The Cochrane review «Solomon SD, Lindsley K, Vedula SS ym. Anti-vascula...»1 aimed to investigate the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular age related macular degeneration (AMD) compared with no anti-VEGF treatment; and the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.
Inclusion croiteria were: randomized controlled trial; patients with neovascular AMD, anti-VEGF treatment was compared with another treatment, sham injection, or no treatment; at least one year follow up. Excluded were studies comparing different doses; studies with aflibercept; and combination tretaments.
Main outcome measure was best-corrected visual acuity (BCVA) at one year follow up; for comparisons the proportion of participants who gained 15 letters or more (3 lines) of BCVA in the study eye when BCVA was measured on a visual acuity chart with a LogMAR scale. Several secondary outcomes were listed including visual acuity, anatomical, quality of life, and safety outcomes.
Literature was search from CENTRAL, Medline, EMBASE, LILACS, mRCT, Clinical Trials, and WHO's ICTRP without date restriction until 27.3.2014. Search was supplemented with hand searches and contacts to pharmaceutical companies.
Altogether 4827 records, 403 clinical trials and 19 additional records were identified. Included in the review are 124 records from 12 studies and 7 ongoing trials with 5496 participants. The mean age of participants was 78–80 years except in one study and at least half of the participants were women. Two studies were international, 4 were conducted at USA, 2 in Austria, 2 in Great Britain, and 1 in France. Five trials included only participants with no previous treatment for choroidal neovascularization (CNV) or AMD. Among the included trials, there were variations in the types of eligible neovascular lesions (e.g., predominantly classic CNV, minimally classic CNV, or occult CNV), lesion sizes, and baseline visual acuities of participants. Four comparisons of interventions were included: one study evaluated three doses of pegaptanib versus sham injection, three studies compared two doses of ranibizumab with sham injections or PDT, two studies compared bevacizumab with other treatments for AMD, and six studies were head-to-head trials of bevacizumab versus ranibizumab. Overall the included studies were at low risk of bias. One small study was not blinded. Follow up time varied from 12 to 24 months.
Bevacizumab (1.25 mg monthly or as needed) versus ranibizumab (0.5 mg monthly or as needed), follow up one year
Gain of 15 letters or more visual acuity (6 studies, n=2446): RR 0.9 (95% confidence interval 0.73-1.11)
Loss of fewer than 15 letters of visual acuity (6 studies, n=2446): RR 1.00 (0.98-1.02)
Mean change in visual acuity (6 studies, n=2446): mean difference (MD)-0.51 (-1.64-0.62)
Mean change in central retinal thickness (4 studies, n=1995): MD -13.97um (-26.52 - -1.41)
No problems for each quality of life subscale (1 study, n=548): RR ranged for subscales between 0.96 (0.9-1.04) – 1.02 (0.89-1.17)
At least one serious adverse event (4 studies, n=2597): RR1.27 (1.06-1.52)
Serious ocular adverse events <5/1000 for both, RR varied between 0.51 and 7.05.
Bevacizumab (1.25 or 1.0 mg) versus control, follow up one year
Gain of 15 letters or more visual acuity (2 studies, n=159): RR 7.80 (2.44-24.98)
Loss of fewer than 15 letters of visual acuity (2 studies, n=159): RR 1.28 (1.09-1.50)
At least one serious adverse event (1 study, n=131): RR 2.03 (0.19-21.85)
Serious ocular adverse events (1 study, n=131): RR 1.86 (0.73-4.74)
Ranibizumab (0.3 or 0.5 mg) versus control, follow-up one year
Gain of 15 letters or more visual acuity (3 studies, n=1322): meta-analysis not performed due to heterogenity (I2=80%). Assessed risk for the controls 59/1000 and for ranibizumab group 230/1000 (95% CI 93–566/1000)
Loss of fewer than 15 letters of visual acuity (3 studies, n=1322): RR 1.53 (1.41–1.64)
Mean change in visual acuity (3 studies, n=1322): MD 17.80 letters (15.95–19.65)
Change in mean vision-related quality of life (2 studies, n=1134): MD 6.69 (3.38–9.99)
At least one serious adverse event (2 studies, n=603): RR ranged from 0.17 to 2.08
Serious ocular adverse events (2 studies, n=603): RR ranged from 0.52 to 2.71.
