Discover Portal

Medication

NIHR Signal Eplerenone does not improve vision in people with central serous chorioretinopathy

Published on 25 March 2020

doi: 10.3310/signal-000893

Eplerenone, a drug used for people with central serous chorioretinopathy, is no more effective than placebo. Neither visual acuity nor the build-up of fluid in the eye shows an important improvement.

Central serous chorioretinopathy is a serious eye condition that causes blurred and distorted vision. Fluid collects underneath the macula, which is the central area of the retina. The condition mostly affects men aged 20–45 years, although it can affect women too. A specific cause is rarely identified.

This NIHR-funded trial is the biggest and most robust one to date that investigates the use of eplerenone for this condition. Results confirm that the drug used for the condition is unlikely to lead to important benefits.

Share your views on the research.

Why was this study needed?

Central serous chorioretinopathy (CSC) usually occurs in one eye. For most people, it gets better by itself within four to six months, without any long-term changes to vision. However, for a small number of people, it can become a long-term problem. For these people, the retina can be damaged by prolonged swelling and lead to loss of sight.

Treatment is usually recommended if the condition lasts longer than six months. Treatment options include thermal laser or photodynamic therapy. There is little current evidence about the effectiveness of alternative drug treatments.

Before this trial, the authors had identified a few small (phase 1) studies of aflibercept, photodynamic laser therapy and eplerenone, but these were statistically underpowered. This means that they had too few participants to be reliable.

This trial, the first randomised superiority trial of its kind, was designed to improve the quality and certainty of evidence and aimed to recruit a sample of 104 patients from 22 UK NHS hospitals.

What did this study do?

On completion, this randomised controlled trial had recruited 114 adults from 22 hospitals in the UK. Patients enrolled had CSC for at least four months, without any previous treatment. In one group, 57 patients were given eplerenone tablets for up to 12 months, alongside usual care. They took 25mg per day for a week, increasing to 50mg per day if their potassium levels were normal. The other 57 patients were given identical-looking placebo tablets for up to 12 months alongside usual care. All patients were followed up after one week, and after one, three, six, nine and 12 months.

No patients, clinicians or people assessing the outcomes knew which group anyone was in.

Visual acuity was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts. These charts have five letters on each line, and the authors specified a clinically important difference or gain in acuity as more than five letters (or one line) on these charts.

This trial was well conducted and the number of participants was sufficient to have found a clinically meaningful difference between the groups if one existed.

What did it find?

  • Best-corrected visual acuity (BCVA) was measured by accredited optometrists using the acuity charts. Mean acuity at 12 months in the eplerenone group was 80.4 letters, and in the placebo group was 79.5 letters (estimated mean difference 1.73 letters, 95% confidence interval -1.12 to 4.57). There was, therefore, no clinically important or statistically significant difference in BCVA between the groups at 12 months.
  • Other outcomes were measured at 12 months, such as subretinal fluid thickness, the average time until the fluid was reabsorbed, and the average time to recurrence of the fluid. None of these showed any significant differences between the groups in favour of eplerenone either.
  • There were no serious adverse events in the eplerenone group. The placebo group reported three serious adverse events, none of which were associated with the placebo tablet. Eight people in each group had to stop their trial tablet due to increased potassium levels.

What does current guidance say on this issue?

There are no national guidelines on the treatment of CSC. Moorfields Eye Hospital NHS Foundation Trust in London has produced a patient information leaflet on the condition. This lists oral medications such as eplerenone as treatment options but highlights that further research is being carried out to evaluate these drugs.

Eplerenone is not currently licensed for treating this condition in the UK.

What are the implications?

This trial has provided good evidence that Eplerenone has little or no meaningful benefit when used to treat patients who have lived with CSC for longer than four months. As such, the search for other treatments can continue.

This trial reinforces the value of well-conducted large trial trials in answering important questions faced by ophthalmologists in practice.

Citation and Funding

Lotery A, Sivaprasad S, O’Connell A et al. Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;395:294-303.

This project was funded by the Efficacy and Mechanism Evaluation Programme (project number 13/94/15), which is a Medical Research Council and National Institute for Health Research partnership.

Bibliography

BNF. Eplerenone. London: BMJ Group and Pharmaceutical Press; 2020.

