Mineralocorticoid Receptor Antagonists in Central Serous Chorioretinopathy

Accepted Manuscript Mineralocorticoid Receptor Antagonists in Central Serous Chorioretinopathy: A MetaAnalysis of Randomized Controlled Trials Sean K. Wang, Peng Sun, MD, Rachel M. Tandias, Brendan K. Seto, Jorge G. Arroyo, MD, MPH PII:

S2468-6530(18)30362-2

DOI:

10.1016/j.oret.2018.09.003

Reference:

ORET 390

To appear in:

Ophthalmology Retina

Received Date: 18 June 2018 Revised Date:

6 September 2018

Accepted Date: 7 September 2018

Please cite this article as: Wang S.K., Sun P., Tandias R.M., Seto B.K. & Arroyo J.G., Mineralocorticoid Receptor Antagonists in Central Serous Chorioretinopathy: A Meta-Analysis of Randomized Controlled Trials, Ophthalmology Retina (2018), doi: https://doi.org/10.1016/j.oret.2018.09.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Mineralocorticoid Receptor Antagonists in Central Serous Chorioretinopathy: A Meta-

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Analysis of Randomized Controlled Trials

3 Authors: Sean K. Wang,1 Peng Sun, MD,1,2 Rachel M. Tandias,1 Brendan K. Seto,1 Jorge G.

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Arroyo, MD, MPH1

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6 Affiliations:

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1. Division of Ophthalmology, Beth Israel Deaconess Medical Center, Harvard Medical School,

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Boston, Massachusetts, USA

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2. Department of Ophthalmology, First Hospital of China Medical University, Shenyang, People's Republic of China

12 Financial Support: None

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Disclosures: No conflicting relationship exists for any author.

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Running head: MR Antagonists in Central Serous Chorioretinopathy

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Address for reprints:

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Jorge G. Arroyo

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Beth Israel Deaconess Medical Center

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Ophthalmology, CC5

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330 Brookline Ave

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Boston, MA 02215, USA

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ABSTRACT

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Topic: A meta-analysis comparing mineralocorticoid receptor (MR) antagonists (eplerenone or

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spironolactone) versus observation or placebo in the treatment of central serous

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chorioretinopathy (CSCR) based on best-corrected visual acuity (BCVA) and subretinal fluid

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(SRF) level data from randomized controlled trials.

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Clinical relevance: CSCR patients may develop decreased visual acuity, reduced contrast

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sensitivity, scotomas, and metamorphopsia. Although multiple treatment options for CSCR have

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been proposed, compelling evidence for any particular modality is still lacking

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Methods: Three databases (PubMed, EMBASE, and BIOSIS) were searched for potentially

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relevant records as of March 2018. Of 114 unique studies identified, five RCTs comparing

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BCVA with either eplerenone or spironolactone versus observation or placebo were included.

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Quality of articles was assessed according to the Cochrane Risk of Bias Tool with any

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discrepancies resolved by author consensus.

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Results: A total of 145 patient eyes with CSCR were included in the meta-analysis. Compared to

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placebo or observation, MR antagonist treatment had a significant positive effect on BCVA after

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both one month (weighted mean difference [WMD] = -0.05 logMAR units [95% confidence

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interval (CI): -0.07 to -0.02], Z = 3.94, P <0.0001) and two months (WMD = -0.10 logMAR

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units [95% CI: -0.14 to -0.06], Z = 4.69, P <0.00001). MR antagonist treatment also significantly

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reduced SRF height in CSCR at 1 month (WMD = -81.15 µm [95% CI: -148.25 to -14.05], Z =

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2.37, P = 0.02). However, this effect was no longer significant at 2 months (WMD = -58.63 µm

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[95% CI: -155.40 to 38.13, Z = 1.19, P = 0.23). None of the patients in the five trials withdrew

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due to adverse effects, and blood electrolyte levels including potassium remained normal in all

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cases.

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Conclusion: Our findings suggest a modest benefit with MR antagonist therapy for CSCR

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patients in improving BCVA. We anticipate that MR antagonists will be well-tolerated by most

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CSCR patients and that barriers to starting a trial of these medications in non-resolving CSCR

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should be low.

