Posterior Segment Age-related Macular Degeneration


Table 1: Unadjusted and Adjusted Outcomes at One Year for the Comparison of Ranibizumab Therapy versus Bevacizumab Therapy79,80


Number of Adverse Events/Number (%) of Patients in the Treatment Group


Adverse Event All-cause mortality


Incident myocardial infarction Bleeding


Incident stroke All-cause mortality


Incident myocardial infarction Bleeding


Incident stroke Ranibizumab


647/19,026 (4.1) 170/19,026 (1.1) 943/19,026 (5.8) 289/19,026 (1.8)


197/4,821 (4.7) 47/4,821 (1.1) 225/4,821 (5.3) 90/4,821 (2.1)


Bevacizumab


July – December 2006** 833/21,815 (4.7) 227/21,815 (1.3) 1017/21,815 (5.6) 405/21,815 (2.2)


Exclusive Providers*** 225/6,147 (4.3) 69/6,147 (1.3) 279/6,147 (5.2) 129/6,147 (2.4)


Hazard ratio (95 % confidence interval) Unadjusted


0.87 (0.76–0.99) 0.84 (0.64–1.08) 1.04 (0.92–1.16) 0.80 (0.65–0.97)


1.11 (0.87–1.43) 0.86 (0.53–1.41) 1.02 (0.81–1.29) 0.88 (0.62–1.26)


Adjusted*


0.86 (0.75–0.98) 0.83 (0.64–1.08) 1.03 (0.92–1.16) 0.78 (0.64–0.96)


1.10 (0.85–1.41) 0.87 (0.53–1.41) 1.01 (0.80–1.28) 0.87 (0.61–1.24)


* Hazard ratios for ranibizumab compared with bevacizumab. **By the end of the study period, almost all newly treated patients received ranibizumab or bevacizumab as first-line therapy. Therefore, in this secondary analysis, the study population was limited to newly treated patients who received ranibizumab or bevacizumab between July and December 2006. ***Patients with higher socioeconomic status may have been more likely to receive ranibizumab versus bevacizumab, so the primary analysis may have been subject to selection bias. Therefore, in this secondary analysis, the study population was limited to patients who received ranibizumab or bevacizumab in a medical practice that performed at least 20 injections and used a single drug in 95 % or more of all intravitreous injections during the third or fourth quarter of 2006.


Figure 5: Plasma Levels of Vascular Endothelial Growth Factor Before and After an Intravitreal Injection of Bevacizumab75


(pg/ml) 300


the US Department of Veterans Affairs (VA) ceased ophthalmological use of Avastin pending the results of an ongoing investigation. In October 2011, interim guidelines were published which permitted the use of bevacizumab only under certain conditions of use. According to these guidelines, only one dose of medication is to be prepared from the vial and administered in a syringe. If both eyes are to be treated, a separate vial and syringe must be utilised.72


200 Systemic Safety 100 0 Before 1 day VEGF = vascular endothelial growth factor.


adverse events and highlighting safety concerns associated with the use of intravitreal bevacizumab.68


This may induce an immunogenic response. Against this theory is that this Fc fragment is immune privileged. However, aflibercept (VEGF-trap) also has an Fc fragment and this inflammation is generally not seen. Another possible explanation is that bevacizumab is packaged for oncological use in 100 mg containers. When these are broken down into smaller units for ocular use, there is a risk of microbial contamination owing to incorrect handling procedures.70


One potential explanation for excessive inflammation may be its larger protein load, a result of the additional Fc fragment not present in ranibizumab.69


The Royal College of Ophthalmologists has warned that when vials of bevacizumab are split to obtain the needed dose, the amount of protein administered to patients is unknown, which could lead to problems due to side effects or reduced effectiveness.71


There is concern about the risk of systemic adverse events following the use of bevacizumab because of its longer systemic half life and systemic absorption after intraocular injection. Most serious drug toxicities are detected through post-marketing safety surveillance or pharmacovigilance but this procedure does not exist for drugs that have unlicensed use so the true risk of adverse events is not being reported.


In human case series, reduced blood-VEGF levels post-intravitreal bevacizumab injection showed that bevacizumab enters the general circulation, giving the potential for systemic effects (see Figure 5).75


When used systemically with chemotherapeutic agents, bevacizumab can double the risk of ATEs compared with chemotherapy alone.76


It has since


called for a review of bevacizumab in AMD. There are significant differences in IgG concentration measured from repackaged bevacizumab syringes. Large particulate matter within some samples has been hypothesised to lead to obstruction of aqueous outflow and subsequent elevation in intraocular pressure.42


In September 2011, 40


A retrospective study of patients treated with at least one intravitreal injection of ranibizumab or bevacizumab found that ATEs occurred in 12.4 % of bevacizumab-treated patients compared with 1.4 % with ranibizumab (p<0.0001). In an elderly population with multiple cardiovascular risk factors, new ATEs may only in part be attributed to the intravitreal bevacizumab administration. These findings raise an issue that needs confirmation in randomised clinical trials.77


The


Canadian retrospective studies found a tendency towards a greater incidence of emergency department presentation within 30 days of


EUROPEAN OPHTHALMIC REVIEW 1 week 1 month


An interim analysis from the Safety assessment of intravitreal lucentis for AMD (SAILOR) study demonstrated a trend for an increase in the incidence of stroke in the group treated with 0.5 mg ranibizumab, compared with the 0.3 mg dose. Furthermore, the incidence of stroke was higher when pre-existing factors were present, specifically either a previous history of stroke or arrhythmia.73,74


All other RCTs of ranibizumab showed that systemic events were rare.13,15,47,49,52,62


Concentrations of immuroreactive VEGF


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68