Lotery, A., Sivaprasad, S., O’Connell, A., Harris, R. A., Culliford, L., Ellis, L., … Chakravarthy, U. (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. The Lancet, 395(10220), 294–303. doi:10.1016/s0140-6736(19)32981-2
Central serous chorioretinopathy (CSCR) is a relatively common and vision threatening retinal disease. It most frequently affects young to middle aged men. Fortunately for most patients, CSCR will resolve spontaneously within 3 months of onset with only mild long-term visual deficit. CSCR is considered chronic if subretinal fluid fails to resolve within this time period. Chronic subretinal fluid can lead to RPE atrophy, retinal atrophy and vision loss. Determining how and when to intervene in these patients is challenging. Over the years, many different approaches have been advocated, but studying these interventions has been difficult. Chronic CSCR is relatively rare and often resolves if given enough time. These attributes make it hard to definitively show a treatment effect without sufficiently powered placebo controlled studies.
Physiologically, the mineralocorticoid receptor antagonist eplerenone makes sense as a treatment target. Exogenous steroid use is a known risk factor for developing CSCR, and animal models have shown that activation of mineralocorticoid receptors in the choroid leads to choroidal vasodilation. Recently, several small studies have shown promising results for oral eplerenone therapy in chronic CSCR. However, many of these trials were not placebo controlled, and the others suffered from limited subject numbers.
The VICI trial was a double masked, randomized controlled clinical trial comparing oral eplerenone therapy to placebo in patients with treatment naïve chronic central serous retinopathy. Patients were included who were between the ages of 18 and 60 years-old, diagnosed with CSCR based on the presence of subfoveal subretinal fluid on OCT, characteristic CSCR findings on fluorescein and ICG angiography, as well as examination and history consistent with CSCR with fluid for >4 months. Patients were excluded who had evidence of CNVM, had been previously treated for CSCR, had any other disease which could produce subretinal fluid, or were myopic (-6D or more). Patients were also excluded for whom eplerenone or diagnostics were felt to be unsafe (renal or hepatic impairment, pregnancy, lactation, allergy) and those on other medications which could interact with eplerenone.
114 patients were randomized 1:1 to receive either eplerenone 25 mg/day for 1 week then 50 mg/day if serum potassium did not exceed 5 mmol/L, or an identical appearing placebo pill. Patients continued their study drug up to 12 months, but if subretinal fluid had resolved at any follow up visit (prespecified at 1 week then 1, 3, 6, 9 and 12 months), they were instructed to discontinue the medication. If subretinal fluid later recurred, the drug was restarted. Patients were also permitted to receive “usual care” at the discretion of the treating doctor. This could include photodynamic therapy or subthreshold macular laser. The primary endpoint was ETDRS BCVA at 1 year. Secondary outcomes included low-luminance BCVA, central subfield thickness, and changes in subretinal fluid thickness, among others.
The final analysis showed that there was no significant difference in the primary endpoint of best corrected visual acuity between the placebo and treatment group (79.5 ETDRS letters vs. 80.4 ETDRS letters, p = 0.236). There were also no significant differences found in favor of eplerenone therapy in central subfield thickness, estimated median time to complete or partial subretinal fluid resolution, estimated median time to recurrence of subretinal fluid or VFQ-25 questionnaire scores. Interestingly, subretinal fluid thickness at 12 months was significantly less in the placebo group compared to the treatment group (72.5 um vs. 120.7 um, p=.0066). Likewise choroidal thickness at 12 months was also significantly less in the placebo group vs. the treatment group (451.4 um vs. 478.0 um, p=.0040). In sum, the authors found no positive treatment signals for eplerenone therapy over placebo in chronic CSCR.
Although this was a very well-designed and executed study there are some limitations. First, more patients in the placebo group received rescue therapy with photodynamic therapy or subthreshold macular laser than in the treatment group (13% vs. 5%). This may have biased the results towards the placebo group. However, the authors state that in a post-hoc analysis, adjusting for PDT administration did not change their results. Second, eplerenone was discontinued at the first visit at which subretinal fluid had resolved. This differs from the clinical practice of many, who prefer to continue eplerenone therapy even after resolution. Finally, visual acuity was quite good in both groups to start, and the ceiling effect may have blunted any potential differences in BCVA. However, secondary anatomical outcomes also did not favor eplerenone.
Despite its limitations, this is by far the highest quality, and largest prospective, placebo-controlled trial to date evaluating treatment for CSCR with eplerenone. It is a welcome addition to the literature, and while not definitive, certainly casts some doubt on the usefulness of eplerenone in chronic CSR.
Christian J. Sanfilippo, MD
The Retina Partners
Los Angeles, CA