Intravitreal Ranibizumab and Bevacizumab: A Review of Risk

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  • Seminars in Ophthalmology, 22:201204, 2007Copyright c Informa Healthcare USA, Inc.ISSN: 0882-0538DOI: 10.1080/08820530701543024

    Intravitreal Ranibizumab and Bevacizumab:A Review of Risk

    Rima M. Daferand Michael SchneckLoyola University Chicago,Stritch School of Medicine,Department of Neurology,Maywood, IL, USA

    Thomas R. FribergUniversity of Pittsburgh Schoolof Medicine, UPMC Eye Center,Pittsburgh, PA, USA

    Walter M. JayLoyola University Chicago,Stritch School of Medicine,Maywood, IL, USA

    ABSTRACT Ranibizumab (LucentisR), a recombinant monoclonal antibody,blocks all active forms of vascular endothelial growth factor A and was thefirst treatment for age-related macular degeneration shown to improve visualacuity in a substantial percentage of patients rather than slowing visual loss.Bevacizumab (AvastinR ) has a similar action, is related to the ranibizumabcompound with respect to its structure, but has not been approved by theFDA for intravitreal use and therefore must be utilized only in an off-labelsetting. While ranibizumab was approved by the FDA at a dose of 0.5 mg perintravitreal injection, the manufacturer recently issued a letter to physicianswarning of the increased risk of stroke at the FDA-approved dose as comparedto a lower studied dose of 0.3 mg. An interim analysis of the ongoing SAILORstudy revealed a 1.2% risk of stroke in the 0.5 mg arm versus 0.3% in the 0.3mg arm (p = 0.02). It is unclear whether the trend toward a higher risk ofstroke in patients receiving 0.5 mg dose of ranibizumab would persist in thefinal analysis, but details such as causality, topography, and severity of strokein the SAILOR study should also be delineated. The risks of intraocular use ofbevacizumab remain largely unknown at this time.

    KEYWORDS ranibizumab, vascular endothelial growth factor, stroke, macular degener-ation

    Age-related macular degeneration (AMD) is the leading cause of irreversibleblindness in people over 50 years of age. Nearly seven million Americans 55years or older suffer from AMD, with the neovascular or wet form accountingfor 100,000 new cases a year. Wet AMD usually causes severe vision loss and ischaracterized by the abnormal growth of new blood vessels under or within themacula. Molecular biology has recently provided a better understanding of thepathogenesis of AMD. Vascular endothelial growth factor A (VEGF), a key mod-ulator for angiogenesis, has been implicated in promoting neovascularizationin AMD.1,2

    Individuals with AMD have an ischemic stroke risk almost twice as highas those without the disease.3,4 In the Blue Mountain Eye Study, prior his-tory of stroke predicted a higher incidence of early AMD (RR 2.32, 95% CI1.085.01). This association remained significant after controlling for conven-tional cardiovascular risk factors.3 Similarly, data from the Arteriosclerosis Risk

    Address correspondence to Walter M.Jay, MD, Department ofOphthalmology, Building 102- Room2603, Loyola University MedicalCenter, 2160 South First Ave.,Maywood, IL 60153, USA. E-mail:wjay@lumc.edu

    201

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  • in Communities Study showed a higher risk of strokein patients with early AMD (hazard rate ratio 1.87,95% CI 1.212.88).4 The nature of the relationshipbetween ischemic stroke and AMD remains unclear.AMD and ischemic stroke share many of the samerisk factors contributing to atherosclerosis, includ-ing cigarette smoking,57 diabetes,7 obesity,6,7 andhypertension.5,8 Similarly, carotid artery disease, a well-established risk factor for stroke, has also been asso-ciated with AMD.9,10 In addition, inflammation ormicrovascular disease involving both the cerebral andretinal circulations may be another potential mecha-nism for both AMD and ischemic stroke.11,12 Othergenetic factors, such as polymorphisms of the genes forapolipoprotein E and complement pathways, may alsocontribute to the development of both conditions.13,14

    Ranibizumab (LucentisR ), a recombinant hu-manized monoclonal antibody, through its anti-angiogenetic VEGF blocking properties, was the firsttreatment for AMD shown to improve visual acuityin clinical trials rather than slowing visual loss.15 TheFDA approved the drug in June 2006 at a dose of0.5 mg per intravitreal injection. However, in January2007, the manufacturer of ranibizumab issued a letterto physicians warning of the increased risk of strokeat the FDA-approved dose of 0.5 mg as compared toa lower studied dose of 0.3 mg. An interim analysisof the ongoing SAILOR (Safety Assessment of Intrav-itreal Lucentis for AMD) study comparing two dosesof intravitreal ranibizumab injection intravitreally forneovascular AMD revealed a 1.2% risk of stroke in the0.5 mg arm versus 0.3% in the 0.3 mg arm (p = 0.02).The SAILOR data suggested that the ischemic strokerisk was greatest among patients with a prior historyof stroke. There was no statistical significant differencein the rate of myocardial infarction or vascular deathbetween the two doses.