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INTRODUCTION Central serous chorioretinopathy (CSCR) is a chorioretinal disorder characterized by choroidal vascular dilation and serous detachment of the neurosensory retina. The disease most

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often affects young males and classically resolves spontaneously within 6 months.1,2

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Nonetheless, up to half of patients with CSCR experience chronic or recurrent cases,3 resulting in

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persistent neurosensory detachments and potentially permanent vision loss. Specifically, CSCR

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patients may develop decreased best-corrected visual acuity (BCVA), reduced contrast

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sensitivity, scotomas, and metamorphopsia.4

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A wide array of treatment options for chronic (>3 months) and recurrent CSCR have been

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proposed, although compelling evidence for any particular modality is still lacking.5,6 Half-dose

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photodynamic therapy (PDT) is presently the preferred initial treatment for chronic CSCR.7

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However, there is a risk of several ocular complications with PDT including choroidal

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neovascularization (CNV), retinal pigment epithelium (RPE) atrophy, severe vision loss, and

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macular scar formation.8 Alternative therapies for CSCR that are being considered include focal

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laser photocoagulation,9 subthreshold or non-damaging retinal laser therapy (NRT),10,11

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intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections,12 and systemic

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medications such as mineralocorticoid receptor antagonists.

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Recent discoveries regarding the pathophysiology of CSCR have implicated over-

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activation of the mineralocorticoid receptor (MR). Studying rat eyes, Zhao et al. first

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characterized the retina as target for mineralocorticoids and found that administration of an MR

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activator produced choroidal vessel dilation and leakage similar to that seen in human CSCR

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patients.13,14 Conceptually, this finding is consistent with the long-term observation that elevated

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cortisol levels increase one’s risk for CSCR as MR may also respond to glucocorticoids.15

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Another line of support for this mechanism came in 2017 when van Dijk et al. identified a

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haplotype in the MR-encoding gene associated with chronic CSCR, strongly supporting a direct

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role for the receptor in the disease.16 Based on this rationale, multiple studies have been performed using either eplerenone or

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spironolactone, both MR antagonists, in CSCR since the first patients were treated with oral

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eplerenone in 2012.14,17 Among these studies, however, there has been substantial variability in

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the observed outcomes, as some demonstrate convincing changes in BCVA and subretinal fluid

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(SRF) levels while others show little to no improvement.18–21 The interpretation of these studies

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is further complicated by the natural history of CSCR and the propensity of the condition to

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resolve spontaneously. Thus, while there are many reported cases of MR antagonists successfully

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treating CSCR and a handful of small randomized controlled studies,20,22–25 it is difficult to gauge

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the true effect of these medications.

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by performing a meta-analysis of the available data from randomized controlled trials (RCTs).

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METHODS

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Search Strategy

We conducted a literature search using three databases (PubMed, EMBASE, and

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Our goal was to better understand the effectiveness of MR antagonists in treating CSCR

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BIOSIS) to identify potentially relevant records for the analysis. For each database, we searched

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the terms “(central serous) AND (mineralocorticoid OR eplerenone OR spironolactone)” under

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either the ‘All Fields’ heading for PubMed and EMBASE or the ‘Topic’ heading for BIOSIS.

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The term “chorioretinopathy” was intentionally omitted from our search strategy to avoid

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exclusion of records in which the disease was classified as “central serous retinopathy” rather

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than “central serous chorioretinopathy.” Searches were conducted until March 2018 with no

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limitations based on the language, country, and time of the record.

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The inclusion criteria of our meta-analysis were trials assessing the use of a

mineralocorticoid receptor antagonist to treat CSCR of any duration characterized by (1)

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randomization, (2) presence of a placebo or observation only control group, (3) assessment of

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BCVA, (4) available full-text, and (5) publication as an article in a peer-reviewed journal. We

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did not set any exclusion criteria for our study.

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Data Extraction

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For each study, we extracted information on the patient population, number of eyes, medication given, dosage and treatment duration, BCVA, and SRF height at each follow-up visit

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while on treatment. BCVA was measured in logMAR units. For one study, ETDRS letter scores

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were converted to logMAR units according to the formula logMAR = 1.7 – 0.02 x letter score.26

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SRF was measured in µm using optical coherence tomography (OCT) scans as either the

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maximum height or at the subfoveal location depending on the study. The timing of follow-up

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visits was rounded to the nearest month after initiating treatment. We defined the change in

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BCVA or SRF height at 1 month to be the difference between values at 1 month compared to

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baseline, and the change in BCVA or SRF height at 2 months to be the difference at 2 months

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compared to baseline. We did not extract data from follow-up examinations occurring after the

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cessation of treatment or a change in treatment arms if the trial was designed as a crossover

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study.

