Ranibitsumabin ja bevasitsumabin turvallisuus kostean silmänpohjan ikärappeuman hoidossa

Raija Sipilä

Näytön aste: B

Ranibitsumabin ja bevasitsumabin välillä ei ilmeisesti ole kliinisesti merkittävää eroa turvallisuudessa kostean silmänpohjan ikärappeuman hoidossa lyhytaikaisessa hoidossa.

Cochrane review «Moja L, Lucenteforte E, Kwag KH ym. Systemic safet...»1 aimed to assess the systemic safety of intravitreal bevacizumab compared with intravitreal ranibizumab in patients with neovascular AMD.

Included were randomized controlled trials with head-to-head comparison of bevacizumab and ranibizumab in treatment of AMD. No other restriction for treatment regimens of participants was set. Primary endpoint was all-cause deaths; all serious systemic adverse events (SSAE); the sum of individuals affected by one or more SSAEs. Secondary outcomes were myocardial infarction (MI); stroke; arteriothrombotic event; serious haemorrhage; serious neutropenia; gastrointestinal perforation; serious infection; treatment related drug discontinuation.

Literature search was conducted from CENTRAL, Medline, EMBASE, mRCT, Clinical Trials, and WHO's ICTRP until 27.3.2014. Search was supplemented with hand search.

Total of 4827 records, 403 clinical trials and 19 conference abstracts were obtained. From 160 full text articles 25 records on 8 studies and 1 ongoing study (n=3665) were included. Six of the studies were completed and published. These studies had 1362 participants in bevacizumab group and 1383 in ranibizumab group. Follow up time was 4 years in 4 studies and 1 year in 2 studies. Two studies were completed but not published and one still ongoing (bevacizumab group n=482 and ranibizumab group n=438). Two were conducted in USA, 6 in Europe and 1 in India. The cardiovascular risk profile varied between the studies. Risk of bias could not be assessed for the unpublish studies. For the published studies the risk of bias was generally low.


All-cause deaths (8 studies, n=3338, follow up 1–2 years): ranibizumab 34/1000, bevacizumab 37/1000, RR 1.10 (95% confidence interval 0.78–1.57)

All serious systemic adverse events (9 studies, n=3665): ranibizumab 222/1000, bevacizumab 240/1000, RR 1.08 (0.90–1.31), I2=41%

Infection (6 studies, n=3190): ranibizumab 37/1000, bevacizumab 50/1000, RR 1.34 (0.97–1.86)

Arteriothrombotic event (6 studies, n=3190): ranibizumab 35/1000, bevacizumab 32/1000, RR 0.92 (0.62–1.37)

Myocardial infarction (6 studies, n=3190): ranibizumab 14/1000, bevacizumab 12/1000, RR 0.84 (0.42–1.66)

Stroke (6 studies, n=3190): ranibizumab 11/1000, bevacizumab 9/1000, RR 0.83 (0.42–1.66)

gastrointestinal disorders (6 studies, n=3190): ranibizumab 16/1000, bevacizumab 29/1000, RR 1.82 (1.04–1.3.19)

In sensitivity analysis the exclusion of unpublished studies RR for death was 1.12 (95% CI 0.78–1.62; p=0.53) and for SSAEs RR 1.21 (1.06–1.37).

  • Tutkimuksen laatu: tasokas
  • Sovellettavuus suomalaiseen väestöön: hyvä

Kommentti: Yksi iso tutkimus «Comparison of Age-related Macular Degeneration Tre...»2 dominoi meta-anayysissä, ja sen poistaminen analyysistä vahvisti kokonaishaittatapahtumissa kohti ei eroa tulosta. Julkaisemattomien tutkimusten poistaminen analyysistä osoitti korkeampaa riskiä kokonaishaittatapahtumissa bevasitsumabiryhmälle verrattuna ranibitsumabiin. Julkaisemattomien tutkimusten osalta harhan riskiä ei ole pystytty tekemään.

Meta-analysis «Chen G, Li W, Tzekov R ym. Bevacizumab versus rani...»3 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: partisipants minimum age 50; and reported 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.

  • Tutkimuksen laatu: tasokas
  • Sovellettavuus suomalaiseen väestöön: hyvä

Kommentti: Mukana on samat julkaistut tutkimukset kuin Cochrane-katsauksenkin «Moja L, Lucenteforte E, Kwag KH ym. Systemic safet...»1 suorassa vertailussa.