    Two other studies, MARINA (Minimally Clas-sic/Occult Trial of the Anti-VEGF AntibodyRanibizumab in the treatment of NeovascularAMD) and ANCHOR (Anti-VEGF Antibody forthe Treatment of Predominantly Classic ChoroidalNeovascularization in AMD), also noted a smallincreased risk of stroke with a 0.5 mg dose, which didnot reach statistical significance.16,17 The MARINAstudy was a randomized double-blind sham controlledtrial comparing intravitreal ranibizumab injections(either 0.3 mg or 0.5 mg) to sham injections in patientswith AMD. In this study, nine patients receiving either

    0.3 mg or 0.5 mg intravitreal ranibizumab injections(1.9%) suffered from ischemic stroke compared totwo patients (0.8%) in the sham arm. There weresix ischemic strokes in the group receiving 0.5 mg ofintravitreal ranibizumab (2.5%), and three (1.3%) in thegroup receiving the lower intravitreal dose of 0.3 mg.In the ANCHOR study, ranibizumab intravitreal in-jection (0.3 mg or 0.5 mg) was compared to verteprofintherapy; only one patient (0.7%) suffered a stroke inthe 0.5 mg arm during 12 months of follow-up.18

    Off-label intravitreal injection of bevacizumab(AvastinR ) has been used for the treatment of neovas-cular and exudative ocular diseases including AMDwith several small trials before ranibizumab was ap-proved and made available. Several case series doc-umenting its use have been published over the pastfew years.1921 Bevacizumab is a VEGF monoclonalantibody structurally related to ranibizumab in thatboth were developed originally from the same mouseantibody. Ranibizumab is much smaller and geneti-cally engineered through a process of selective muta-tion to increase its affinity for binding and inhibit-ing all the biologically active forms of the vascularendothelial growth factor A. Bevacizumab, on theother hand, has two Fab fragments as well as an Fcfragment.

    While there have only been a few well-documentedreports of adverse events with off-label use of beva-cizumab, the reporting of such cases is often haphaz-ard. Physicians may not inquire about a patients sys-temic health at each visit or between visits and oftendo not specifically ask whether a patient has suffereda myocardial infarction (MI), transient ischemic attack(TIA), or stroke between visits. A recent internet-basedsurvey seeking to better define adverse events rates didnot exceed 0.21 percent.22 However, the event rate inthis survey was so low for this age group that the legit-imacy of the findings was questioned in a subsequentletter to the editor in the same journal.23 It is known,of course, that the on-label use of bevacizumab primar-ily for the treatment of cancer carries caveats commen-surate with the FDAs black box warning on the drugpackaging. Adverse events occurring with on-label usewhen the drug is given intravenously includes bloodpressure elevation, transient ischemic attack, ischemicstroke, and death.24 Blood pressure elevation with ei-ther ranibizumab or bevacizumab may explain the pos-sible association of ischemic stroke with the treatmentof AMD.

    R. M. Dafer et al. 202

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  • As with many drugs, studies conducted by the spon-sor are typically powered to determine efficacy ratherthan safety. Safety is monitored, but it is not at all un-usual to find serious risks after a drug has been marketedor been available for several years. In some cases, theseevents have led to removal of the drug from the mar-ket. Outside of a carefully conducted clinical trial, thereporting of adverse drug-related events depends on thephysicians or nurses point of view. There is often lit-tle incentive to report adverse events, and if a patientis in an age group where such events (stroke) are notrare, the risk attributable to the use of the drug maybe camouflaged. Furthermore, if one suspects that anadverse event has occurred because of a drug, the re-porting of that event may be haphazard. There are websites, including the MedWatch website, where eventscan be entered into a database but such databases, how-ever, may or may not have the detailed informationdesired by a physician or patient trying to understandwhat precisely occurred. In fact, the reports of eventsare often line items and details of the clinical course ofthe patient are absent. If details are sought, a petitionvia the Freedom of Information Act may be required(MedWatch).

    For many physicians, MIs and strokes are not un-usual and they aver that they have not observed anyextra risks in the patients that they have treated. Un-fortunately, such a viewpoint is strongly biased and caneasily be incorrect, unless the physician has treated veryhigh numbers of patients and has followed them forseveral months. If the risk is a few percent, hundreds ofpatients will need to have been treated and followed.