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Quality Assessment The quality of articles was assessed according to the Cochrane Risk of Bias Tool27 with any discrepancies resolved by author consensus. Risk for each bias was evaluated as low if there

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was documentation of methods to minimize the bias (e.g. random sequence generation or

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blinding of participants and personnel), high if no such documentation was present, and unclear

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if methods to minimize the bias were alluded to but not explicitly stated in the text.

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Statistical Analysis

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All statistical analyses were performed in Review Manager 5.328 using extracted values for mean, standard deviation (SD), and sample size. For articles in which values for SD were

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provided only for the baseline examination, SD at follow-up examinations were assumed to be

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equal to those at baseline. For each variable examined, the weighted mean difference (WMD)

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between treatment and observation or placebo groups was estimated with studies weighted

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according to the inverse of the variance.

Heterogeneity was explored using the Q-test to calculate the I2 statistic. A value of

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I2>50% was considered to indicate substantial heterogeneity. In cases of low statistical

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heterogeneity (I2 <30%), the fixed effects model was chosen. Otherwise, the random effects

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model was used.

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Given the low number (<10) of studies in our meta-analysis, we opted not to evaluate for

publication bias to avoid the possibility of drawing a misleading conclusion.29

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RESULTS

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Study selection for our meta-analysis is depicted in Figure 1. From database queries, we

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identified 114 unique records. Of these, 32 were considered relevant articles for which full-texts

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were obtained. We subsequently excluded 27 of these articles due to lack of an adequate control

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group (n = 25) or lack of randomization (n = 2).

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The remaining five studies20,22–25 were included in our analysis and are summarized in Table 1. Collectively, these trials examined 145 patient eyes with CSCR over a period of 1-3

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months. Two of the studies tested spironolactone, two tested eplerenone, and one tested both

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medications. In four of the studies, only patients with chronic CSCR (>3 months) were enrolled,

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while one study specifically enrolled CSCR cases with duration <3 months. All five trials

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randomized their subjects to either a treatment or control regimen, with patients undergoing

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observation or a receiving an inert placebo (e.g. lactose pill) in the latter group. A primary

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outcome measure was defined in four of the five studies. Change in SRF height from baseline

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was used in three trials, while change in BCVA from baseline was used in one.

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We next sought to evaluate potential biases in each of the five studies according to the

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criteria displayed in Figure 2. Overall, the risk of bias in the included studies was low, and all

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five studies were deemed acceptable by the authors to include in the analysis.

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To assess the effect of MR antagonists on visual acuity in patients with CSCR, we conducted a fixed effects model as shown in Figure 3. We examined the changes in BCVA at 1

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month and 2 months after initiating treatment as we had data from multiple trials at these

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intervals. For both time points, the analysis found a small but significant positive effect of MR

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antagonist treatment on BCVA (WMD = -0.05 logMAR units [95% confidence interval (CI): -

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0.07 to -0.02], Z = 3.94, P <0.0001 for 1 month; WMD = -0.10 logMAR units [95% CI: -0.14 to

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-0.06], Z = 4.69, P <0.00001 for 2 months). Heterogeneity among these studies was low (I2 = 0%

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at both 1 and 2 months).

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As seen in Figure 4, our analysis also demonstrated a significant positive effect of MR antagonist treatment on reducing SRF height in CSCR at 1 month (WMD = -81.15 µm [95% CI:

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-148.25 to -14.05], Z = 2.37, P = 0.02). However, this effect was no longer significant at 2

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months (WMD = -58.63 µm [95% CI: -155.40 to 38.13, Z = 1.19, P = 0.23). Random effects

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models were used to analyze SRF height given significant heterogeneity among the trials (I2 =

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88% at 1 month and 92% at 2 months).