Khan Y, Mapani A, Islam N, Tufail A. Patient information: central serous chorio-retinopathy (CSCR). London: Moorfields Eye Hospital NHS Foundation Trust; 2018.

Lowth, M. Macular disorders. Leeds: Patient; 2019.

RNIB. Central serous retinopathy. London: Royal National Institute of Blind People. [Accessed on 25 March 2020].

Why was this study needed?

Central serous chorioretinopathy (CSC) usually occurs in one eye. For most people, it gets better by itself within four to six months, without any long-term changes to vision. However, for a small number of people, it can become a long-term problem. For these people, the retina can be damaged by prolonged swelling and lead to loss of sight.

Treatment is usually recommended if the condition lasts longer than six months. Treatment options include thermal laser or photodynamic therapy. There is little current evidence about the effectiveness of alternative drug treatments.

Before this trial, the authors had identified a few small (phase 1) studies of aflibercept, photodynamic laser therapy and eplerenone, but these were statistically underpowered. This means that they had too few participants to be reliable.

This trial, the first randomised superiority trial of its kind, was designed to improve the quality and certainty of evidence and aimed to recruit a sample of 104 patients from 22 UK NHS hospitals.

What did this study do?

On completion, this randomised controlled trial had recruited 114 adults from 22 hospitals in the UK. Patients enrolled had CSC for at least four months, without any previous treatment. In one group, 57 patients were given eplerenone tablets for up to 12 months, alongside usual care. They took 25mg per day for a week, increasing to 50mg per day if their potassium levels were normal. The other 57 patients were given identical-looking placebo tablets for up to 12 months alongside usual care. All patients were followed up after one week, and after one, three, six, nine and 12 months.

No patients, clinicians or people assessing the outcomes knew which group anyone was in.

Visual acuity was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts. These charts have five letters on each line, and the authors specified a clinically important difference or gain in acuity as more than five letters (or one line) on these charts.

This trial was well conducted and the number of participants was sufficient to have found a clinically meaningful difference between the groups if one existed.

What did it find?

  • Best-corrected visual acuity (BCVA) was measured by accredited optometrists using the acuity charts. Mean acuity at 12 months in the eplerenone group was 80.4 letters, and in the placebo group was 79.5 letters (estimated mean difference 1.73 letters, 95% confidence interval -1.12 to 4.57). There was, therefore, no clinically important or statistically significant difference in BCVA between the groups at 12 months.
  • Other outcomes were measured at 12 months, such as subretinal fluid thickness, the average time until the fluid was reabsorbed, and the average time to recurrence of the fluid. None of these showed any significant differences between the groups in favour of eplerenone either.
  • There were no serious adverse events in the eplerenone group. The placebo group reported three serious adverse events, none of which were associated with the placebo tablet. Eight people in each group had to stop their trial tablet due to increased potassium levels.

What does current guidance say on this issue?

There are no national guidelines on the treatment of CSC. Moorfields Eye Hospital NHS Foundation Trust in London has produced a patient information leaflet on the condition. This lists oral medications such as eplerenone as treatment options but highlights that further research is being carried out to evaluate these drugs.

Eplerenone is not currently licensed for treating this condition in the UK.

What are the implications?

This trial has provided good evidence that Eplerenone has little or no meaningful benefit when used to treat patients who have lived with CSC for longer than four months. As such, the search for other treatments can continue.

This trial reinforces the value of well-conducted large trial trials in answering important questions faced by ophthalmologists in practice.

Citation and Funding

Lotery A, Sivaprasad S, O’Connell A et al. Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;395:294-303.

This project was funded by the Efficacy and Mechanism Evaluation Programme (project number 13/94/15), which is a Medical Research Council and National Institute for Health Research partnership.

Bibliography

BNF. Eplerenone. London: BMJ Group and Pharmaceutical Press; 2020.

Khan Y, Mapani A, Islam N, Tufail A. Patient information: central serous chorio-retinopathy (CSCR). London: Moorfields Eye Hospital NHS Foundation Trust; 2018.

Lowth, M. Macular disorders. Leeds: Patient; 2019.

RNIB. Central serous retinopathy. London: Royal National Institute of Blind People. [Accessed on 25 March 2020].

Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial

Published on 23 January 2020

Lotery, A, Sivaprasad, S, O’Connell, A, Harris, RA, Culliford, L, Ellis, L, Cree, A, Madhusudhan, S, Behar-Cohen, F, Chakravarthy, U, Peto, T, Rogers, CA and Reeves, BC

Lancet The , 2020

Background In chronic central serous chorioretinopathy (CSCR), fluid accumulates in the subretinal space. CSCR is a common visually disabling condition that develops in individuals up to 60 years of age, and there is no definitive treatment. Previous research suggests the mineralocorticoid receptor antagonist, eplerenone, is effective for treating CSCR; however, this drug is not licensed for the treatment of patients with CSCR. We aimed to evaluate whether eplerenone was superior to placebo in terms of improving visual acuity in patients with chronic CSCR. Methods This randomised, double-blind, parallel-group, multicentre placebo-controlled trial was done at 22 hospitals in the UK. Participants were eligible if they were aged 18–60 years and had had treatment-naive CSCR for 4 months or more. Patients were randomly assigned (1:1) to either the eplerenone or the placebo group by a trial statistician through a password-protected system online. Allocation was stratified by best-corrected visual acuity (BCVA) and hospital. Patients were given either oral eplerenone (25 mg/day for 1 week, increasing to 50 mg/day for up to 12 months) plus usual care or placebo plus usual care for up to 12 months. All participants, care teams, outcome assessors, pharmacists, and members of the trial management group were masked to the treatment allocation. The primary outcome was BCVA, measured as letters read, at 12 months. All outcomes apart from safety were analysed on a modified intention-to-treat basis (participants who withdrew consent without contributing a post-randomisation BCVA measurement were excluded from the primary analysis population and from most secondary analysis populations). The trial is registered with ISRCTN, ISRCTN92746680, and is completed. Findings Between Jan 11, 2017, and Feb 22, 2018, we enrolled and randomly assigned 114 patients to receive either eplerenone (n=57) or placebo (n=57). Three participants in the placebo group withdrew consent without contributing a post-randomisation BCVA measurement and were excluded from the primary outcome analysis population. All patients from the eplerenone group and 54 patients from the placebo group were included in the primary outcome. Modelled mean BCVA at 12 months was 79·5 letters (SD 4·5) in the placebo group and 80·4 letters (4·6) in the eplerenone group, with an adjusted estimated mean difference of 1·73 letters (95% CI −1·12 to 4·57; p=0·24) at 12 months. Hyperkalaemia occurred in eight (14%) patients in each group. No serious adverse events were reported in the eplerenone group and three unrelated serious adverse events were reported in the placebo group (myocardial infarction [anticipated], diverticulitis [unanticipated], and metabolic surgery [unanticipated]). Interpretation Eplerenone was not superior to placebo for improving BCVA in people with chronic CSCR after 12 months of treatment. Ophthalmologists who currently prescribe eplerenone for CSCR should discontinue this practice.

  • Early Treatment Diabetic Retinopathy Study (ETDRS) charts are made of rows of letters of different sizes. They are similar to the usual charts found hanging on the wall in health professionals’ rooms.
  • ETDRS charts are more consistently lit and have equal numbers of letters, five on each row. This means that they are more consistent in a research setting.
  • Visual acuity is measured according to the number of letters that a person can read.
  • This trial was designed to detect a difference of five or more letters between the two groups or one line.

Expert commentary

Central serous chorioretinopathy (CSC) is a rare condition, mostly found in middle-aged men, where fluid accumulates beneath the centre of the retina. This study randomised people with CSC, persisting for at least four months but with relatively good vision, to either placebo tablets or eplerenone, a drug that counteracts the effect of steroids produced by the body.

The study found no important benefit on vision with oral eplerenone up to 12 months of follow-up in such patients, because visual acuity slightly improved with placebo to a similar extent. There was also no effect on anatomic outcomes such as the amount of fluid under the retina, which is the hallmark of active disease. The thickening of the vessel layer beneath the retina, the choroid, which is involved in the pathological process, was also no different with eplerenone versus placebo.

This landmark randomised study suggests that eplerenone should not be used in most patients with CSC. This evidence may not apply to people with more severe visual loss due to long-standing recurrent CSC, or to other drugs of the same class, such as spironolactone.

Gianni Virgili, Associate Professor of Ophthalmology at the University of Florence, Firenze, Italy; Executive Editor, American Journal of Ophthalmology

The commentator declares no conflicting interests