Agentes antiinflamatorios no esteroideos para el tratamiento del edema macular cistoide posterior a la cirugía de catarata
Resumen
Antecedentes
La cirugía de cataratas es la cirugía por incisión ambulatoria más frecuente que se realiza en EE.UU. El edema macular cistoide (EMC), la acumulación de líquido en la retina central debido a fugas de los capilares dilatados, es la causa más común de deterioro de la visión tras la cirugía de cataratas. El EMC agudo, definido como un edema de menos de cuatro meses de duración, a menudo se resuelve de forma espontánea. El EMC que persiste durante cuatro meses o más se denomina EMC crónico. Para tratar el EMC se han utilizado los antiinflamatorios no esteroideos (AINE). Esta actualización añade nueva evidencia y análisis a la revisión publicada anteriormente.
Objetivos
Examinar la efectividad de los AINE en el tratamiento del EMC después de la cirugía de cataratas.
Métodos de búsqueda
Se realizaron búsquedas en las bases de datos CENTRAL (2022, número 3); Ovid MEDLINE; Embase; PubMed; LILACS; mRCT (interrumpida en 2014, última búsqueda en agosto de 2011), ClinicalTrials.gov e ICTRP de la OMS. No se utilizaron restricciones de fecha ni de idioma en la búsqueda electrónica de los ensayos. El 20 de marzo de 2022 se realizó la última búsqueda en las bases de datos electrónicas.
Criterios de selección
Se incluyeron los ensayos controlados aleatorizados que evaluaron los efectos de los AINE en el tratamiento del EMC después de la cirugía de cataratas.
Obtención y análisis de los datos
Dos autores de la revisión examinaron de forma independiente todos los títulos y resúmenes, revisaron las publicaciones de texto completo según los criterios de elegibilidad, extrajeron de forma independiente los datos de los nuevos ensayos incluidos y evaluaron el riesgo de sesgo de cada ensayo incluido. Se estableció contacto con los autores de los ensayos para obtener aclaraciones o solicitar la información faltante. Se proporcionó una síntesis narrativa de todos los ensayos incluidos y sus resultados. En el caso de los desenlaces continuos y dicotómicos, se realizaron análisis agrupados por separado y se proporcionó la diferencia de medias (DM) y la razón de riesgos (RR), así como el intervalo de confianza (IC) del 95% asociado, siempre que fue posible. Dos autores de la revisión evaluaron de forma independiente la certeza general de la evidencia para cada desenlace mediante el método GRADE.
Resultados principales
Se incluyeron nueve ensayos con un total de 390 participantes (393 ojos). La media de edad de los participantes del estudio fue 72,2 años (intervalo intercuartílico [IQR]: 68,8 a 73,6) y el 72% fueron mujeres (IQR: 69% a 74%). Tres ensayos incluyeron participantes con EMC agudo y cuatro incluyeron participantes con EMC crónico. Los dos ensayos restantes incluyeron tanto participantes con EMC agudo como crónico o participantes con EMC de duración desconocida. Los ensayos se consideraron de riesgo de sesgo incierto (33%) o alto (67%).
Mejoría visual de dos o más líneas al final del tratamiento
Los datos de un ensayo en participantes con EMC agudo no muestran efectos del tratamiento con ketorolaco tópico en comparación con placebo (RR 2,00; IC del 95%: 0,46 a 8,76; 22 participantes). Los datos de un ensayo de tres grupos en participantes con EMC agudo demuestran que, en comparación con la prednisolona tópica, el ketorolaco tópico (RR 1,33; IC del 95%: 0,58 a 3,07; 17 participantes) o el tratamiento combinado con ketorolaco tópico y prednisolona (RR 1,78; IC del 95%: 0,86 a 3,69; 17 participantes) podrían tener poco o ningún efecto sobre la mejoría visual. Los resultados del análisis de subgrupos de dos estudios en participantes con EMC crónico indican que, después del tratamiento durante 90 días o más, los AINE podrían aumentar la probabilidad de mejoría visual de los participantes en 1,87 veces (RR 2,87; IC del 95%: 1,58 a 5,22; I2 = 33%; dos ensayos, 121 participantes) en relación con el placebo. Sin embargo, no hubo evidencia de efectos del tratamiento en el subgrupo con dos meses de tratamiento o menos (RR 0,72; IC del 95%: 0,30 a 1,73; p = 0,19; I2 = 41%; dos ensayos, 34 participantes). En general, esta evidencia es de certeza muy baja.
La estimación de un solo estudio en pacientes con EMC mixto indica que el diclofenaco tópico podría aumentar la probabilidad de mejoría visual en un 40% en comparación con el ketorolaco tópico (RR 1,40; IC del 95%: 1,02 a 1,94; 68 participantes). Sin embargo, el mismo ensayo no informó diferencias entre los grupos en la agudeza visual final media en líneas de Snellen (DM 0,40; IC del 95%: ‐0,93 a 1,73). Un ensayo de tres grupos en pacientes con EMC mixto que informó cambios visuales en las letras ETDRS en comparaciones entre ketorolaco y diclofenaco (34 participantes) o bromfenaco (34 participantes) no indica evidencia de efectos. En general, los AINE podrían mejorar ligeramente la agudeza visual en participantes con EMC mixto, pero la evidencia no está muy clara.
Persistencia de la mejoría de la visión un mes después de la interrupción del tratamiento
Un ensayo de participantes con EMC crónico probó indometacina por vía oral (RR 0,40; IC del 95%: 0,10 a 1,60; 20 participantes) y el otro comparó ketorolaco tópico con placebo (RR 4,00; IC del 95%: 0,51 a 31,1; 26 participantes). Aunque no hay evidencia de efectos del tratamiento, la evidencia indica una heterogeneidad importante entre los grupos (p = 0,07, I2 = 69,9%; evidencia de certeza muy baja). Ninguno de los ensayos en pacientes con EMC agudo o mixto informó acerca de este desenlace.
Proporción de participantes con mejoría de la fuga en la angiografía con fluoresceína del fondo de ojo
Un ensayo de tres grupos en participantes con EMC agudo muestra que, en comparación con la prednisolona tópica, no hay efecto terapéutico beneficioso del ketorolaco tópico (RR 1,11; IC del 95%: 0,45 a 2,75; 17 participantes) o del tratamiento combinado con ketorolaco tópico y prednisolona tópica (RR 1,56; IC del 95%: 0,72 a 3,38; 17 participantes). La evidencia es de certeza muy baja.
La estimación combinada de dos ensayos en participantes con EMC crónico indica que los AINE tienen poco o ningún efecto sobre el placebo en la mejoría de las fugas (RR 1,93; IC del 95%: 0,62 a 6,02; 40 participantes; evidencia de certeza muy baja). Ninguno de los ensayos en pacientes con EMC mixto informó acerca de este desenlace.
Proporción de participantes con sensibilidad al contraste mejorada
Evidencia de certeza muy baja de un ensayo en participantes con EMC agudo no muestra efectos beneficiosos del tratamiento con ketorolaco (RR 1,11; IC del 95%: 0,45 a 2,75; 17 participantes) o del tratamiento combinado con ketorolaco y prednisolona (RR 1,78; IC del 95%: 0,86 a 3,69; 17 participantes) en comparación con la prednisolona tópica. Ninguno de los ensayos en pacientes con EMC crónico o mixto informó acerca de este desenlace.
Proporción de participantes con mejoría del grosor macular central en la tomografía de coherencia óptica; medidas de calidad de vida
Ningún ensayo incluido informó acerca de estos desenlaces.
Efectos adversos
La mayoría de los ensayos no observaron diferencias en los episodios adversos oculares, como toxicidad corneal o presión intraocular elevada, entre los grupos de comparación.
Conclusiones de los autores
La evidencia sobre los efectos de los AINE en pacientes con EMC es muy incierta y se justifica la realización de más estudios de investigación. Los hallazgos de esta revisión se ven limitados por el pequeño tamaño muestral y la heterogeneidad de las intervenciones, las evaluaciones y los informes de los desenlaces clínicamente importantes.
PICO
Resumen en términos sencillos
¿Cuáles son los efectos beneficiosos de los AINE para tratar la acumulación de líquido en la retina central (mácula) tras la cirugía de cataratas?
Mensajes clave
• Se actualizó la evidencia sobre los efectos de los medicamentos antiinflamatorios no esteroideos (AINE, como el ibuprofeno) entre los individuos con acumulación aguda o crónica de líquido en la retina central (mácula) después de la cirugía de cataratas.
• Solo hubo evidencia no muy clara de que los AINE pudieran mejorar la visión o reducir la acumulación de líquido en la mácula.
• Se necesitan más estudios de investigación para aportar evidencia de calidad.
¿Qué es el edema macular cistoide (EMC)?
La cirugía de cataratas es la intervención ambulatoria más frecuente en EE.UU. A veces, tras la cirugía de cataratas, la inflamación del interior del ojo provoca la salida de líquido de los vasos sanguíneos de la retina, lo que da lugar a la acumulación de líquido en espacios similares a quistes y a la inflamación de la parte central de la retina (mácula). Esto se denomina "edema macular cistoide", o EMC, y puede causar visión reducida o distorsionada. El EMC es una de las complicaciones más frecuentes tras la cirugía de cataratas.
¿Cómo se trata el EMC?
El EMC que se produce después de la cirugía de cataratas se suele tratar con AINE u otros medicamentos para reducir la inflamación dentro del ojo. Los AINE se suelen aplicar directamente en el ojo (tópicos) en forma de colirio. Se pueden administrar solos o con otro medicamento, como un esteroide tópico u otro AINE.
¿Qué se quería averiguar?