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Both spironolactone and eplerenone were tolerated by the vast majority of subjects in the

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five studies we examined. None of the patients withdrew due to adverse effects, and blood

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electrolyte levels including potassium remained normal in all cases.20,22–25 Of the 46 total patients

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who received spironolactone as treatment, only one (2.2%) was reported to have developed

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gynecomastia.22

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DISCUSSION

We present to our knowledge the first meta-analysis examining the effectiveness of MR

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antagonists in treating CSCR. Utilizing data from five RCTs, we found that the use of either

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eplerenone or spironolactone was modestly superior to observation or placebo alone in

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improving the BCVA of CSCR patients, resulting in an average additional improvement of 0.05

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logMAR (half a Snellen line) after one month of treatment and 0.10 logMar (one Snellen line)

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after two months. Treatment with an MR antagonist also reduced SRF height to a greater extent

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than observation or placebo alone after one month, although we did not observe a statistically

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significant difference between the two groups after two months possibly due to data from fewer

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patients being available at this time point. Clinically, the management of CSCR can be

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challenging as its chronicity varies from individual to individual and available treatment

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modalities, if offered, are not always effective. MR antagonists therefore pose a reasonable

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treatment option for CSCR in that they are easy to administer, relatively inexpensive, and based

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on our findings, superior to observation in improving short-term visual outcomes.

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Nonetheless, several limitations of our meta-analysis should be acknowledged. Despite a broad literature search encompassing three major biomedical databases, we were only able to

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identify five RCTs assessing the use of MR antagonists in CSCR. Small sample sizes, sometimes

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fewer than 10 patients per group, were also employed in each of these RCTs, providing us a total

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of only 145 eyes for analysis. Much of this can be attributed to two factors: 1) the self-limiting

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nature of most cases of CSCR such that patients are often undertreated, and 2) the low incidence

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of CSCR in the general population, typically reported as 1 in 10,000 annually among men and 1

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in 100,000 among women.3 Further RCTs with larger patient enrollment are ultimately needed to

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address these issues. In addition to small sample sizes, the five RCTs we analyzed assessed

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differing doses and durations of either eplerenone or spironolactone, ranging from 50 mg daily

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for one month to 80 mg daily for two months.23,25 Despite these variations, we observed low

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heterogeneity in our BCVA analysis at both one and two months, suggesting that the therapeutic

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benefit of MR antagonists in CSCR may occur over a range of doses at least in the short term.

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Longer studies will be needed to evaluate the utility of MR antagonists beyond two months and

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the effects they may have on preventing CSCR recurrences.

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Mechanistically, spironolactone and eplerenone are similar in that they both compete

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with aldosterone for binding to intracellular receptors, resulting in MR antagonism. In CSCR

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specifically, it has been proposed that either glucocorticoids or aldosterone triggers excess MR

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activity within choroidal endothelial cells. MR signaling subsequently upregulates ion channels

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such as the KCa2.3 potassium channel which induces smooth muscle relaxation in the choroidal

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vessels, facilitating SRF accumulation.30 Relative to spironolactone, eplerenone has greater

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affinity and selectivity for the MR as well as reduced binding to sex-hormone receptors, leading

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to fewer side effects.31 Of the RCTs we examined, only Pichi et al. compared both

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spironolactone and eplerenone in CSCR, finding a statistically superior effect with

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spironolactone versus eplerenone in improving BCVA.22 In contrast, a retrospective comparison

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of CSCR patients who were administered either spironolactone or eplerenone found accelerated

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improvement in visual acuity with both treatments compared to observation and no detectable

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difference in efficacy between the two drugs.32

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Another comparison of interest regarding MR antagonists in CSCR is their effectiveness versus half-dose PDT, currently the preferred initial treatment option for non-resolving

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CSCR.7,33 To date, only one published study has examined this question, reporting comparable

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BCVA outcomes for spironolactone versus half-dose PDT after three months.34 While these

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results encourage the consideration of MR antagonists as a potential first-line CSCR therapy,

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future research should include an RCT comparing either spironolactone or eplerenone with half-

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dose PDT to definitively address this question. Regardless, one notable difference between MR

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antagonists and half-dose PDT is the focality of therapy. Relative to MR antagonists which are

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systemically delivered, half-dose PDT may be more suited for cases in which a focal leak has

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been identified. On the other hand, it might be easier to initially treat with an MR antagonist if

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the disease process is found to be more diffuse. Finally, the combination of half-dose PDT with

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an MR antagonist for treating CSCR should also be investigated.

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Both spironolactone and eplerenone have been used in the management of other conditions such as systemic hypertension and heart failure as MR antagonists contribute to

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cardiac remodeling and may have beneficial effects on vascular inflammation and fibrosis.35

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Consequently, their long-term safety and side effect profiles are well-established. All five RCTs

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in our analysis monitored for possible hypotension and hyperkalemia, and fortunately none of the

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study patients experienced these adverse effects. While one subject taking spironolactone did

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develop gynecomastia,22 this symptom is generally thought to be reversible following

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discontinuation of the drug.36 We thus anticipate that MR antagonists will be well-tolerated by

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most CSCR patients and that barriers to starting a trial of these medications in non-resolving

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CSCR should be low.