Meta-analysis «Chen G, Li W, Tzekov R ym. Bevacizumab versus rani...»2 evaluated the relative efficacy and safety of bevacizumab versus ranibizumab for the treatment of the neovascular form of age-related macular degeneration.
Included were randomized controlled trials with head-to-head comparisons of bevacizumab with ranibizumab in treatment of neovascular AMD. In addition inclusion criteria were: participants minimum age 50; and results on mean change in BCVA, mean change in central macular thickness, the proportion of patients with death, arteriotrombotic events, venous trombotic events, and at least one serious systemic adverse event.
Literature search was conducted from PubMed, EMBASE and Cochrane Library until December 2013 and supplemented with manual search. Efficacy estimates were determined by comparing weighted mean differences in the change of BCVA and central macular thickness from baseline. Safety estimates were determined by calculating the risk ratio for rates of death, arteriothrombotic events, venous thrombotic events, and at least 1 serious systemic adverse event.
A total of 6 randomized controlled trials were included with 2612 patients (n=1292 in the bevacizumab group and 1320 in the ranibizumab group). Risk of bias was assessed to be low. Weighted mean difference between bevacizumab and ranibizumab in BCVA at 1 year or 2 years (2 studies) was -0.40 (95% confidence interval (CI) -1.48 to 0.69, p=0.47) and -1.16 (-2.82 to 0.51, p=0.17). Weighted mean difference for reducing central macular thickness at 1 year was 4.35 (0.92-7.78, p=0.01) favoring ranibizumab. The pooled risk ratios comparing the rates of serious systemic adverse events at 1 year and 2 years were slightly in favor of ranibizumab (1.24, 95% CI 1.04-1.48, p=0.02 and 1.20, 95%CI, 1.05-1.37, p=0.008, respectively). The rates of death, arteriothrombotic events, and venous thrombotic events did not differ statistically.
Kommentti: Mukana on samat tutkimukset kuin Cochrane-katsauksenkin «Solomon SD, Lindsley K, Vedula SS ym. Anti-vascula...»1 suorassa vertailussa. Makulan paksuuden muutoksessa yhden kohtalaisen pienen tutkimuksen painoarvo on yli 90%. BCVA-tuloksissa CATT-tutkimuksen painoarvo on 39%, muutoin yli puolet.
Meta-analysis and network meta-analysis «Schmid MK, Bachmann LM, Fäs L ym. Efficacy and adv...»3aimed at quantifying the gain in visual acuity and serious side effects of ranibizumab, bevacizumab and aflibercept in AMD.
Included were randomised controlled trials comparing aflibercept, bevacizumab or ranibizumab against placebo or in a head-to head fashion with at least one year follow-up data. Outcome measures had to include visual acuity and serious side effects.
Literature was searched until June 2013 from (Pre)Medline, EMBASE, SCOPUS, Cochrane Library (until April 2013), Science Citation Index and reference lists were searched. Separate searches for efficacy and side effects were performed. Outcomes were 1-year follow-up data of visual acuity (letters gained) and serious (vascular death, any death, stroke, myocardial infarction, transient ischaemic attack) and thrombotic events.
Meta-analysis included 11 trials (8341 patients) assessing five active treatments: ranibizumab 0.3 mg (4 studies, n=1782), ranibizumab 0.5 mg (11 studies, n=3566), bevasizumab 1.25 mg (2 studies, n=882), aflibercebt 0.5 mg (2 studies, n=597), and aflibercebt 2 mg (2 studies, n=1220). Number of patients in placebo group was 294. Mean age of the participants was 76.7 years and 57% were women. Compared with placebo, all study treatments had a significantly higher percentage of letters gained.
Visual acuity, letters gained (%) compared to placebo
Ranibizumab 0.3 mg: 2.39% (95% confidence interval (CI) 1.59-3.19; p<0.001)
Ranibizumab 0.5 mg: 3.56% (2.58-4.13; p<0.001)
Bevacizumab 1.25 mg: 2.14% (0.47-3.82; p0.012)
Aflibercept 0.5 mg: 2.91% (0.99-4.82; p=0.003)
Aflibercept 2 mg: 3.44% (1.73-5.14; p<0.001).
In networkanalysis there were no statistically significant differences between the regimens.
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