21 eyes that underwent the switch and its reversal for statistical analysis&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">As for patient characteristics&#44; mean age was 56&#46;4<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>7&#46;1&#59; 13 were males and 30 were females&#46; Patients had previously received a mean of 4<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>1&#46;8 bevacizumab injections and the mean duration of oedema was 12<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>10&#46;5 months &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Patients who switched to ranibizumab exhibited statistically significant BCVA improvement of 0&#46;67<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>0&#46;39 to 0&#46;55<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>0&#46;36 logMAR &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Overall&#44; the patients exhibited statistically significant CST reduction having a mean value of 475&#46;3<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>122&#46;8 to 417&#46;3<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>109&#46;1 &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">A search for correlations between BCVA changes and patient characteristics found that neither sex&#44; age nor previous photocoagulation stage or number of previous injection and duration of oedema influenced patient results &#40;<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a>&#41;&#46; Similar results were obtained when correlating CST changes with demographic and clinical factors&#46; However&#44; it was observed that patients with neurosensory detachment &#40;NSD&#41; with or without intraretinal cysts &#40;IRCs&#41; exhibited a significantly higher anatomical improvement &#40;118&#46;69<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>169&#46;4<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; when compared to patients with only IRC &#40;31&#46;7<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>65&#46;7<span class="elsevierStyleHsp" style=""></span>&#956;m&#59; <span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;019&#41;&#46; Similarly&#44; when seeking a correlation between CST changes and baseline CST it was observed that patients with higher baseline CST exhibited more reduction than those with lower baseline CST &#40;<span class="elsevierStyleItalic">P</span>&#160;&#60;&#160;0&#46;05&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Out of the 43 eyes that took part of the study&#44; 21 were switched to ranibizumab and switched back again to bevacizumab&#46; These patients exhibited significant CST reduction &#40;<span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;003&#41; as well as important BCVA improvement &#40;<span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;001&#41; after the switch to ranibizumab&#46; However&#44; when reversing the change to bevacizumab&#44; the mean CST increased slightly from 374<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>72<span class="elsevierStyleHsp" style=""></span>&#956;m &#40;post-switch to ranibizumab&#41; to a mean of 404&#46;9<span class="elsevierStyleHsp" style=""></span>&#160;&#177;&#160;<span class="elsevierStyleHsp" style=""></span>106&#46;3 post-switch back to bevacizumab &#40;<span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;197&#41;&#46; A similar observation was made for BCVA&#58; after the switch the mean was 0&#46;3<span class="elsevierStyleHsp" style=""></span>logMAR&#44; and after reversing the switch a slight and nonsignificant worsening to 0&#46;4<span class="elsevierStyleHsp" style=""></span>logMAR &#40;<span class="elsevierStyleItalic">P</span>&#160;&#61;&#160;0&#46;266&#41; was observed &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Few studies have analysed the effect of changing bevacizumab for other anti-VEGF in DME patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">11&#44;12</span></a> This is in contrast with wet age-related macular degeneration where the effect of switching between anti-VEGF in refractory cases has been broadly studied&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">17&#8211;23</span></a> The switch to aflibercept or ranibizumab has been demonstrated in refractory cases and has generally shown variable degrees of visual and anatomic improvement&#44; making this a reasonable option in selected wet age-related macular degeneration patients&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Very few studies have investigated the effect of switching from bevacizumab to ranibizumab in patients with DME&#46; The REEF study<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> was one of the longest studies researching this switch&#46; The number of patients included in the said study was 43&#44; who had received 4&#46;7 bevacizumab injections before the switch&#46; The patients were assessed after 3 injections of ranibizumab 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg and&#44; if exhibiting residual oedema&#44; were switched to 3 injections of ranibizumab 2&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#46; Patients exhibited an improvement of &#43;6&#46;4 letters by the third month with central macular thickness reduction of 113<span class="elsevierStyleHsp" style=""></span>&#956;m&#46; The present study produced similar results&#44; with a significant improvement in visual acuity and anatomy of patients previously treated with bevacizumab&#46; This study also analysed a subgroup to identify factors that could indicate improved response to the switch&#46; It identified that age&#44; sex&#44; previous number of injections and duration of the oedema had no effect on the response obtained after the switch&#46; It can be assumed that the previous number of injections is in some way related to the duration of oedema and that it does not influence the response to the switch&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">An interesting factor was the response based on OCT characteristics&#58; it was found that cases with NSD&#44; with