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33. van Dijk EHC, Fauser S, Breukink MB, et al. Half-Dose Photodynamic Therapy versus

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High-Density Subthreshold Micropulse Laser Treatment in Patients with Chronic Central Serous

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Chorioretinopathy. Ophthalmology. 2018.

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34. Lee JH, Lee SC, Kim H, Lee CS. COMPARISON OF SHORT-TERM EFFICACY

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BETWEEN ORAL SPIRONOLACTONE TREATMENT AND PHOTODYNAMIC THERAPY

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FOR THE TREATMENT OF NONRESOLVING CENTRAL SEROUS

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CHORIORETINOPATHY. Retina. 2017:1.

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35. Markowitz M, Messineo F, Coplan NL. Aldosterone Receptor Antagonists in Cardiovascular

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Disease: A Review of the Recent Literature and Insight Into Potential Future Indications. Clin

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Cardiol. 2012;35:605–609.

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36. Haynes BA, Mookadam F. Male gynecomastia. Mayo Clin Proc. 2009;84:672.

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335 FIGURE LEGENDS

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Figure 1. Selection process for eligible studies and reasons for exclusion.

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Figure 2. Evaluation of biases in the included studies. Green indicates low risk of bias, yellow

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indicates uncertain risk of bias, and red indicates high risk of bias.

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Figure 3. (A) Difference in BCVA (logMAR) at 1 month among CSCR subjects receiving MR

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antagonist treatment versus control. (B) Difference in BCVA at 2 months among CSCR subjects

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receiving MR antagonist treatment versus control.

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Figure 4. (A) Difference in SRF height (µm) at 1 month among CSCR subjects receiving MR

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antagonist treatment versus control. (B) Difference in SRF height at 2 months among CSCR

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subjects receiving MR antagonist treatment versus control.

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Table 1. Characteristics of Included Studies CSCR duration

Medication

Treatment pattern

Number of eyes for analysis

Follow-up (months)

Treatment

Observation or placebo

Baseline BCVA (logMAR ± SD)

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Study

Baseline SRF height (µm ± SD)

Treatment

Observation or placebo

Treatment

Observation or placebo

1

0.21 ± 0.22

0.24 ± 0.19

348 ± 125

340 ± 87

1

0.23 ± 0.16

0.25 ± 0.19

212 ± 151

136 ± 290

2

0.40 ± 0.28

0.31 ± 0.09

139 ± 59

136 ± 22

>3 months

Spironolactone

50 mg daily for 1 month

8

7

Pichi 20 2016

>3 months

Spironolactone or eplerenone

25 mg daily for 1 week, then 50 mg daily for 3 weeks

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20

Rahimy 22 2017

>3 months

Eplerenone

25 mg daily for 1 week, then up to 50 mg daily for 8 weeks

15

6

Schwartz 18 2017

>4 months

Eplerenone

25 mg daily for 1 week, then 50 mg daily for 11 weeks

13

6

1, 2, and 3

0.60 ± 0.80

0.20 ± 0.24

143 ±49

182 ± 131

<3 months

Spironolactone

80 mg daily for 2 months

18

12

1 and 2

0.25 ± 0.18

0.25 ± 0.22

341 ± 127

315 ± 154

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Sun 2017

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Bousquet 23 2015

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Records identified through database searching (n = 237)

Additional records identified through other sources (n = 0)

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Identification

PRISMA 2009 Flow Diagram

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Records screened (n = 114)

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Full-text articles assessed for eligibility (n = 32)

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Included

Eligibility

Screening

Records after duplicates removed (n = 114)

Records excluded (n = 82)

Full-text articles excluded, with reasons (n = 27): - No control group (n = 25) - No randomization (n = 2)

Studies included in qualitative synthesis (n = 5)

Studies included in quantitative synthesis (meta-analysis) (n = 5)

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and MetaAnalyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit www.prisma-statement.org.

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Précis: Based on data from five randomized controlled trials, use of either eplerenone or spironolactone is superior to observation in improving the visual acuity of patients with central

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serous chorioretinopathy.