Meta-analysis and network meta-analysis «Schmid MK, Bachmann LM, Fäs L ym. Efficacy and adv...»5 aimed 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), bevacizumab1.25 mg (2 studies, n=882), aflibercept 0.5 mg (2 studies, n=597), and aflibercept 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. Compared with placebo, serious side effects were higher in all active treatments: ranibizumab 0.3 mg 4.41% (95% confidence interval (CI) 3.42-5.40; p<0.001), ranibizumab 0.5 mg 5.33% (4.37-6.30; p<0.001), bevacizumab 1.25 mg 5.58% (3.567-7.6), aflibercept 0.5 mg 5.65% (3.28-8.02; p<0.001) and aflibercept 2 mg 5.29% (3.18-7.39; p<0.001). Compared with placebo, systemic thrombotic events occurred for 3.6% (2.69-4.56; p<0.01), 3.94% (3.02-4.86; p<0.001), 4.12% (2.27-5.97), and 3.94% (1.03-6.84; p=0.008), respectively. An estimate for aflibercept 2 mg could not be calculated. In the network analysis relationship between efficacy and serious side effects was assessed and no significant differences between the regimens were detected.

  • Tutkimuksen laatu: kelvollinen
  • Sovellettavuus suomalaiseen väestöön: hyvä

Kommentti: Puutteellisen raportoinnin vuoksi tutkijat ovat imputoineet joitakin arvoja. Vertailu lumeeseen perustuu kahden pienen tutkimuksen lumeryhmiin.

A cohort study «Daniel E, Toth CA, Grunwald JE ym. Risk of scar in...»4 within a randomized clinical trial «Comparison of Age-related Macular Degeneration Tre...»2 assessed risk factors for scar in eyes treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD).

For the original trial (CATT, n=1185) patients with active choroidal neovascularization (CNV) secondary to AMD and no scar at foveal center on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment were included. Other inclusion criteria were age >50 years and visual acuity between 20/25 and 20/320 in the study eye. To the cohort study only patients without scar at baseline and with gradable photographs at both 1 and 2 years were included (n=1059). Eyes were assigned to ranibizumab or bevacizumab treatment for 2 years to 1 of 3 dosing regimens: monthly injection, monthly evaluation with pro re nata injections, or 3 monthly injections and thereafter pro re nata injections. CFP and FA scans were obtained at baseline, 1 year, and 2 years. Masked readers assessed CFP and FA. Scars were classified as fibrotic or nonfibrotic. Main outcome measure was scar formation.

Scar developed in 339 of 1059 eyes (32%) by 1 year and in 480 (45.3%) by 2 years. Fibrotic scars developed in 24.7%of eyes, and nonfibrotic scars developed in 20.6% of eyes. Baseline characteristics associated with greater risk of scarring were predominantly classic CNV (adjusted hazard ratio aHR, 3.1; 95% CI, 2.4-3.9) versus occult CNV, blocked fluorescence (aHR, 1.4; CI, 1.1-1.8), foveal retinal thickness >212 μm (aHR, 2.4; CI, 1.7-3.6) versus <120 μm, foveal subretinal tissue complex thickness >275 μm (aHR, 2.4; CI, 1.7-3.6) versus ≤75 μm, foveal subretinal fluid (aHR, 1.5; CI, 1.1-2.0) versus no subretinal fluid, and subretinal hyperreflective material (SHRM) (aHR, 1.7; CI, 1.3-2.3) versus no SHRM. Eyes with elevation of the retinal pigment epithelium had lower risk (aHR, 0.6; CI, 0.5-0.8) versus no elevation. Drug, dosing regimen, and genotype had no statistically significant association with scarring.

  • Tutkimuksen laatu: kelvollinen
  • Sovellettavuus suomalaiseen väestöön: hyvä


  1. Moja L, Lucenteforte E, Kwag KH ym. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2014;(9):CD011230 «PMID: 25220133»PubMed
  2. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG ym. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119:1388-98 «PMID: 22555112»PubMed
  3. Chen G, Li W, Tzekov R ym. Bevacizumab versus ranibizumab for neovascular age-related macular degeneration: a meta-analysis of randomized controlled trials. Retina 2015;35:187-93 «PMID: 25105318»PubMed
  4. Daniel E, Toth CA, Grunwald JE ym. Risk of scar in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2014;121:656-66 «PMID: 24314839»PubMed
  5. Schmid MK, Bachmann LM, Fäs L ym. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br J Ophthalmol 2015;99:141-6 «PMID: 25271911»PubMed