Se quería saber si los AINE, administrados solos o combinados con otros medicamentos, pueden ayudar a las personas con EMC tras una operación de cataratas a ver con más claridad.
¿Qué se hizo?
Se buscaron estudios que asignaran al azar adultos con EMC después de la cirugía de cataratas para ser tratados con AINE, solos o con otros medicamentos. Los estudios compararon los AINE con placebo (un medicamento ficticio sin principios activos) u otro tratamiento activo (esteroide u otro AINE). Se compararon y resumieron los resultados de los estudios y la confianza en la evidencia se evaluó sobre la base de factores como la metodología y el tamaño de los estudios.
¿Qué se encontró?
Se incluyeron nueve estudios con un total de 390 personas con una media de edad de 72 años. El 72% eran mujeres. Tres estudios incluyeron exclusivamente a personas con EMC agudo (acumulación de líquido en la mácula de menos de cuatro meses de duración) después de la cirugía de cataratas, cuatro estudios incluyeron a personas con EMC crónico (presencia de líquido en la mácula que persistió durante cuatro meses o más) después de la cirugía de cataratas, y los dos estudios restantes incluyeron a personas con duraciones variables de acumulación de líquido en la mácula después de la cirugía.
• Personas con EMC agudo: Los AINE podrían mejorar la visión o reducir la inflamación de la retina en comparación con placebo o un esteroide tópico (tres estudios).
• Personas con EMC crónico: dos estudios que trataron a personas con EMC crónico con AINE durante dos meses o menos no mostraron efectos sobre la mejoría de la visión. Por el contrario, los otros dos estudios indicaron que los AINE podrían mejorar la visión tras 90 a 120 días de tratamiento. No se encontró evidencia acerca de los efectos de los AINE sobre otros desenlaces, como la mejoría persistente de la visión después de interrumpir el tratamiento o la reducción de la acumulación de líquido en la mácula.
• No se sabe la duración del EMC: un AINE tópico podría tener poco o ningún efecto sobre la visión en comparación con otro AINE.
La mayoría de los estudios incluidos no proporcionaron datos sobre los efectos no deseados o no informaron sobre las diferencias en los efectos no deseados entre los grupos que recibieron diferentes tratamientos.
¿Cuáles son las limitaciones de la evidencia?
La confianza en la evidencia fue limitada porque los estudios no incluyeron muchos participantes y utilizaron diferentes medicamentos en distintas cantidades durante diversas duraciones. Los estudios no examinaron todos los desenlaces de interés. Los resultados también se vieron limitados por el hecho de que los ensayos se publicaron entre 1977 y 2006, y desde entonces se han producido muchos avances en las técnicas de cirugía de cataratas.
¿Cuál es el grado de actualización de esta evidencia?
La evidencia está actualizada hasta marzo de 2022.
Authors' conclusions
Summary of findings
| Non‐steroidal anti‐inflammatory drug vs placebo or active control for acute cystoid macular edema following cataract surgery | ||||||
|---|---|---|---|---|---|---|
| Patient population: participants with acute CME (< 4 months) following cataract surgery Settings: private clinics or medical centers in the USA Intervention: ketorolac, diclofenac Comparison: placebo, prednisolone, ketorolac + prednisolone | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No. of participants (RCTs) | Certainty of evidence (GRADE) | Comments | |
| Assumed risk* Placebo or prednisolone | Corresponding risk NSAID ± prednisolone | |||||
| Visual improvement at end of treatment, as defined by two or more Snellen lines | Placebo | Ketorolac 36 (8 to 100) per 100 | RR 2.00 (0.46 to 8.76) | 22 (1 RCT) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better. Besides Flach 1998 (22 participants) and Heier 2000 (26 participants), Rho 2003 (34 participants) compared mean final VA between participants receiving ketorolac with those receiving diclofenac (20/50 vs 20/49) and concluded no overall differences |
| Prednisolone 50 per 100
| Ketorolac 67 (29 to 100) per 100 | RR 1.33 (0.58 to 3.07) | 17 (1 RCT) | |||
| Ketorolac + prednisolone 89 (43 to 100) per 100 | RR 1.78 (0.86 to 3.69) | 17 (1 RCT) | ||||
| Persistence of visual improvement one month after discontinuation of treatment | Not measured by any included trial
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| Improvement in leakage on FFA
| Prednisolone 50 per 100
| Ketorolac 56 (23 to 100) per 100 | RR 1.11 (0.45 to 2.75) | 17 (1 RCT) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better. Data from the same 3‐arm trial (Heier 2000) |
| Ketorolac + prednisolone 78 (36 to 100) per 100 | RR 1.56 (0.72 to 3.38) | 17 (1 RCT) | ||||
| Improvement in central macular thickness on OCT | Not measured by any included trial
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| Improved contrast sensitivity
| Prednisolone 50 per 100 | Ketorolac 56 (23 to 100) per 100 | RR 1.11 (0.45 to 2.75) | 17 (1 RCT) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better Data from the same 3‐arm trial (Heier 2000) |
| Ketorolac + prednisolone 89 (43 to 100) per 100 | RR 1.78 (0.86 to 3.69) | 17 (1 RCT) | ||||
| Change in QoL | Not measured by any included trial
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| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and the associated 95% CI).
CI: confidence interval; CME: cystoid macular edema; FFA: fundus fluorescein angiography (angiogram); NSAID: non‐steroidal anti‐inflammatory drug; OCT: optical coherence tomography; QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded for risk of bias (‐1), imprecision (‐1) and heterogeneity (‐1). | ||||||
| Non‐steroidal anti‐inflammatory drug vs active control for chronic cystoid macular edema following cataract surgery | ||||||
|---|---|---|---|---|---|---|
| Patient population: participants with chronic CME (≥ 4 months) following cataract surgery Settings: medical centers in the USA Intervention: topical ketorolac, topical fenoprofen, oral indomethacin Comparison: placebo (vehicle or saline) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No. of participants (RCTs) | Certainty of evidence (GRADE) | Comments | |
| Assumed risk* Placebo | Corresponding risk NSAID | |||||
| Visual improvement at end of treatment, as defined by two or more Snellen lines
| Treatment duration ≤ 2 months 44 per 100 | 32 (13 to 76) per 100 | RR 0.72 (0.30 to 1.73) | 34 (2 RCTs) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better. When excluding Yannuzzi 1977, which examined oral NSAID, there was no evidence of subgroup differences and the combined RR was 2.33 (95% CI 1.17 to 4.66; 3 RCTs, 135 participants), favoring topical NSAIDs over placebo in visual improvement after at least 90 days of treatment. |
| Treatment duration 90‐120 days 18 per 100 | 52 (28 to 94) per 100 | RR 2.87 (1.58 to 5.22) | 121 (2 RCTs) | |||
| Persistence of visual improvement one month after discontinuation of treatment | 26 per 100 | 30 (11 to 80) per 100 | RR 1.17 (0.44 to 3.07) | 46 (2 RCTs) | ⊕⊝⊝⊝ Very lowb |
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| Improvement in leakage on FFA
| 14 per 100 | 27 (9 to 84) per 100 | RR 1.93 (0.62 to 6.02) | 40 (2 RCTs) | ⊕⊝⊝⊝ Very lowb | RR > 1 is better. |
| Improvement in central macular thickness on OCT | Not measured by any included trial |
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| Improved contrast sensitivity | Not measured by any included trial |
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| Change in QoL | Not measured by any included trial |
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| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and the associated 95% CI).
CI: confidence interval; CME: cystoid macular edema; FFA: fundus fluorescein angiography (angiogram); NSAID: non‐steroidal anti‐inflammatory drug; OCT: optical coherence tomography; QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded for risk of bias (‐1), imprecision (‐1) and heterogeneity (‐1). | ||||||
| Non‐steroidal anti‐inflammatory drug vs active control for cystoid macular edema following cataract surgery | ||||||
|---|---|---|---|---|---|---|
| Patient population: participants with acute or chronic CME following cataract surgery Settings: private clinics in the USA or medical centers in Canada Intervention: bromfenac, diclofenac ± prednisolone, ketorolac ± prednisolone Comparison: ketorolac ± prednisolone | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No. of participants (RCTs) | Certainty of evidence (GRADE) | Comments | |
| Assumed risk* Active control | Corresponding risk NSAID | |||||
| Visual improvement at end of treatment, as defined by two or more Snellen lines | Diclofenac + prednisolone 59 per 100 | Ketorolac + prednisolone 83 (60 to 100) per 100 | RR 1.40 (1.02 to 1.94) | 68 (1 RCT) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better. Rho 2004 also reported this outcome in Snellen lines (MD 0.40, 95% CI −0.93 to 1.73; 68 participants) Rho 2006 reported in ETDRS letters (MD 0.90, 95% CI −4.31 to 6.11; 34 participants) considering data from the diclofenac group or (MD 1.20, 95% CI −4.58 to 6.98; 34 participants) considering data from the bromfenac group |
| Persistence of visual improvement one month after discontinuation of treatment | Not measured by any included trial
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| Improvement in leakage on FFA | Not measured by any included trial
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| Improvement in central macular thickness on OCT | Not measured by any included trial
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| Improved contrast sensitivity | Not measured by any included trial |
| ||||
| Change in QoL | Not measured by any included trial |
| ||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and the associated 95% CI).
