Vitamin A and fish oils for preventing the progression of retinitis pigmentosa.

The Cochrane database of systematic reviews

Jun 2020

DOI: 10.1002/14651858.CD008428.pub3

Citations:40

Influential Citations:2

Systematic Reviews / Meta-Analyses

Enhanced Details

Methods

Four randomized controlled trials (three parallel-group; one factorial) enrolling 944 participants with retinitis pigmentosa (RP), aged 4–55 years. Two trials enrolled only X-linked RP; two included RP across various genetic predispositions. Trials conducted in the USA; two also included Canada. Sex distribution varied: two trials included both genders; two enrolled only males. RP diagnosed by ophthalmologists. Follow-up ranged 4–6 years. Outcomes included visual field sensitivity, visual acuity, ERG amplitudes, and OCT (reported in one trial). Risk of bias generally low across domains in three trials; Ho man 2014 had incomplete outcome data and selective reporting concerns.

Intervention

Berson 1993: Vitamin A 15,000 IU/day (oral) with Vitamin E trace; duration 4 years. Berson 2004a: DHA 1,200 mg/day + Vitamin A 15,000 IU/day (oral) + Vitamin E trace; duration 3–4 years. Ho man 2004: DHA 400 mg/day (oral); duration 4 years. Ho man 2014: DHA 30 mg/kg/day (oral; range 600–3600 mg/day); duration 4 years.

Results

Across four randomized controlled trials (n=881 analyzed) in RP, vitamin A or DHA alone or in combination did not demonstrate a clear, consistent benefit in slowing disease progression over about four years. In Ho man 2014, DHA showed slower decline in four-year visual field rates in foveal, macular, peripheral, and total fields (P=0.039, 0.031, <0.001, <0.001), but certainty is very low. In Berson 1993, vitamin A was associated with a possible slower decline in cone ERG amplitude in a high baseline amplitude subgroup (P=0.01), not replicated elsewhere. Visual acuity changes were small and not significantly different across trials. Adverse events were rare; one trial reported 42 events in 60 participants. Overall, evidence is very uncertain; no routine recommendation for vitamin A or DHA supplementation for RP progression. Future trials should assess ERG amplitude changes and use standardized outcomes.

Limitations

Limitations include clinical heterogeneity (genetic forms, baseline severity), varied regimens (different DHA doses and presence/absence of vitamin A), and different outcome measures, which prevented meta-analysis. Small sample sizes in several trials and missing data in at least one study reduce precision. Certainty of evidence is very low across outcomes; adverse-event data are sparse beyond one trial; generalizability is limited due to strict inclusion criteria.

Abstract

BACKGROUND Retinitis pigmentosa (RP) comprises a group of hereditary eye diseases characterized by progressive degeneration of retinal photoreceptors. It results in severe visual loss that may lead to blindness. Symptoms may become manifest during childhood or adulthood which include poor night vision (nyctalopia) and constriction of peripheral vision (visual field loss). Visual field loss is progressive and affects central vision later in the disease course. The worldwide prevalence of RP is approximately 1 in 4000, with 100,000 individuals affected in the USA. At this time, there is no proven therapy for RP. OBJECTIVES The objective of this review was to synthesize the best available evidence regarding the effectiveness and safety of vitamin A and fish oils (docosahexaenoic acid (DHA)) in preventing the progression of RP. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (2020, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP); and OpenGrey. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 7 February 2020. SELECTION CRITERIA We included randomized controlled trials that enrolled participants of any age diagnosed with any degree of severity or type of RP, and evaluated the effectiveness of vitamin A, fish oils (DHA), or both compared to placebo, vitamins (other than vitamin A), or no therapy, as a treatment for RP. We excluded cluster-randomized trials and cross-over trials. DATA COLLECTION AND ANALYSIS We prespecified the following outcomes: mean change from baseline visual field, mean change from baseline electroretinogram (ERG) amplitudes, and anatomic changes as measured by optical coherence tomography (OCT), at one-year follow-up, and mean change in visual acuity, at five-year follow-up. Two review authors independently extracted data and evaluated risk of bias for all included trials. We also contacted study investigators for further information when necessary. MAIN RESULTS In addition to three trials from the previous version of this review, we included a total of four trials with 944 participants aged 4 to 55 years. Two trials included only participants with X-linked RP and the other two included participants with RP of all forms of genetic predisposition. Two trials evaluated the effect of DHA alone; one trial evaluated vitamin A alone; and one trial evaluated DHA and vitamin A versus vitamin A alone. Two trials recruited participants from the USA, and the other two recruited from the USA and Canada. All trials were at low risk of bias for most domains. We did not perform meta-analysis due to clinical heterogeneity. Four trials assessed visual field sensitivity. Investigators found no evidence of a difference in mean values between the groups. However, one trial found that the annual rate of change of visual field sensitivity over four years favored the DHA group in foveal (-0.02 ± 0.55 (standard error (SE)) dB versus -0.47 ± 0.03 dB, P = 0.039), macular (-0.42 ± 0.05 dB versus -0.85 ± 0.03 dB, P = 0.031), peripheral (-0.39 ± 0.02 versus -0.86 ± 0.02 dB, P < 0.001), and total visual field sensitivity (-0.39 ± 0.02 versus -0.86 ± 0.02 dB, P < 0.001). The certainty of the evidence was very low. The four trials evaluated visual acuity (LogMAR scale) at a follow-up of four to six years. In one trial (208 participants), investigators found no evidence of a difference between the two groups, as both groups lost 0.7 letters of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity per year. In another trial (41 participants), DHA showed no evidence of effect on visual acuity (mean difference -0.01 logMAR units (95% confidence interval -0.14 to 0.12; one letter difference between the two groups; very low-certainty evidence). In the third trial (60 participants), annual change in mean number of letters correct was -0.8 (DHA) and 1.4 letters (placebo), with no evidence of between-group difference. In the fourth trial (572 participants), which evaluated (vitamin A + vitamin E trace) compared with (vitamin A trace + vitamin E trace), decline in ETDRS visual acuity was 1.1 versus 0.9 letters per year, respectively. All four trials reported electroretinography (ERG). Investigators of two trials found no evidence of a difference between the DHA and placebo group in yearly rates of change in 31 Hz cone ERG amplitude (mean ± SE) (-0.028 ± 0.001 log μV versus -0.022 ± 0.002 log μV; P = 0.30); rod ERG amplitude (mean ± SE) (-0.010 ± 0.001 log μV versus -0.023 ± 0.001 log μV; P = 0.27); and maximal ERG amplitude (mean ± SE) (-0.042 ± 0.001 log μV versus -0.036 ± 0.001 log μV; P = 0.65). In another trial, a slight difference (6.1% versus 7.1%) in decline of ERG per year favored vitamin A (P = 0.01). The certainty of the evidence was very low. One trial (51 participants) that assessed optical coherence tomography found no evidence of a difference in ellipsoid zone constriction (P = 0.87) over two years, with very low-certainty evidence. The other three trials did not report this outcome. Only one trial reported adverse events, which found that 27/60 participants experienced 42 treatment-related emergent adverse events (22 in DHA group, 20 in placebo group). The certainty of evidence was very low. The rest of the trials reported no adverse events, and no study reported any evidence of benefit of vitamin supplementation on the progression of visual acuity loss. AUTHORS' CONCLUSIONS Based on the results of four studies, it is uncertain if there is a benefit of treatment with vitamin A or DHA, or both for people with RP. Future trials should also take into account the changes observed in ERG amplitudes and other outcome show less