or without IRC&#44; exhibited a significantly higher response to the switch compared to cases with IRC only&#46; Even though the exact reason is not clear&#44; previous data of a subsequent RISE&#47;RIDE analysis showed that patients with NSD exhibited a better anatomical response to ranibizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> However&#44; recent data from the BOLT study&#44; that researched the effects of bevacizumab in DME&#44; demonstrated that 57&#37; of nonresponders had baseline NSD and persistent oedema at 24 months&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</span></a> It has not yet been determined whether patients with NSD tend to be more refractory to bevacizumab or if cases that are refractory to bevacizumab simply respond better to the switch&#46; It has also been found that patients with higher baseline CST exhibited a more robust response to the switch&#46; These data seem to match those of the T Protocol which demonstrated a significant anatomical superiority of ranibizumab compared to bevacizumab in DME cases&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> Perhaps bevacizumab is not able to adequately treat patients with increased macular thickness and the switch enables enhanced anatomical improvements&#46; It should be noted that this difference was not accompanied by visual acuity improvements in patients with increased CST&#44; who did not exhibit better visual results&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The second part of the study involved reversing the switch for patients who had responded to the initial switch back again to the original medicament&#44; i&#46;e&#46;&#44; bevacizumab&#46; The results indicated that&#44; after reversing the switch&#44; the patients did not exhibit anatomical or visual improvements&#46; However&#44; a slight and not statistically significant worsening of the subfoveal central thickness was evidenced&#46; The concept of switching both medicaments has become controversial&#46; Some authors recommend an early switch while others recommend a later switch in the course of treatment enabling the identification of late responders&#46; Proponents of later switches affirm that patients showing poor early response actually respond later to continuous treatment&#46; A post hoc analysis of BOLT&#44; RISE&#47;RIDE and the I Protocol identified a subgroup of patients defined as late responders who exhibited said belated response with successful final visual acuity&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">13&#8211;15</span></a> Likewise&#44; a recent CATT analysis demonstrated that visual and anatomic gains reported in patients with age-related macular degeneration who switched from bevacizumab to aflibercept was similar to the gains obtained by CATT patients eligible for a switch at month 3 of treatment but were maintained with the same medicaments during one year&#46; Said analysis concluded that these patients are part of a &#8220;slow responder&#8221; group that eventually respond to ongoing treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a> On the other hand&#44; recent data of a Protocol I analysis carried out by Dugel demonstrated that patients with robust early response &#40;&#8805;10 letters by week 12&#41; maintained this significant response in time and in turn patients with limited response after three injections &#40;&#60;5 letter gain&#41; demonstrated small improvement throughout the 3-year-long study&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In any debate related to switching medicaments&#44; the crux of the matter is always whether patients who switched the drug improved due to being slow responders or to the switch itself&#46; In the present study&#44; the fact that patients who demonstrated initial response to ranibizumab halted their improvement seems to indicate that it was due to the effect of the new drug&#46; If it would have been due to a slow response&#44; the majority would have continued after reversing the switch&#46; This study was designed to obtain a specific answer to that question but not to address long-term treatment results&#46; It is still not known whether in the long term&#44; after several ranibizumab injections&#44; patients will evolve better or worse than those who continued with bevacizumab&#46; In any case&#44; the data of the last two years of the T Protocol have demonstrated that patients treated with bevacizumab&#44; aflibercept or ranibizumab exhibited improvements with similar visual acuity and that the main difference between them is anatomical&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> If these anatomical differences change in the course of a five-year treatment is yet to be determined&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">A limitation of the present study was the relatively small number of patients&#44; the absence of randomization and a control group maintaining the same treatment without switches&#46; However&#44; the anatomical inclusion criteria reduced bias and was prospective&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In conclusion&#44; switching from bevacizumab to ranibizumab could influence the short-term results in patients with refractory DME regardless of age&#44; sex or treatment length&#46; At any rate&#44; it appears that patients with thicker baseline CST and NSD exhibited the best response when switching from bevacizumab to ranibizumab&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interest</span><p id="par0110" class="elsevierStylePara elsevierViewall">Patricio Schlottman&#58; <span class="elsevierStyleItalic">speaker</span> for Bayer&#44; Novartis and Genentech&#59; consultant of Novartis and Roche&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Mohammed Ashraf&#44; Ahmed Souka&#44; Hassan El Kayal&#44; Malena Daich Varela&#58; These authors declare no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Abstract"
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    "fechaRecibido" => "2017-11-04"
    "fechaAceptado" => "2018-04-09"