CI: confidence interval; CME: cystoid macular edema; ETDRS: Early Treatment Diabetic Retinopathy Study; FFA: fundus fluorescein angiography (angiogram); NSAID: non‐steroidal anti‐inflammatory drug; OCT: optical coherence tomography; QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded for risk of bias (‐1), imprecision (‐1) and inconsistency (‐1). | ||||||
Background
Cystoid macular edema (CME) is the presence of excess fluid in the extracellular space of the neurosensory retina presenting clinically with cyst‐like spaces and abnormal thickening of the central part of the retina (the macula). Cystoid macular edema following cataract surgery was first described by Irvine in 1953 (Irvine 1953), and Gass and Norton published the first detailed microscopic and fluorescein angiographic description of this condition in 1966 (Gass 1966); the entity later became known as Irvine‐Gass syndrome or pseudophakic CME. Cataract surgery is the most common ambulatory incisional surgery performed in the USA (Steiner 2014), with CME being one of its most frequent postoperative complications.
Description of the condition
Pseudophakic CME impairing patients’ vision has been reported to occur in 1% to 2% of patients, with a peak incidence occurring six weeks postoperatively, but subclinical CME may be observed on fluorescein angiography in about 30% of patients, and on optical coherence tomography in up to 40% of patients (Henderson 2007; Perente 2007; Shelsta 2010). Despite the many advances in cataract surgery techniques, clinically significant CME following modern cataract surgery has been reported to occur in about 2% of cases (Kessel 2014; Malwankar 2022; Taipale 2019).
Presentation and diagnosis
Pseudophakic CME may be asymptomatic or present with decreased or distorted vision, or both, with a peak incidence six weeks after cataract surgery. Slit‐lamp biomicroscopy may demonstrate retinal thickening; a blunted, or loss of, foveal depression; a yellowish appearance of the central macula; and a honeycomb appearance at the macula. Clinical findings may be best observed using a fundus contact lens, and red‐free light may facilitate detection of cystic changes. Fluorescein angiography may demonstrate perifoveal retinal telangiectasis, dilated capillaries, and perifoveal leakage in a 'petaloid’ pattern. Optic nerve staining may also be observed and helps to distinguish pseudophakic CME from other causes of CME. On optical coherence tomography, CME is characterized by a loss of the foveal depression, retinal thickening, intraretinal cystic hyporeflective lesions and, in some cases, hyporeflectivity under the central macula, indicating the presence of subretinal fluid.
Description of the intervention
Although the pathogenesis of pseudophakic CME remains incompletely understood, it is believed that inflammation leading to a breakdown of the blood‐retinal barrier plays a major role. It has been hypothesized that surgical manipulation causes significant release, by the anterior uveal tissue, of prostaglandins and other inflammatory mediators; the latter increase permeability of the perifoveal capillaries, leading to accumulation of fluid and cystic changes in the outer plexiform and inner nuclear layers of the retina (Miyake 2002). Corticosteroids and non‐steroidal anti‐inflammatory drugs (NSAIDs) have been used both pre‐ and postoperatively to try to prevent and treat pseudophakic CME (Brandsdorfer 2019; Grzybowski 2016; Orski 2021).
How the intervention might work
It is hypothesized that inflammation plays a major role in the pathogenesis of CME. Since NSAIDs inhibit cyclooxygenase, a rate‐limiting enzyme in the production of prostaglandins, NSAIDs may be effective in treating CME by reducing the production of inflammatory factors.
Why it is important to do this review
This is an update of a review last published in 2012, which examined the effects of topical NSAIDs on acute CME (3 trials) and chronic CME (4 trials), and concluded that the effects of NSAIDs in both acute and chronic CME remained unclear (Sivaprasad 2012). Therefore, we attempted to update the evidence base by including newly available trials evaluating treatment effects of topical NSAIDs on either acute or chronic CME, and by including additional analyses.
Objectives
To examine the effectiveness of NSAIDs in the treatment of CME following cataract surgery.
Methods
Criteria for considering studies for this review
Types of studies
This review included randomized controlled trials (RCTs).
Types of participants
Participants in the trials were adults who developed CME following cataract surgery in an eye with no history of ocular inflammatory disease, trauma or previous intraocular surgery. Surgery and the postoperative course of cataract are different in children and adults, so we excluded children from the review. We classified CME as either acute, defined as edema of less than four months' duration, or chronic, defined by CME that had persisted for four months or longer. In the current update, we also considered inclusion of trials that did not specify types of CME in their inclusion criteria (see Differences between protocol and review).
Types of interventions
We included trials that compared NSAIDs in any form or dosage to placebo, no treatment or another treatment modality with the aim of treating CME following cataract surgery. There was no minimum or maximum limit on the duration of treatment. To be consistent with the previous reviews (Sivaprasad 2004; Sivaprasad 2009; Sivaprasad 2012), we also considered trials that compared different NSAIDs as eligible.
Types of outcome measures
Primary outcomes
Critical outcomes
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Improvement of visual acuity, defined by two or more lines in Snellen visual acuity or equivalent, at the end of treatment
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Persistence of visual improvement one month after discontinuation of treatment
Secondary outcomes
Important outcomes
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Improvement in CME, quantified by proportion of participants with:
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improvement in leakage on fundus fluorescein angiography (FFA) as defined by the original study;
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improvement in central macular thickness on optical coherence tomography (OCT) as defined by the original study; or
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improvement in contrast sensitivity.
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Change in quality of life as measured by validated questionnaires such as the National Eye Institute Visual Function Questionnaire (NEI‐VFQ 25; Mangione 2001) or the 36‐Item Short Form Health Survey (SF‐36; Hays 2001).
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for randomized controlled trials and controlled clinical trials. There were no language or publication year restrictions. The electronic databases were last searched on 20 March 2022.
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Cochrane Central Register of Controlled Trials (CENTRAL; 2022, Issue 3) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 20 March 2022) (Appendix 1).
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MEDLINE Ovid (1946 to 20 March 2022) (Appendix 2).
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Embase.com (1947 to 20 March 2022) (Appendix 3).
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PubMed (1946 to 20 March 2022) (Appendix 4).
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Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to 20 March 2022) (Appendix 5).
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metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com; discontinued in 2014; last searched August 2011) (Appendix 6).
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 20 March 2022) (Appendix 7).
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 20 March 2022) (Appendix 8).
Searching other resources
We handsearched reference lists of all identified trials and previous reviews for additional trials but did not identify eligible studies. We did not handsearch conference abstracts as they are already included in CENTRAL.
Data collection and analysis
Selection of studies
The Information Specialist updated the search strategies and performed the searches. We imported separate search results to the web‐based review management software, Covidence, to automatically identify and remove duplicates. Two review authors independently screened the titles and abstracts and classified each record as 'relevant (yes)', 'maybe relevant', or 'not relevant (no)' according to the eligibility criteria. We then retrieved full‐text articles that were classified as 'relevant' or 'maybe relevant' for additional review for inclusion. Two review authors independently assessed the full‐text articles and resolved any disagreements by discussion.
We also contacted trial authors to request clarification about trial design and the availability of full‐text publications besides the conference abstracts that were available to the review authors. If the trial authors did not respond within two weeks, we used the information available to determine eligibility whenever feasible. Specifically, we classified trials as 'awaiting classification' if they were completed but no trial results were publicly available on the trial registry website or in any indexed databases.
Data extraction and management
Two review authors independently extracted data in Covidence using data abstraction forms developed by Cochrane Eyes and Vision. We extracted information regarding the trial setting; countries where participant recruitment and intervention took place; sample size; trial duration and treatment duration; trial design elements (unit of randomization, unit of analysis); method of analysis (intent‐to‐treat or complete case analysis); sources of funding and potential conflicts of interests; characteristics of participants; intervention medications and dosage; and study outcomes (domain, specific measurement and metric, method of aggregation, and time points of reporting). Two review authors compared the extracted data, resolving discrepancies by discussion. One review author entered data into RevMan Web 2022 and a second review author verified the data entered.
Assessment of risk of bias in included studies
Two review authors independently assessed the quality of each trial identified for this update and we achieved consensus via discussion. We applied risk of bias assessment following the guidance in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Specific domains for consideration included the following.
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Selection bias: were the randomization procedure and the allocation concealment adequate?
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Performance bias: were the participants and people administering the treatment masked to the intervention?
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Attrition bias:
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were withdrawals and dropouts completely described?
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was the analysis by intent‐to‐treat or 'available case' analysis?
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Detection bias: were outcome assessors masked to the intervention?
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Reporting bias: was there selective outcome reporting?
We graded trials as having low risk, high risk or, when the information reported was insufficient to make an assessment, unclear risk of bias. We documented supporting statements for our consensus assessments and presented these overall assessment results in a risk of bias summary figure (Higgins 2011). In the current update, we did not exclude trials based on the assessed levels of risk of bias.
Measures of treatment effect
We compared mean differences (MD) for continuous outcomes, such as mean improvement in visual acuity at the end of treatment in lines of Snellen acuity or Early Treatment Diabetic Retinopathy Study (ETDRS) letters. We estimated risk ratios (RR) for comparing dichotomous outcomes, such as proportions of participants with improvement in leakage on FFA or improved contrast sensitivity. We also reported 95% confidence intervals (CI) to express the uncertainty surrounding the point estimates.
Unit of analysis issues
All included trials enrolled participants with only one affected eye, except for Yannuzzi 1977, in which the investigators recruited three participants whose eyes were both treated with the same intervention. All trials reported outcomes at the individual, not the eye, level, including one cross‐over trial (Flach 1998).
Dealing with missing data
We did not impute any missing data. When the quality or specific metric of the available data prevented any statistical pooling, we excluded the trial from quantitative analyses and reported the data in a narrative manner when appropriate.
Assessment of heterogeneity
We examined the overall characteristics of the included trials, in particular the types of participants, types of interventions, and study design, to assess the extent to which the studies were sufficiently similar to permit a meaningful meta‐analysis of review outcomes. We considered the size and direction of intervention effects, and took into account the amount of heterogeneity as quantified by the I² statistic (Higgins 2002). As suggested in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2022), we used the following thresholds to interpret I² values:
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0% to 40%: might not be important;
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30% to 60%: may represent moderate heterogeneity;
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50% to 90%: may represent substantial heterogeneity;
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75% to 100%: considerable heterogeneity.