    While stroke secondary to an anti-VEGF medica-tion is plausible biologically, the exact mechanism ofischemic stroke with the 0.5 mg does of intravitrealranibizumab is unclear. The role of VEGF in brainischemia remains unknown and its role in the man-agement of acute ischemic stroke through therapeuticangiogenesis remains controversial. Administration ofVEGF is shown to promote angiogenesis in ischemicbrain, reduce deficits and improve functional neuro-logical outcome during stroke recovery.2528 Recentresearch suggests multiple roles for VEGF includingneuroprotective, neurotrophic, and neurotropic activ-ities both in the peripheral and central nervous sys-tem, exerting a direct action on neurons, astrocytes, andmicroglia. VEGF overexpression acquires significantfunctions of neuronal protection and repairs injuredbrain.28,29 Could the lower dose of ranibizumab have

    relatively minimal effect on the expression of VEGF?There are reports demonstrating potential harm ratherthan promoting recovery from administration of VEGFat angiogenetic and non-angiogenetic doses due to re-lated macrophage hyperactivation and infiltration, notonly to ischemic brain, but to normal tissue as well. In-hibition of VEGF attenuates vascular permeability andreduces brain edema formation and cerebral venous in-farction in acute stages of ischemic stroke,30 suggestingthat endogenous VEGF is in part responsible for dis-ruption of the blood brain barrier during the early stageof focal cerebral ischemia.31

    Several issues should be considered when assessingan association between intravitreal ranibizumab or be-vacizumab and stroke risk. Was the study carefully con-ducted and was the sample size appropriate to achieveadequate power to determine a small (few percent)risk? It is unclear at present whether the trend towardhigher risk of stroke in patients receiving 0.5 mg dose ofranibizumab will persist after final follow-up and afteradjustment for comorbidities, age, and the use of cer-tain medications known to decrease the risk of stroke inpatients at high risk, such as antihypertensives, statins,and antithrombotics.

    REFERENCES[1] Ferrara N. Vascular endothelial growth factor: basic science and clin-

    ical progress. Endocr Rev 2004; 25(4):581611.[2] Okamoto N, Tobe T, Hackett SF, et al. Transgenic mice with increased

    expression of vascular endothelial growth factor in the retina: a newmodel of intraretinal and subretinal neovascularization. Am J Pathol1997; 151(1):28191.

    [3] Tan JS, Mitchell P, Smith W, Wang JJ. Cardiovascular risk factors andthe long-term incidence of age-related macular degeneration, TheBlue Mountains Eye Study. Ophthalmology 2007; 114(6):114350.

    [4] Wong TY, Klein R, Sun C, et al. Age-related macular degenerationand risk for stroke. Ann Intern Med 2006; 145(2):98106.

    [5] Risk factors associated with age-related macular degeneration.A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology 2000;107(12):222432.

    [6] Clemons TE, Milton RC, Klein R, et al. Risk factors for the incidenceof advanced age-related macular degeneration in the Age-RelatedEye Disease Study (AREDS) AREDS report no. 19. Ophthalmology2005; 112(4):5339.

    [7] Klein R, Deng Y, Klein BE, et al. Cardiovascular disease, its risk factorsand treatment, and age-related macular degeneration: WomensHealth Initiative sight exam ancillary study. Am J Ophthalmol 2007;143(3):47383.

    [8] Wong T, Mitchell P. The eye in hypertension. Lancet 2007;369(9559):42535.

    [9] Vingerling JR DI, Bots ML, Hofman A, Grobbee DE, de Jong PT. Age-related macular degeneration is associated with atherosclerosis. TheRotterdam Study. Am J Epidemiol 1995; 15(142):4049.

    [10] van Leeuwen R, Ikram MK, Vingerling JR, et al. Blood pressure,atherosclerosis, and the incidence of age-related maculopathy: theRotterdam Study. Invest Ophthalmol Vis Sci 2003; 44(9):37717.

    203 Intravitreal Ranibizumab and Bevacizumab

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  • [11] Despriet DD, Klaver CC, Witteman JC, et al. Complement factorH polymorphism, complement activators, and risk of age-relatedmacular degeneration. JAMA 2006; 296(3):3019.

    [12] Seddon JM, George S, Rosner B, Rifai N. Progression of age-relatedmacular degeneration: prospective assessment of C-reactive protein,interleukin 6, and other cardiovascular biomarkers. Arch Ophthal-mol 2005; 123(6):77482.

    [13] Tikellis G, Sun C, Gorin MB, et al. Apolipoprotein e gene and age-related maculopathy in older individuals: the cardiovascular healthstudy. Arch Ophthalmol 2007; 125(1):6873.

    [14] Wong TY, Shankar A, Klein R, et al. Apolipoprotein E gene and earlyage-related maculopathy: the Atherosclerosis Risk in CommunitiesStudy. Ophthalmology 2006; 113(2):2559.

    [15] Ferrara N DL, Shams N, Lowman H, Kim R. Development ofranibizumab, an anti-vascular endothelial growth factor antigenbinding fragment, as therapy for neovascular age-related maculardegeneration. Retin...

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