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          "palabras" => array:7 [
            0 => "Retina"
            1 => "Macula"
            2 => "Diabetic macular oedema"
            3 => "Refractory"
            4 => "Ranibizumab"
            5 => "Bevacizumab"
            6 => "Switch"
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1040911"
          "palabras" => array:7 [
            0 => "Retina"
            1 => "M&#225;cula"
            2 => "Edema macular diab&#233;tico"
            3 => "Refractario"
            4 => "Ranibizumab"
            5 => "Bevacizumab"
            6 => "Cambio"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Aim</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the efficacy of switching to ranibizumab in patients with diabetic macular oedema refractory to treatment with bevacizumab&#44; and to evaluate the outcomes when switching back to bevacizumab&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective study was conducted that included 43 eyes of 31 patients refractory to previous bevacizumab treatment&#46; The patients were switched to ranibizumab&#44; and optical coherence tomography was performed one month post-injection&#46; Patients showing improvement &#40;&#62;10&#37; reduction in central sub-field thickness&#41; were switched back to bevacizumab&#44; and optical coherence tomography was performed one month post-switch back&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The 34 eyes switched to ranibizumab showed a statistically significant improvement in mean best corrected visual acuity from 0&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;39 logMAR to a mean of 0&#46;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;36 logMAR &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; In addition&#44; there was a statistically significant decrease in central subfield thickness &#40;CST&#41; from a mean of 475&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>122&#46;8 to a mean of 417&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>109&#46;1 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; In the 21 eyes that were switched back to bevacizumab&#44; there was no significant difference either in the change in CST or in the change in best corrected visual acuity post-switch back&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Switching to ranibizumab in patients improves both the best corrected visual acuity and CST in diabetic patients refractory to previous bevacizumab treatment&#46; This effect is pronounced in patients with increased CST prior to the switch&#46; Switching back to bevacizumab adds no further improvement&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Determinar la eficacia del cambio a ranibizumab en pacientes con edema macular diab&#233;tico refractario a bevacizumab y&#44; posteriormente&#44; evaluar los resultados tras volver al tratamiento inicial con bevacizumab&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se llev&#243; a cabo un estudio prospectivo que incluy&#243; 43 ojos de 31 pacientes refractarios al tratamiento previo con bevacizumab&#46; Se realiz&#243; el cambio a ranibizumab y se control&#243; mediante tomograf&#237;a &#243;ptica de coherencia un mes despu&#233;s de la inyecci&#243;n&#46; A aquellos que mostraron mejor&#237;a &#40;reducci&#243;n &#62;10&#37; en el espesor macular central&#41; se les realiz&#243; una reversi&#243;n del cambio a bevacizumab y fueron evaluados con tomograf&#237;a &#243;ptica de coherencia un mes despu&#233;s de este cambio&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los pacientes tratados con el cambio a ranibizumab mostraron una mejor&#237;a estad&#237;sticamente significativa en su mejor agudeza visual corregida&#44; con una media de 0&#44;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;39 a 0&#44;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;36 logMAR &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; Asimismo&#44; hubo una disminuci&#243;n estad&#237;sticamente significativa en el espesor macular con una media de 475&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>122&#44;8 a 417&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>109&#44;1 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; A 21 ojos se les realiz&#243; una reversi&#243;n del cambio a bevacizumab&#46; No hubo una diferencia significativa en el espesor del subcampo central &#40;ESC&#41; ni en la mejor agudeza visual corregida tras este cambio&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El cambio a ranibizumab mejor&#243; tanto la agudeza visual como el ESC en pacientes diab&#233;ticos refractarios al tratamiento previo con bevacizumab&#46; Este efecto fue m&#225;s marcado en pacientes con aumento del ESC antes del cambio a ranibizumab&#46; Volver al tratamiento con bevacizumab no supuso ninguna mejor&#237;a&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Please cite this article as&#58; Ashraf M&#44; Souka AA&#44; Daich Varela M&#44; el Kayal H&#44; Schlottmann PG&#46; Cambio a ranibizumab en edema macular diab&#233;tico refractario al tratamiento con bevacizumab&#46; Arch Soc Esp Oftalmol&#46; 2018&#59;93&#58;523&#8211;529&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">SD&#58; standard deviation&#59; NSD&#58; neurosensory detachment&#59; OCT&#58; optical coherence tomography&#59; PFC&#58; retinal panphotocoagulation&#59; IRC&#58; intra-retinal cysts&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD or number of cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age in years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">56&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sex &#40;male&#47;female&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Previous injections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Duration of oedema prior to switch&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">OCT characteristics &#40;NSD&#47;IRC&#41; &#40;43 eyes&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#47;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PFC&#47;no PFC &#40;43 eyes&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#47;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Demographic data of patients before switching to ranibizumab &#40;43 eyes of 31 patients&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">CST&#58; central subfield thickness &#40;central macular thickness&#41;&#59; SD&#58; standard deviation&#59; BCVA&#58; best corrected visual acuity&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Prior to switch&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Post-switch&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Significance test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">BCVA &#40;LogMar&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleItalic">t</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;37<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a></td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">&#60;0&#46;05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Median&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">CST &#40;&#956;m&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">475&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>122&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">417&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>109&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Z</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;3&#46;7<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;&#42;</span></a></td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">&#60;0&#46;05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Median&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">462&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">396&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Paired <span class="elsevierStyleItalic">t</span>-test&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "&#42;&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Range test with Wilcoxon sign of obtained results was 5&#37;&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Comparison between the baseline and post-switch best corrected visual acuity and macular thickness&#46;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">CST&#58; central subfield thickness &#40;central macular thickness&#41;&#59; NSD&#58; neurosensory detachment&#59; BCVA&#58; best corrected visual acuity&#59; PFC&#58; retinal panphotocoagulation&#59; IRC&#58; intraretinal cysts&#59; OCT&#58; optical coherence tomography&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Changes in BCVA &#40;Log MAR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Sig&#46; test &#40;<span class="elsevierStyleItalic">t</span>-test&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Changes in CST &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Sig&#46; test &#40;<span class="elsevierStyleItalic">t</span>-test&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Sex</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;10<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;103&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>52&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;123<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">59&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>131&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Characteristics in OCT</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>NSD&#177;IRC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;166<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;224&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">118&#46;69<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>169&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;019<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>IRC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;095<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>65&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">PFC</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>PFC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;13<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>117&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;214&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>No PFC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;092<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">69&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>106&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Ratio between BCVA and CST changes post-switch to ranibizumab and sex&#44; PFC status and characteristics in OCT&#46;</p>"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">The significance of obtained results was 5&#37;&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">CST&#58; central subfield thickness &#40;central macular thickness&#41;&#59; BCVA&#58; best corrected visual acuity&#46;</p>"
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                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Change in BCVA &#40;Log MAR&#41; <span class="elsevierStyleItalic">r</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;197&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Ratio between age&#44; oedema duration&#44; number of injections and baseline CST and post-switch BCVA and CST changes utilizing Spearman&#39;s correlation &#40;<span class="elsevierStyleItalic">r</span>&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">The significance of obtained results was 0&#46;0125&#37; &#40;Bonferroni correction&#41;&#46;</p>"
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Post-switch&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Comparison between best corrected visual acuity &#40;logMAR&#41; and central macular thickness espesor macular pre-switch&#44; post-switch to ranibizumab and post-switch reversion to bevacizumab&#46;</p>"
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      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:25 [