Assessment of reporting biases
We did not assess small‐study effects via funnel plots, which would also signal for potential publication bias, given that fewer than 10 trials contributed data to any meta‐analysis. We assessed selective outcome reporting as part of the risk of bias assessment.
Data synthesis
We performed pooled analysis following the guidance in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions for data synthesis and analysis (McKenzie 2022). We applied the fixed‐effect model to synthesize data from fewer than three trials reporting the same outcome data. Additionally, we provided a narrative synthesis of all included trials and their results.
We compared NSAIDs with placebo or another active treatment (alone or in combination) and reported treatment effects in RR and the associated 95% CI. In some comparisons, we switched the intervention and comparator groups in the forest plot to present comparison results versus the same comparator (ketorolac 0.5%).
Subgroup analysis and investigation of heterogeneity
Previous reviews did not plan for any subgroup analysis. We performed post‐hoc subgroup analysis to explore potential sources of heterogeneity, such as treatment duration.
Sensitivity analysis
Previous reviews did not specify any sensitivity analysis. We did not perform any sensitivity analysis either because of the small numbers of trials reporting on the same review outcomes in the pooled analysis.
Summary of findings and assessment of the certainty of the evidence
For the current update, we prepared summary of findings tables presenting relative or absolute risks (Schünemann 2022a). Two review authors independently graded the overall certainty of the evidence for each outcome using the GRADE approach (Schünemann 2013).
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Proportion of participants with improvement of two or more lines in Snellen visual acuity or equivalent at end of treatment
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Proportion of participants with persistence of vision improvement one month after discontinuation of treatment
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Proportion of participants with improvement in leakage on FFA
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Proportion of participants with improvement in central macular thickness on OCT
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Proportion of participants with improvement in contrast sensitivity
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Change in quality of life
We graded the certainty of the evidence as 'high,' 'moderate,' 'low,' or 'very low' according to
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risk of bias among included trials;
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indirectness of evidence;
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unexplained heterogeneity or inconsistency of results;
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low precision of results; and
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risk of publication bias (Schünemann 2013).
We downgraded certainty of the evidence by two levels when contextual considerations suggested extreme imprecision according to the recently published guidance by Schünemann and others (Schünemann 2022b).
We resolved discrepancies between the two review authors by discussion.
Results
Description of studies
Results of the search
In the first version of the review (Sivaprasad 2004), review authors screened 382 records and included seven eligible trials involving 266 participants (Burnett 1983; Flach 1987; Flach 1991; Flach 1998; Heier 2000; Rho 2003; Yannuzzi 1977). Additional updated searches in 2006, 2008, and 2011 resulted in 138, 56, and 77 records, but the review authors did not identify any new eligible trials for the published updates (Sivaprasad 2009; Sivaprasad 2012).
From the updated searches performed in March 2022, we screened 1560 records and excluded 1547 titles and abstracts. We assessed 13 full‐text articles for eligibility. From these, we found three trials that were already included in the previous review (Flach 1991; Heier 2000; Rho 2003), and we excluded five trials with reasons documented for exclusion (Aaronson 2020; Ginsburg 1994; NCT00438243; NCT01769352; Wolfensberger 1999).
In total, we included two new trials for the current update (Rho 2004; Rho 2006; Figure 1). We also classified two trials as 'awaiting classification' (NCT00595543; Yüksel 2017) because of unavailability of trial results or unclear information about study design despite our attempts to contact trial authors.
Study flow diagram
Included studies
In total, we included nine trials (390 participants, 393 eyes) in this review for qualitative synthesis and six in meta‐analyses that each included two to four trials (Figure 1).
Types of studies and setting
All trials included were of parallel‐group design, except for Flach 1998, which randomized the study participants initially and then again at the end of the first 30‐day treatment period. Despite the reported two‐week washout period, the authors of Flach 1998 did not provide separate outcome data for the second treatment period; we decided to extract and use only outcome data reported at the end of the first 30‐day period.
Seven of the trials were two‐arm trials. The remaining two trials were three‐arm trials, which compared the effects of a topical NSAID with two other active treatments (Heier 2000; Rho 2006). All of the included trials were conducted in the USA. Two trials were conducted in a single medical center (Yannuzzi 1977; Burnett 1983) and one in a private clinic (Rho 2003); investigators of three other trials reported multi‐site involvement (Flach 1987; Flach 1991; Heier 2000). The remaining three trials did not report trial setting (Flach 1998; Rho 2004; Rho 2006).
Types of participants
According to the post‐surgical intervals that study participants had from the latest cataract surgery or the duration with which the study participants had been diagnosed with CME before study enrollment, study participants of these nine trials could be classified into those with acute CME, defined as CME of less than four months' duration (Flach 1998; Heier 2000; Rho 2003), those with chronic CME, defined as CME which persisted for four months or longer (Burnett 1983; Flach 1987; Flach 1991; Yannuzzi 1977), or those with unspecified CME type (Rho 2004; Rho 2006). Only a few trials provided information about the CME duration when recruiting participants at baseline, which ranged from 4.1 weeks to 7 weeks for participants with acute CME (Heier 2000; Rho 2003), and 6 to 24 months for those with chronic CME (Burnett 1983). On average, each trial enrolled a median number of 30 participants (interquartile range [IQR] 22 to 52) or 30 eyes (IQR 23 to 52). Authors of four trials did not report sex distributions (Flach 1991; Flach 1998; Rho 2004; Rho 2006) or age compositions (Flach 1991) of their study participants. Based on other trials that reported age data, the average age of the study participants was 72.2 years (IQR 68.8 to 73.6); 72% were women (IQR 69% to 74%).
Types of interventions
We included trials in which NSAIDs in any form or dosage were compared to placebo, no treatment or another therapeutic modality with the aim of treating CME after cataract surgery (previous reviews also included comparisons of different types of NSAIDs [Sivaprasad 2004; Sivaprasad 2009; Sivaprasad 2012]). We did not specify a minimum or maximum duration of treatment.
In the three trials that enrolled patients with acute CME:
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Flach 1998 compared the effect of topical ketorolac tromethamine 0.5% with placebo;
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Heier 2000 compared topical ketorolac tromethamine 0.5% with topical prednisolone acetate 1% as well as with a combination of topical ketorolac tromethamine 0.5% and topical prednisolone acetate 1%; and
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Rho 2003 compared topical ketorolac tromethamine 0.5% with topical diclofenac sodium 0.1%.
In the four trials that enrolled patients with chronic CME:
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Yannuzzi 1977 compared the effect of oral indomethacin with placebo;
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Burnett 1983 compared topical fenoprofen 1% with placebo; and
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Flach 1987 and Flach 1991 compared topical ketorolac tromethamine 0.5% with placebo.
Two trials included participants with CME of unclear duration (Rho 2004, Rho 2006), and compared NSAID with one or more active treatment:
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Rho 2004 reported comparison results of topical ketorolac tromethamine 0.5% versus topical diclofenac sodium 1%; participants in both groups were also treated with topical prednisolone acetate 1%;
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Rho 2006, a three‐arm trial, compared the effect of topical bromfenac 0.09% with topical diclofenac sodium 0.1% and with topical ketorolac tromethamine 0.5%.
Across these trials, topical ketorolac tromethamine 0.5% was the most frequently used interventional NSAID (Flach 1987; Flach 1991; Rho 2004; Rho 2006), followed by topical diclofenac sodium 1% (Rho 2004; Rho 2006), topical bromfenac 0.09% (Rho 2006), topical fenoprofen sodium 1% (Burnett 1983), and oral indomethacin (Yannuzzi 1977). Besides placebo (or vehicle), active treatments under comparison included another NSAID (Rho 2003; Rho 2004; Rho 2006), and topical prednisolone acetate 1% alone (Heier 2000) or in combination with another NSAID (Heier 2000).
Types of outcomes
Critical outcomes
Improvement of two or more lines in Snellen visual acuity or equivalent at end of treatment
Six trials reported an improvement in Snellen visual acuity of two or more lines at the end of treatment (Flach 1987; Flach 1991; Flach 1998; Heier 2000; Rho 2004; Yannuzzi 1977). Heier 2000 and Rho 2004 also reported mean final visual acuity in Snellen lines, whereas Rho 2006 reported visual acuity in ETDRS letters.
Persistence of improvement of vision one month after discontinuation of treatment
Three trials reported persistent visual improvement at one month following cessation of treatment (Flach 1987; Flach 1991; Yannuzzi 1977).
Important outcomes
Proportion of participants with improvement in leakage on FFA
Six trials performed FFA as a diagnostic or monitoring tool (Burnett 1983; Flach 1987; Flach 1991; Heier 2000; Rho 2003; Yannuzzi 1977), although not all participants received repeat FFA at follow‐up in Rho 2003. Only three trials reported decreased leakage on FFA as an outcome measure (Burnett 1983; Flach 1987; Heier 2000).
Proportion of participants with improvement in central macular thickness on OCT
None of the included trials measured this outcome.
Proportion of participants with improved contrast sensitivity
Only one trial assessed contrast sensitivity (Heier 2000).
Change in quality of life
None of the included trials measured this outcome.
Excluded studies
The previous review (Sivaprasad 2004), excluded nine trials (Ahluwalia 1988; Azzolini 1986; IDSG 1997; Jampol 1994; Kraff 1985; Miyake 1995; Rossetti 1996; Singal 2004; Stark 1984) because they either tested NSAIDs for prophylactic purposes or tested efficacy of prednisolone, rather than an NSAID. The prior review update (Sivaprasad 2012) further excluded four trials (Asano 2008; Mathys 2010; Miyake 2007; Warren 2010).
For the current update, we excluded three trials that were not RCTs (Aaronson 2020; Ginsburg 1994; Wolfensberger 1999); one that examined effects of topical steroid (NCT01769352); and one trial that was withdrawn before enrolling participants (NCT00438243). Overall, we excluded 18 trials, as documented in the Characteristics of excluded studies.
Risk of bias in included studies
In this update, we applied the Cochrane risk of bias tool to assess the quality of the two newly‐added trials (Rho 2004; Rho 2006), as well as the seven trials included in the previous review (Sivaprasad 2012). We did not deem any of the included nine trials as low risk across all bias domains (Figure 2). We assessed three trials (Flach 1987; Flach 1991; Flach 1998) as having unclear risk of bias overall (33%) and the other six as having high (67%) risk of bias (see Figure 3 for risk of bias items presented as percentages).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Allocation
Random sequence generation
Three trials used computer‐generated random sequences for the randomization process, which we deemed at low risk of bias (Flach 1987; Flach 1991; Flach 1998). One trial used centralized randomization by a pharmacy, but did not state their method of sequence generation, so we deemed it at unclear risk of bias (Heier 2000). The trial authors of the remaining five trials stated that the groups were randomly allocated, but the method of treatment assignment was unclear, so we deemed these trials at unclear risk of bias (56%; Burnett 1983; Rho 2003; Rho 2004; Rho 2006; Yannuzzi 1977).
Allocation concealment before assignment
Flach 1998 distributed treatment "in a double‐masked fashion", so we deemed this trial to be at low risk of bias (11%). In Heier 2000, the "randomization was performed by the pharmacy that supplied the premasked medications", suggesting that the pharmacy might have had the knowledge of the corresponding sequences of randomization and medications; we deemed this trial at high risk of bias (11%). The other seven trials did not describe how they concealed allocation, and we deemed them at unclear risk of bias (78%; Burnett 1983; Flach 1987; Flach 1991; Rho 2003; Rho 2004; Rho 2006; Yannuzzi 1977).
Blinding
Masking of participants and personnel
All of the included trials, except Rho 2003, Rho 2004 and Rho 2006, were double‐masked and we deemed them to be at low risk of bias (67%). Rho 2003 and Rho 2006 did not report on masking, and we deemed them at unclear risk of bias (22%). In Rho 2004, the medication bottles were unmasked; we deemed this trial at high risk of bias for this domain (11%).
Masking of outcome assessment
Four of the nine trials were reportedly "double‐masked" for both study participants and clinical investigators or examiners; we deemed these to be at low risk of bias (50%; Flach 1987; Flach 1991; Flach 1998; Heier 2000). In Burnett 1983 and Yannuzzi 1977, it was not clear whether or not all examiners and trial personnel performing and interpreting ocular examinations at follow‐up visits were masked; thus, we deemed these two trials at unclear risk of bias. Rho 2003 and Rho 2006 did not report on masking and we also deemed them at unclear risk of bias (44%). In Rho 2004, the medication bottles were unmasked; we deemed this trial at high risk of bias for this domain (11%).
Incomplete outcome data
Seven of the included nine trials reported outcome data for all or nearly all randomized participants; we deemed these trials at low risk of bias (78%; Burnett 1983; Flach 1987; Flach 1998; Heier 2000; Rho 2003; Rho 2006; Yannuzzi 1977). We deemed Flach 1991 and Rho 2004 as having unclear risk of bias: Flach 1991 excluded substantial proportions of participants (25% in the intervention group and 17% in the placebo group) from the analysis due to loss to follow‐up; Rho 2004 did not report the group‐specific follow‐up rates nor the planned study duration.
Selective reporting
We deemed five trials to be at low risk of bias because they reported all of their prespecified outcomes (56%; Burnett 1983; Flach 1987; Flach 1991; Heier 2000; Rho 2003). We judged three trials to be at unclear risk of bias (Flach 1998; Rho 2004; Rho 2006) because no trial protocol or detailed methods description was available for assessment. We also deemed Yannuzzi 1977 to be at unclear risk of bias because the authors did not clearly report FFA results in a conventional way and the unit of analysis was the eye, while the unit of randomization was the person.
Other potential sources of bias
We deemed five of the nine trials to be at unclear risk of bias (56%; Burnett 1983; Flach 1991; Flach 1998; Heier 2000; Yannuzzi 1977). Although the respective trials were supported, at least in part, by industry, the trial authors did not report or disclose relevant conflicts of interest. We also deemed Rho 2003 to be at unclear risk of bias although the author reported that he had no financial or proprietary interest "in any material or method mentioned"; the author was on the speaker's bureau of a company that made one of the drugs investigated in the trial. Similarly, we deemed Flach 1987 to be at unclear risk of bias because the first author served as a consultant for the same company that funded the trial. We deemed Rho 2004 and Rho 2006 to be at high risk of bias because the first author of these publications reported a commercial relationship with a company that made one of the drugs investigated in each of these trials.
Effects of interventions
See: Summary of findings 1 NSAID versus placebo or active control in acute cystoid macular edema; Summary of findings 2 NSAID versus placebo in chronic cystoid macular edema; Summary of findings 3 NSAID versus active control in mixed cystoid macular edema
Comparison 1: NSAID versus placebo or active control in participants with acute CME
Three of the nine included trials enrolled participants whose CME had been diagnosed within four months before study entry (Flach 1998; Heier 2000; Rho 2003). Flach 1998 compared topical ketorolac with placebo whereas the other two trials (Heier 2000; Rho 2003) compared topical ketorolac with one or more active treatments. See summary of findings Table 1 showing findings of trials comparing NSAIDs with placebo or active control in participants with acute CME.
Critical outcomes
Improvement of two or more lines in Snellen visual acuity or equivalent at end of treatment
Two of the three trials reported on improvement in Snellen visual acuity of two or more lines at the end of treatment (Flach 1998; Heier 2000).
In Flach 1998, after the first 30‐day treatment period in this cross‐over study (22 participants), a two‐line visual acuity improvement was achieved in 4 of 11 (36%) participants treated with topical ketorolac tromethamine 0.5% and 2 of 11 (18%) participants in the placebo group, suggesting that there was no treatment benefit of ketorolac on visual improvement compared with placebo (RR 2.00, 95% CI 0.46 to 8.76; Figure 4). The authors also reported seven‐year outcomes of the 22 participants included in the study, demonstrating improved vision without additional medical or surgical treatment at the time of their last examination in all but two participants, whose decreased vision was unrelated to CME (anterior ischemic optic neuropathy in one participant, glaucoma in the other).
Forest plot of comparison1: NSAID versus placebo or active control in acute CME, outcome 1.1 Proportion of participants with visual improvement
In the three‐arm trial (Heier 2000), participants were treated until the CME resolved or for three months before tapering. When compared with topical prednisolone acetate 1.0%, topical ketorolac tromethamine 0.5% may have little or no effect on visual acuity improvement (RR 1.33, 95%: 0.58 to 3.07; 17 participants). Similarly, ketorolac 0.5% and prednisolone 1.0% combination therapy may not increase or decrease the likelihood of improved visual acuity when compared with prednisolone alone (RR 1.78, 95% CI 0.86 to 3.69; 18 participants; Figure 4). The trial authors further compared visual acuity improvement in Snellen lines (Analysis 1.2), but found inconsistent results. Ketorolac had little or no effect on visual improvement (MD 0.80 Snellen lines, 95% CI 0.08 to 1.52; 18 participants) when compared with prednisolone alone. In contrast, the combination therapy was associated with an improvement in visual acuity of 2.70 more lines (95% CI 1.99 to 3.41; 17 participants) than was observed with prednisolone alone at three months.
Instead of reporting visual acuity improvement from baseline, Rho 2003 found no differences within 26 weeks in the mean final visual acuity between the ketorolac and diclofenac groups among all study participants (20/58 versus 20/49, P = 0.74; 34 participants), in the subgroup of participants who experienced CME reduction (20/30 versus 20/30, P = 1.0), and in the subgroup of participants with complete resolution of CME (20/25 versus 20/25, P = 1.0).
Overall, when compared with placebo or active treatment, the evidence on the treatment effects of ketorolac 0.5% on visual acuity improvement at the end of treatment is very uncertain. The certainty level of the evidence for this outcome was very low after we downgraded it for risk of bias, imprecision, and inconsistency.
Persistence of improvement of vision one month after discontinuation of treatment
None of the included trials reported this outcome.
Important outcomes
Proportion of participants with improvement in leakage on FFA
Heier 2000 observed improvement in leakage on FFA in 5 of 9 (55%) participants treated with ketorolac tromethamine 0.5%, 4 of 8 participants (50%) treated with prednisolone acetate 1.0%, and 7 of 9 participants (77%) treated with ketorolac and prednisolone combination therapy. When compared with prednisolone alone (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or with combination therapy (RR 1.56, 95% CI 0.72 to 3.38; 17 participants), we found no evidence that ketorolac had additional treatment benefits (Analysis 1.3). The certainty of the evidence for this outcome was very low after we downgraded it for risk of bias, imprecision, and heterogeneity.
Proportion of participants with improvement in central macular thickness on OCT
None of the included trials reported this outcome.
Proportion of participants with improved contrast sensitivity
Heier 2000 found improvement in contrast sensitivity in 5 of 9 participants (55%) treated with ketorolac tromethamine 0.5%, 4 of 8 participants (50%) treated with prednisolone acetate 1.0%, and 8 of 9 of participants (89%) treated with ketorolac and prednisolone combination therapy. When compared with prednisolone alone (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or with combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants), there was no evidence that ketorolac had additional treatment benefits (Analysis 1.4). The certainty of the evidence for this outcome was very low after we downgraded it for risk of bias, imprecision, and heterogeneity.