            0 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetic retinopathy and diabetic macular edema&#58; pathophysiology&#44; screening&#44; and novel therapies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "T&#46;A&#46; Ciulla"
                            1 => "A&#46;G&#46; Amador"
                            2 => "B&#46; Zinman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
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                        "volumen" => "26"
                        "paginaInicial" => "2653"
                        "paginaFinal" => "2664"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12941734"
                            "web" => "Medline"
                          ]
                        ]
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                          "estado" => "S300"
                          "issn" => "02105705"
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              "etiqueta" => "2"
              "referencia" => array:1 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema&#58; the RESTORE extension study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "U&#46; Schmidt-Erfurth"
                            1 => "G&#46;E&#46; Lang"
                            2 => "F&#46;G&#46; Holz"
                            3 => "R&#46;O&#46; Schlingemann"
                            4 => "P&#46; Lanzetta"
                            5 => "P&#46; Massin"
                          ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ophtha.2013.11.041"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ophthalmology"
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                        "paginaInicial" => "1045"
                        "paginaFinal" => "1053"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24491642"
                            "web" => "Medline"
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              "identificador" => "bib0140"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intravitreal aflibercept for diabetic macular edema"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;F&#46; Korobelnik"
                            1 => "D&#46;V&#46; Do"
                            2 => "U&#46; Schmidt-Erfurth"
                            3 => "D&#46;S&#46; Boyer"
                            4 => "F&#46;G&#46; Holz"
                            5 => "J&#46;S&#46; Heier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ophtha.2014.05.006"
                      "Revista" => array:6 [
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                        "paginaInicial" => "2247"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25012934"
                            "web" => "Medline"
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            3 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "4"
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                0 => array:3 [
                  "comentario" => "e1072"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema &#40;BOLT study&#41; 12-month data&#58; Report 2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Michaelides"
                            1 => "A&#46; Kaines"
                            2 => "R&#46;D&#46; Hamilton"
                            3 => "S&#46; Fraser-Bell"
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                          ]
                        ]
                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ophtha.2010.03.045"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ophthalmology"
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                        "volumen" => "117"
                        "paginaInicial" => "1078"
                        "paginaFinal" => "1086"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20416952"
                            "web" => "Medline"
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                        ]
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            4 => array:3 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Ranibizumab for diabetic macular edema&#58; results from 2 phase III randomized trials&#58; RISE and RIDE"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Q&#46;D&#46; Nguyen"
                            1 => "D&#46;M&#46; Brown"
                            2 => "D&#46;M&#46; Marcus"
                            3 => "D&#46;S&#46; Boyer"
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                            5 => "L&#46; Feiner"
                          ]
                        ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ophtha.2011.12.039"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ophthalmology"
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                        "volumen" => "119"
                        "paginaInicial" => "789"
                        "paginaFinal" => "801"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22330964"
                            "web" => "Medline"
                          ]
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                      ]
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            5 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment&#58; three-year randomized trial results"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "Diabetic Retinopathy Clinical Research Network&#46;"
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;J&#46; Elman"
                            1 => "H&#46; Qin"
                            2 => "L&#46;P&#46; Aiello"
                            3 => "R&#46;W&#46; Beck"
                            4 => "N&#46;M&#46; Bressler"
                            5 => "F&#46;L&#46; Ferris 3rd&#46;"
                          ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ophtha.2012.08.022"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ophthalmology"
                        "fecha" => "2012"
                        "volumen" => "119"
                        "paginaInicial" => "2312"
                        "paginaFinal" => "2318"
                        "link" => array:1 [
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