Change in quality of life
None of the included trials reported this outcome.
Other outcomes reported by the included trials
Improvement or reduction of CME by biomicroscopic examination
Rho 2003 repeatedly assessed participants for severity of CME by Goldmann contact lens biomicroscopy during the follow‐up period. FFA "was repeated if clinical CME persisted". At the end of the 26‐week treatment, there was no evidence that diclofenac may have effects on completely resolving CME (RR 1.04, 95% CI 0.71 to 1.51; 34 participants) when compared to ketorolac (Analysis 1.5). The authors also concluded that reported time (in weeks) to CME reduction was comparable in the ketorolac (mean 8.0, standard deviation [SD] 1.8) and diclofenac groups (mean 7.5, SD 1.5).
Adverse events
Flach 1998 reported that "there were no complaints about burning or stinging following eyedrop instillation and "none of the patients developed any signs of ocular toxicity during the study." Rho 2003 found no adverse events of superficial punctate keratitis, allergic reaction, or other ocular changes "that prevented [patients] from completing the study". Heier 2000 did not mention any adverse events associated with the intervention treatments.
Comparison 2: NSAID versus placebo in participants with chronic CME
Four of the nine included trials enrolled participants whose CME had been diagnosed for at least four months prior to the study entry (Burnett 1983; Flach 1987; Flach 1991; Yannuzzi 1977). See summary of findings Table 2 for review findings of trials comparing NSAIDs versus placebo in participants with chronic CME.
Critical outcomes
Improvement of two or more lines in Snellen visual acuity or equivalent at end of treatment
All four trials reported an improvement in Snellen visual acuity of two or more lines at the end of treatment.
Burnett 1983 compared topical fenoprofen sodium 1% (6 participants) with placebo (8 participants). At the end of the eight‐week treatment period, an improvement of two or more lines in Snellen visual acuity was similarly achieved in the fenoprofen group compared with the placebo group (RR 1.33, 95% CI 0.40 to 4.43).
Flach 1987 randomized 30 eyes of 30 patients to treatment with either topical ketorolac tromethamine 0.5% or placebo, four times daily for no more than 90 days. Four participants failed to complete the study: one participant was lost to follow‐up and another developed an ocular allergy in the ketorolac group; two participants in the placebo group did not complete the study due to poor compliance and myocardial infarction, respectively. Eight of 13 participants (62%) In the ketorolac group and 1 of 13 participants (8%) in the placebo group, achieved an improvement of two or more lines of Snellen visual acuity at day 60, showing an increased likelihood of visual improvement when treated with NSAIDs versus placebo (RR 8.00, 95% CI 1.16 to 55.2; 26 participants).
Flach 1991 randomized 120 eyes of 120 patients to either topical ketorolac tromethamine 0.5% or placebo, four times a day for no more than 120 days. However, only 46 of the 61 participants (75%) enrolled in the ketorolac group and 49 of the 59 participants (83%) enrolled in the placebo group were examined at day 90 or day 120, depending on results of distance visual acuity at day 90. By three months of treatment, 48% and 20% of the returning participants in the ketorolac group and placebo group, respectively, had a visual acuity improvement of two lines or more (RR 2.34, 95% CI 1.25 to 4.40; 95 participants).
Yannuzzi 1977 randomized 20 participants (23 eyes) to receive either 25 mg of orally administered indomethacin three times per day (10 participants, 10 eyes) or placebo three times per day (10 participants, 13 eyes) for six weeks. Participants were re‐assessed at weeks 3, 6, and 10. At the end of treatment (week 6), 2 of 10 (20%) eyes in the indomethacin group and 4 of 13 (31%) eyes in the placebo group had achieved an improvement of two or more lines in Snellen visual acuity; the estimated treatment effect at the person level was RR 0.40 (95% CI 0.10 to 1.60; 20 participants) comparing indomethacin with placebo.
Because of evidence of subgroup differences (P = 0.01, I2 = 84.7%), we did not combine estimates from trials that had treated participants with different durations of therapy (Analysis 2.1). Results from subgroups suggested that NSAIDs may increase participants' likelihood of visual improvement by 1.87 fold (RR 2.87, 95% CI 1.58 to 5.22; I2 = 33%; 2 trials, 121 participants) relative to placebo after treatment of 90 days or longer; however, there was no evidence of treatment effect of NSAID in the subgroup with two months or shorter use of NSAID (RR 0.72, 95% CI 0.30 to 1.73; P = 0.19, I2 = 41%; 2 trials, 34 participants; Figure 5).
Forest plot of comparison 2: NSAID versus placebo in chronic CME, outcome 2.1 Proportion of participants with visual improvement
In a post‐hoc sensitivity analysis that excluded a trial that had examined oral indomethacin (Yannuzzi 1977), the between‐group heterogeneity attenuated (P = 0.30, I2 = 7.9%), and the combined results suggested that topical NSAIDs may increase participants' visual improvement as compared to placebo (RR 2.33, 95% CI 1.17 to 4.66; I2 = 22%; 3 trials, 135 participants; Analysis 2.2).
Overall, the certainty level of the evidence for this outcome was very low after we downgraded it for risk of bias, imprecision, and heterogeneity.
Persistence of improvement of vision one month after discontinuation of treatment
Yannuzzi 1977 reported persistence of visual acuity at one month following cessation of treatment. Two eyes of two participants in the indomethacin group and five eyes of five participants in the placebo group that had improved by two or more lines of vision after 6 weeks of treatment still maintained at least a two‐line visual acuity improvement one month following cessation of treatment (at day 70). The single‐study estimate for oral NSAID was RR 0.40 (95% CI 0.10 to 1.60; 20 participants) when compared to placebo. Similarly, in Flach 1987, four of the eight participants in the ketorolac group and one participant in the placebo group who achieved visual improvement at the end of the 60‐day treatment period still maintained two lines or more of visual improvement on day 90. The single‐study estimate was equivocal (RR 4.00, 95% CI 0.51 to 31.13; 26 participants). Although we did not combine results of these two trials due to between‐group heterogeneity (P = 0.07, I2 = 69.9%), overall, the estimate of either subgroup suggests that NSAIDs had no effect on persistent visual improvement one month after the treatment ended (Figure 6). The certainty of the evidence for this outcome was very low, downgraded one level due to risk of bias and two levels due to extreme imprecision.
Forest plot of comparison 2: NSAID versus placebo in chronic CME, outcome 2.2 Proportion of participants with persistent visual improvement one month after discontinuation of treatment
Important outcomes
Proportion of participants with improvement in leakage on FFA
Two of the four trials reported on this outcome (Burnett 1983; Flach 1987; Analysis 2.4). Burnett 1983 observed decreased leakage on FFA in three participants in each of the fenoprofen (6 participants, 50%) and placebo groups (8 participants, 38%), corresponding to a single‐study estimated RR of 1.33 (95% CI 0.40 to 4.43). Flach 1987 observed decreased leakage on FFA in two of the 13 participants (15%) receiving ketorolac and none in the placebo group (13 participants). The combined estimate of RR for improvement in leakage on FFA was 1.93 (95% CI 0.62 to 6.02, 40 participants), indicating that NSAIDs had little to no beneficial effect over placebo (I2 = 0%; Figure 7). The certainty level of the evidence for this outcome was very low after downgrading for risk of bias (−1) and extreme imprecision (−2).
Forest plot of comparison 2: NSAID versus placebo in chronic CME, outcome 2.3 Proportion of participants with improved FFA
Proportion of participants with improvement in central macular thickness on OCT
None of the included trials reported this outcome.
Proportion of participants with improved contrast sensitivity
None of the included trials reported this outcome.
Change in quality of life
None of the included trials reported this outcome.
Other outcomes reported by the included trials
Proportion of participants with complete resolution of CME
Burnett 1983 reported that there was no leakage on FFA at the final study visit in one of the six participants (17%) in the fenoprofen group and one of the eight participants (13%) in the placebo group after eight weeks of treatment with fenoprofen 1% versus placebo (Analysis 2.5).
Adverse events
Across trials, one participant in Flach 1987 assigned to treatment with ketorolac did not complete the study due to ocular allergy. Flach 1991 reported that there were no statistically significant differences in the number or severity of adverse events between treatment groups.
Comparison 3: NSAID versus active control in participants with mixed duration of CME
Two trials did not specify the types (or durations) of CME in the inclusion criteria for the primary study (Rho 2004; Rho 2006). See summary of findings Table 3 for review findings comparing NSAID versus active treatments in participants with probably mixed types of CME.
Critical outcomes
Improvement of two or more lines in Snellen visual acuity or equivalent at end of treatment
One trial reported an improvement in Snellen visual acuity of two or more lines at the end of treatment (Rho 2004). Rho 2004 was a two‐arm trial that randomized 68 eyes of 68 patients to topical diclofenac sodium 0.1% or topical ketorolac tromethamine 0.5%. Both comparison groups were also provided with topical prednisolone acetate 0.1%. All participants reportedly completed at least three months of treatment yet the exact follow‐up duration was not reported. Based on the single‐study estimate, diclofenac + prednisolone may increase participants' likelihood of visual improvement by 40% when compared to ketorolac + prednisolone (RR 1.40, 95% CI 1.02 to 1.94; 68 participants; Analysis 3.1).
Rho 2004 also reported visual acuity improvement in Snellen lines (Analysis 3.2). However, the single‐study estimate showed no effect of diclofenac over ketorolac in increasing or decreasing Snellen lines of visual acuity at the end of treatment (MD 0.40, 95% CI −0.93 to 1.73; 68 participants).
Similarly, Rho 2006 reported visual improvement in ETDRS letters when participants completed the study at three months. Rho 2006 randomized 52 eyes of 52 patients to one of three regimens: topical bromfenac 0.09% twice daily, topical diclofenac sodium 0.0.1% four times daily, or topical ketorolac tromethamine 0.05% four times daily. The single‐study estimates showed that either diclofenac (MD 0.90, 95% CI −4.31 to 6.11 ETDRS letters; 34 participants) or bromfenac alone (MD 1.20, 95% CI −4.58 to 6.98 ETDRS letters; 34 participants) had no effect on visual improvement (Analysis 3.3).
Overall, NSAID may slightly increase participants' likelihood of visual improvement but the evidence is very uncertain. The certainty of the evidence for this outcome was very low because we downgraded it for risk of bias, imprecision, and inconsistency (summary of findings Table 3).
Persistence of visual improvement of vision one month after discontinuation of treatment
None of the included trials reported this outcome.
Important outcomes
Proportion of participants with improvement in leakage on FFA
None of the included trials reported this outcome.
Proportion of participants with improvement in central macular thickness on OCT
None of the included trials reported this outcome.
Proportion of participants with improved contrast sensitivity
None of the included trials reported this outcome.
Change in quality of life
None of the included trials reported this outcome.
Other outcomes reported by the included trials
Complete resolution of CME by unspecified measurement or examination
Rho 2004 reported complete resolution of CME without specifying how it was determined. Rho 2004 observed that 10 of 36 participants (28%) in the diclofenac group and 8 of 32 participants (25%) in the ketorolac group achieved complete resolution of CME. The single‐study estimate suggests that diclofenac had no or little effect on CME resolution (RR 1.11, 95% CI 0.50 to 2.47; 68 participants; Analysis 3.4) when compared with another NSAID (ketorolac).
Adverse events
Rho 2004 stated that none of the participants "showed signs of corneal toxicity or significant intraocular pressure rise during the treatment period." There was no mention of ocular adverse events in Rho 2006.
Discussion
Summary of main results
We based our findings on data from nine RCTs that investigated the effectiveness of any form or dosage of NSAIDs compared to placebo, no treatment or another active treatment modality, including different types of NSAIDs, with the aim of treating CME following cataract surgery. NSAIDs may not improve visual acuity at the end of treatment for any type of CME. Although there was evidence that NSAIDs may slightly increase the likelihood of visual acuity improvement with 90 days or longer of treatment for patients with chronic CME, the overall evidence was very uncertain (very low‐certainty evidence). We did not find evidence that NSAIDs had an effect on persistent visual improvement after treatment discontinuation (very low‐certainty evidence); improvement of leakage on FFA (very low‐certainty evidence); or improvement in contrast sensitivity (very low‐certainty evidence). None of the included trials reported on improvement in central macular thickness on OCT or change in quality of life. Thus, this review found that evidence on the effects of NSAIDs in acute or chronic CME is very uncertain and further investigation is warranted.
Overall completeness and applicability of evidence
The findings of this review may be applicable to patients with CME of various durations after cataract surgery. However, because the majority of the included primary studies excluded high‐risk patients (those with pre‐existing macular disease, poorly controlled diabetes or hypertension), our review findings are not generalizable to such individuals. In addition, our findings are limited by small sample sizes of primary studies, a deficient number of eligible trials reporting on the same outcomes, heterogeneity in interventions (varying treatment medications or durations) and different follow‐up durations.
Further, the publication dates of the trials included in this review range from 1977 to 2006, and there have been many advancements in cataract surgery techniques throughout and since that time. For example, cataract surgery has progressed from intracapsular cataract extraction to extracapsular cataract extraction to phacoemulsification cataract surgery; from large sutured wounds to small, nonsutured wounds; from scleral to corneal incisions; and from retrobulbar or peribulbar anesthesia to topical anesthesia (Davis 2016; Fichman 1996). Advancements in cataract surgery may lead to differences in the underlying risks of developing CME postoperatively over time. However, several published studies indicate that, even after the many advancements in cataract surgery techniques, the rate of clinically significant CME following modern cataract surgery is about 2% (Kessel 2014; Malwankar 2022; Taipale 2019). The lack of a placebo group across CME types prohibited us from inferring any overall treatment benefits of NSAIDs and from distinguishing treatment effect from spontaneous resolution of CME.
It should also be noted that most of the trials included in this review were performed before the widespread use of OCT (Fujimoto 2016). Due to its non‐contact and non‐invasive approach, quick image acquisition, high‐resolution images, and safety profile, OCT has become a leading diagnostic imaging modality for pseudophakic CME (Trichonas 2014), although in some cases, obtaining FFA imaging may be useful in differentiating pseudophakic CME from other conditions such as diabetic macular edema.
Moreover, standards of conducting and reporting intervention trials have evolved over time, particularly since the publication of the first CONSORT (Consolidated Standards of Reporting Trials) Statement in 1996 (Begg 1996). Inadequate reporting of participant characteristics and heterogeneity in the study design, such as the treatment duration, follow‐up duration, and frequency of outcome measurements (without clearly pre‐specified study endpoints), contributed to the generally low certainty of the evidence. In addition, the lack of consistent and valid methods for assessing and reporting outcomes created a barrier to synthesizing the evidence.
Certainty of the evidence
None of the included nine trials was deemed as low risk across all bias domains; we assessed the majority of the trials as high risk of bias. We assessed most of the trials to be at unclear or high risk of bias on the random sequence generation and allocation concealment domains, and five of the trials at unclear or high risk of bias on the blinding of outcome assessment domain. Concerns in multiple bias domains, including unmasking of participants or assessors, substantial dropout rates, and selective outcome reporting, further downgraded the certainty level of the evidence for most, if not all, review outcomes. The evidence in the nine trials was very low certainty due to such factors as small sample sizes, poorly reported outcomes, inconsistent results, and the inability to distinguish drug effect from spontaneous resolution of CME.
Quality of the evidence
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Potential biases in the review process
We applied the standard Cochrane methods to conduct this update and avoided potential biases in the processes of literature search, critical appraisal, data extraction and entry, data analysis and interpretation. Although not always successful, we also contacted trial authors and publication authors to request clarification or detailed information regarding study design and outcome in attempts to reduce information bias. To reduce inter‐rater biases, two review authors also independently re‐assessed risk of bias in the seven eligible trials of the previous review (Sivaprasad 2004).
Agreements and disagreements with other studies or reviews
A recently published systematic review, which investigated the effect of NSAIDs for acute and chronic CME (Orski 2021), included seven trials, two of which were RCTs, and reported visual acuity improvement and central macular thickness reduction. However, similar to our review, the trials in that review were constrained by small sample sizes, as well as heterogeneity in interventions, treatment durations, follow‐up intervals, and outcome assessments. Because of these study limitations, the authors of Orski 2021 also concluded that the available evidence is insufficient to formulate strong conclusions regarding NSAIDs for the treatment of either acute or chronic CME following cataract surgery.
Similarly, the American Academy of Ophthalmology (AAO) released an Ophthalmic Technology Assessment (OTA) regarding the use of topical NSAIDs after cataract surgery (Kim 2015), and concluded that there was a lack of level I evidence to support the long‐term benefit of topical NSAIDs to prevent vision loss from CME at three months or more after cataract surgery. This OTA was based on a literature search of PubMed and the Cochrane Library in January 2015.
Study flow diagram
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Forest plot of comparison1: NSAID versus placebo or active control in acute CME, outcome 1.1 Proportion of participants with visual improvement
Forest plot of comparison 2: NSAID versus placebo in chronic CME, outcome 2.1 Proportion of participants with visual improvement
Forest plot of comparison 2: NSAID versus placebo in chronic CME, outcome 2.2 Proportion of participants with persistent visual improvement one month after discontinuation of treatment
Forest plot of comparison 2: NSAID versus placebo in chronic CME, outcome 2.3 Proportion of participants with improved FFA
Comparison 1: NSAID versus placebo or active control in acute CME, Outcome 1: Proportion of participants with visual improvement
Comparison 1: NSAID versus placebo or active control in acute CME, Outcome 2: Improvement in VA, Snellen lines*
Comparison 1: NSAID versus placebo or active control in acute CME, Outcome 3: Proportion of participants with improved FFA
Comparison 1: NSAID versus placebo or active control in acute CME, Outcome 4: Proportion of participants with improved contrast sensitivity
Comparison 1: NSAID versus placebo or active control in acute CME, Outcome 5: Proportion of participants with complete resolution*
Comparison 2: NSAID versus placebo in chronic CME, Outcome 1: Proportion of participants with visual improvement
Comparison 2: NSAID versus placebo in chronic CME, Outcome 2: Proportion of participants with visual improvement ‐ sensitivity analysis
Comparison 2: NSAID versus placebo in chronic CME, Outcome 3: Proportion of participants with persistent visual improvement one month after discontinuation of treatment
Comparison 2: NSAID versus placebo in chronic CME, Outcome 4: Proportion of participants with improved FFA
Comparison 2: NSAID versus placebo in chronic CME, Outcome 5: Proportion of participants with complete resolution
Comparison 3: NSAID versus active control in mixed CME, Outcome 1: Proportion of participants with visual improvement
Comparison 3: NSAID versus active control in mixed CME, Outcome 2: Improvement in VA, Snellen lines*
Comparison 3: NSAID versus active control in mixed CME, Outcome 3: Improvement in VA, ETDRS letters*
Comparison 3: NSAID versus active control in mixed CME, Outcome 4: Proportion of participants with complete resolution*
| Non‐steroidal anti‐inflammatory drug vs placebo or active control for acute cystoid macular edema following cataract surgery | ||||||
|---|---|---|---|---|---|---|
| Patient population: participants with acute CME (< 4 months) following cataract surgery Settings: private clinics or medical centers in the USA Intervention: ketorolac, diclofenac Comparison: placebo, prednisolone, ketorolac + prednisolone | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No. of participants (RCTs) | Certainty of evidence (GRADE) | Comments | |
| Assumed risk* Placebo or prednisolone | Corresponding risk NSAID ± prednisolone | |||||
| Visual improvement at end of treatment, as defined by two or more Snellen lines | Placebo | Ketorolac 36 (8 to 100) per 100 | RR 2.00 (0.46 to 8.76) | 22 (1 RCT) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better. Besides Flach 1998 (22 participants) and Heier 2000 (26 participants), Rho 2003 (34 participants) compared mean final VA between participants receiving ketorolac with those receiving diclofenac (20/50 vs 20/49) and concluded no overall differences |
| Prednisolone 50 per 100
| Ketorolac 67 (29 to 100) per 100 | RR 1.33 (0.58 to 3.07) | 17 (1 RCT) | |||
| Ketorolac + prednisolone 89 (43 to 100) per 100 | RR 1.78 (0.86 to 3.69) | 17 (1 RCT) | ||||
| Persistence of visual improvement one month after discontinuation of treatment | Not measured by any included trial
|
| ||||
| Improvement in leakage on FFA
| Prednisolone 50 per 100
| Ketorolac 56 (23 to 100) per 100 | RR 1.11 (0.45 to 2.75) | 17 (1 RCT) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better. Data from the same 3‐arm trial (Heier 2000) |
| Ketorolac + prednisolone 78 (36 to 100) per 100 | RR 1.56 (0.72 to 3.38) | 17 (1 RCT) | ||||
| Improvement in central macular thickness on OCT | Not measured by any included trial
|
| ||||
| Improved contrast sensitivity
| Prednisolone 50 per 100 | Ketorolac 56 (23 to 100) per 100 | RR 1.11 (0.45 to 2.75) | 17 (1 RCT) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better Data from the same 3‐arm trial (Heier 2000) |
| Ketorolac + prednisolone 89 (43 to 100) per 100 | RR 1.78 (0.86 to 3.69) | 17 (1 RCT) | ||||
| Change in QoL | Not measured by any included trial
|
| ||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and the associated 95% CI).
CI: confidence interval; CME: cystoid macular edema; FFA: fundus fluorescein angiography (angiogram); NSAID: non‐steroidal anti‐inflammatory drug; OCT: optical coherence tomography; QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded for risk of bias (‐1), imprecision (‐1) and heterogeneity (‐1). | ||||||
| Non‐steroidal anti‐inflammatory drug vs active control for chronic cystoid macular edema following cataract surgery | ||||||
|---|---|---|---|---|---|---|
| Patient population: participants with chronic CME (≥ 4 months) following cataract surgery Settings: medical centers in the USA Intervention: topical ketorolac, topical fenoprofen, oral indomethacin Comparison: placebo (vehicle or saline) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No. of participants (RCTs) | Certainty of evidence (GRADE) | Comments | |
| Assumed risk* Placebo | Corresponding risk NSAID | |||||
| Visual improvement at end of treatment, as defined by two or more Snellen lines
| Treatment duration ≤ 2 months 44 per 100 | 32 (13 to 76) per 100 | RR 0.72 (0.30 to 1.73) | 34 (2 RCTs) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better. When excluding Yannuzzi 1977, which examined oral NSAID, there was no evidence of subgroup differences and the combined RR was 2.33 (95% CI 1.17 to 4.66; 3 RCTs, 135 participants), favoring topical NSAIDs over placebo in visual improvement after at least 90 days of treatment. |
| Treatment duration 90‐120 days 18 per 100 | 52 (28 to 94) per 100 | RR 2.87 (1.58 to 5.22) | 121 (2 RCTs) | |||
| Persistence of visual improvement one month after discontinuation of treatment | 26 per 100 | 30 (11 to 80) per 100 | RR 1.17 (0.44 to 3.07) | 46 (2 RCTs) | ⊕⊝⊝⊝ Very lowb |
|
| Improvement in leakage on FFA
| 14 per 100 | 27 (9 to 84) per 100 | RR 1.93 (0.62 to 6.02) | 40 (2 RCTs) | ⊕⊝⊝⊝ Very lowb | RR > 1 is better. |
| Improvement in central macular thickness on OCT | Not measured by any included trial |
|
|
|
| |
| Improved contrast sensitivity | Not measured by any included trial |
|
|
|
| |
| Change in QoL | Not measured by any included trial |
|
|
|
| |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and the associated 95% CI).
CI: confidence interval; CME: cystoid macular edema; FFA: fundus fluorescein angiography (angiogram); NSAID: non‐steroidal anti‐inflammatory drug; OCT: optical coherence tomography; QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded for risk of bias (‐1), imprecision (‐1) and heterogeneity (‐1). | ||||||
| Non‐steroidal anti‐inflammatory drug vs active control for cystoid macular edema following cataract surgery | ||||||
|---|---|---|---|---|---|---|
| Patient population: participants with acute or chronic CME following cataract surgery Settings: private clinics in the USA or medical centers in Canada Intervention: bromfenac, diclofenac ± prednisolone, ketorolac ± prednisolone Comparison: ketorolac ± prednisolone | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No. of participants (RCTs) | Certainty of evidence (GRADE) | Comments | |
| Assumed risk* Active control | Corresponding risk NSAID | |||||
| Visual improvement at end of treatment, as defined by two or more Snellen lines | Diclofenac + prednisolone 59 per 100 | Ketorolac + prednisolone 83 (60 to 100) per 100 | RR 1.40 (1.02 to 1.94) | 68 (1 RCT) | ⊕⊝⊝⊝ Very lowa | RR > 1 is better. Rho 2004 also reported this outcome in Snellen lines (MD 0.40, 95% CI −0.93 to 1.73; 68 participants) Rho 2006 reported in ETDRS letters (MD 0.90, 95% CI −4.31 to 6.11; 34 participants) considering data from the diclofenac group or (MD 1.20, 95% CI −4.58 to 6.98; 34 participants) considering data from the bromfenac group |
| Persistence of visual improvement one month after discontinuation of treatment | Not measured by any included trial
|
| ||||
| Improvement in leakage on FFA | Not measured by any included trial
|
| ||||
| Improvement in central macular thickness on OCT | Not measured by any included trial
|
| ||||
| Improved contrast sensitivity | Not measured by any included trial |
| ||||
| Change in QoL | Not measured by any included trial |
| ||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and the associated 95% CI).
CI: confidence interval; CME: cystoid macular edema; ETDRS: Early Treatment Diabetic Retinopathy Study; FFA: fundus fluorescein angiography (angiogram); NSAID: non‐steroidal anti‐inflammatory drug; OCT: optical coherence tomography; QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded for risk of bias (‐1), imprecision (‐1) and inconsistency (‐1). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Proportion of participants with visual improvement Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1.1 Ketorolac 0.5% vs vehicle | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1.2 Ketorolac 0.5% vs prednisolone 1.0% | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1.3 Ketorolac 0.5% & prednisolone 1.0% vs prednisolone 1.0% | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.2 Improvement in VA, Snellen lines* Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.2.1 Ketorolac 0.5% | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.2.2 Ketorolac 0.5% & Prednisolone 1.0% | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.3 Proportion of participants with improved FFA Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.3.1 Ketorolac 0.5% | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.3.2 Ketorolac 0.5% & prednisolone 1.0% | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4 Proportion of participants with improved contrast sensitivity Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4.1 Ketorolac 0.5% | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4.2 Ketorolac 0.5% & prednisolone 1.0% | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 Proportion of participants with complete resolution* Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Proportion of participants with visual improvement Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1.1 Chronic CME, treatment ≤ 2 months | 2 | 34 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.30, 1.73] |
| 2.1.2 Chronic CME, treatment 90‐120 days | 2 | 121 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.87 [1.58, 5.22] |
| 2.2 Proportion of participants with visual improvement ‐ sensitivity analysis Show forest plot | 3 | 135 | Risk Ratio (M‐H, Random, 95% CI) | 2.33 [1.17, 4.66] |
| 2.2.1 Chronic CME, treatment ≤ 2 months | 1 | 14 | Risk Ratio (M‐H, Random, 95% CI) | 1.33 [0.40, 4.43] |
| 2.2.2 Chronic CME, treatment 90‐120 days | 2 | 121 | Risk Ratio (M‐H, Random, 95% CI) | 3.10 [1.10, 8.74] |
| 2.3 Proportion of participants with persistent visual improvement one month after discontinuation of treatment Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.3.1 Topical | 1 | 26 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.00 [0.51, 31.13] |
| 2.3.2 Oral | 1 | 20 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.10, 1.60] |
| 2.4 Proportion of participants with improved FFA Show forest plot | 2 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.93 [0.62, 6.02] |
| 2.5 Proportion of participants with complete resolution Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Proportion of participants with visual improvement Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2 Improvement in VA, Snellen lines* Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.3 Improvement in VA, ETDRS letters* Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.3.1 Diclofenac 0.1% | 1 | 34 | Mean Difference (IV, Fixed, 95% CI) | 0.90 [‐4.31, 6.11] |
| 3.3.2 Bromofenac 0.09% | 1 | 34 | Mean Difference (IV, Fixed, 95% CI) | 1.20 [‐4.58, 6.98] |
| 3.4 Proportion of participants with complete resolution* Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
