Correspondence

Ranibizumab for Neovascular Age-Related Macular Degeneration

N Engl J Med 2007; 356:747-750February 15, 2007

Article

To the Editor:

The results of the MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration) study and the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration) study (Oct. 5 issue)1,2 show the remarkable and reassuring safety of ranibizumab in the treatment of neovascular age-related macular degeneration. We are concerned, however, by the low reported rate of arterial thromboembolic events in both ranibizumab groups (4.6% over a period of 2 years among patients receiving 0.3 mg or 0.5 mg) and sham injection (3.8%) in the MARINA study, since patients with age-related macular degeneration may have an increased risk of stroke.3

In the population-based Blue Mountains Eye Study,4 conducted from 1992 through 1994 and involving 3654 adults over the age of 49 years, we observed 19 arterial thromboembolic events (incident nonfatal stroke, nonfatal myocardial infarction, and deaths from stroke or coronary heart disease) among 49 subjects with neovascular age-related macular degeneration after 5 years of follow-up, an incidence of 38.8% (Table 1Table 1Cardiovascular Risk Factors and Arterial Thromboembolic Events among Patients with Neovascular Age-Related Macular Degeneration in the MARINA Trial and the Blue Mountains Eye Study.). Although we are comparing data from a 2-year clinical trial with those from a 5-year observational trial, the annualized incidence rate for arterial thromboembolic events in our study (7.8%) was more than three times the rates in the MARINA trial (1.9% for the sham-injection group and 2.3% for the ranibizumab groups).

Apart from a 3-year difference in the mean age, subjects in our study were demographically similar to those in the MARINA trial. A possible explanation is the well-recognized selection bias in clinical trials whereby subjects with existing cardiovascular disease are underrecruited. This factor may limit the generalizability of trial-safety data to all patients with age-related macular degeneration in the community and underscores the importance of post-marketing surveillance to monitor the long-term systemic safety of ranibizumab.

Gerald Liew, M.D., M.Med.
Paul Mitchell, M.D., Ph.D.
University of Sydney, Sydney 2006, Australia
paul_mitchell@wmi.usyd.edu.au

Dr. Liew reports serving as a visual-acuity examiner for several clinical trials sponsored by Genentech and Pfizer, including the ANCHOR trial, and Dr. Mitchell reports serving as an investigator on the ANCHOR trial. Dr. Mitchell also reports serving on advisory boards for Novartis and Pfizer. He has received honoraria or lecture fees, as well as travel and accommodation payments to attend meetings, from both companies.

5 References

1. 1

   Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-1431
   Full Text | Web of Science | Medline

2. 2

   Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-1444
   Full Text | Web of Science | Medline

3. 3

   Wong TY, Klein R, Sun C, et al. Age-related macular degeneration and risk for stroke. Ann Intern Med 2006;145:98-106
   Web of Science | Medline

4. 4

   Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia: the Blue Mountains Eye Study. Ophthalmology 1995;102:1450-1460
   Web of Science | Medline

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   Mitchell P, Wang JJ, Wong TY, Smith W, Klein R, Leeder SR. Retinal microvascular signs and risk of stroke and stroke mortality. Neurology 2005;65:1005-1009
   CrossRef | Web of Science | Medline

To the Editor:

The articles on the MARINA and ANCHOR trials give the impression that ranibizumab is not associated with higher rates of nonocular hemorrhage (e.g., cerebral, vaginal, and gastrointestinal hemorrhage, as listed in Table 6 of the Supplementary Appendix accompanying the MARINA study online). Using data from both trials, we compared the rates of nonocular hemorrhage between patients who were treated with ranibizumab (either 0.3 mg or 0.5 mg) and the control groups (Table 1Table 1Rate of Nonocular Hemorrhage in Combined Data from the MARINA and ANCHOR Trials.). The rate of nonocular hemorrhage was higher in ranibizumab-treated patients in both studies, and this difference was statistically significant when data from the two studies were combined (7.8% for the ranibizumab groups vs. 4.2% for the control groups, P=0.01). Although our analysis was performed post hoc and is limited by different follow-up intervals between the two trials, these data suggest the importance of careful monitoring of systemic side effects related to the inhibition of vascular endothelial growth factor (VEGF), particularly since prospectively collected data on the systemic safety of other anti-VEGF agents (including bevacizumab) are not yet available.1,2

Mark C. Gillies, M.B., B.S., Ph.D.
University of Sydney, Sydney 2001, Australia
mark@eye.usyd.edu.au

Tien Y. Wong, M.D., Ph.D.
University of Melbourne, Melbourne 3002, Australia

Dr. Gillies reports receiving honoraria and travel and accommodation payments for attendance at meetings of national and international advisory boards of Novartis, Allergan, and Pfizer. He has also received research funding from Allergan and is an investigator for the ANCHOR trial. Dr. Wong reports receiving honoraria and travel and accommodation payments for attendance at meetings of national and international advisory boards of Novartis and Pfizer. He has also received research funding from Novartis, Pfizer, and Allergan.

2 References

1. 1

   Steinbrook R. The price of sight -- ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 2006;355:1409-1412
   Full Text | Web of Science | Medline

2. 2

   Gillies MC. What we don't know about avastin might hurt us. Arch Ophthalmol 2006;124:1478-1479
   CrossRef | Web of Science | Medline

Author/Editor Response

We acknowledge that safety data from controlled clinical trials may be subject to selection biases, but we disagree with the suggestion by Liew and Mitchell that the Blue Mountains Eye Study provides a more accurate estimate of the rates of arterial thromboembolic events in patients with neovascular age-related macular degeneration. First, we do not believe that the rates of arterial thromboembolic events obtained from an Australian cohort of only 49 patients would better represent the rates in the U.S. population than the rates obtained from the MARINA and ANCHOR trials, with 1133 patients who could be evaluated. Second, observational studies such as the Blue Mountains Eye Study are well known to have their own biases and limitations, which differ from those of controlled trials; therefore, adverse-event rates obtained from the two sources should be considered to be complementary rather than competing estimates of the true rate of an adverse event.

Third, patients with risk factors for arterial thromboembolic events, including a history of such events, were not excluded from the MARINA and ANCHOR trials. The low rates of arterial thromboembolic events may instead reflect the close medical scrutiny these patients underwent during a prospective trial requiring monthly visits for 2 years, resulting in both greater access to interventions that could reduce the likelihood of an arterial thromboembolic event and better overall health, as compared with the cohort in the Blue Mountains Eye Study. Fourth, the rates of myocardial infarction and stroke for patients with neovascular age-related macular degeneration that were reported in several other studies1-4 are intermediate between those reported in the MARINA and ANCHOR trials and those reported in the Blue Mountains Eye Study; specifically, the 1-year incidence rate for arterial thromboembolic events was 4.4% in an administrative-claims database.4

Fifth, the table provided by Liew and Mitchell contains data only for patients who received 0.3 mg of ranibizumab, whereas the two trials also included similar-size groups of patients who received the 0.5-mg dose recommended in the ranibizumab package insert. The similarity in rates of arterial thromboembolic events between the 0.3-mg and 0.5-mg groups suggests that these rates are representative of our study population. Finally, we would argue that the best measure of drug-related safety is the comparison of adverse-event rates in treated patients and in the control group in a randomized trial, and with respect to this comparison, Liew and Mitchell's argument does not apply.

We agree with Drs. Gillies and Wong that reliable estimates of the expected rates of hemorrhagic events associated with intravitreal VEGF inhibitors are a priority because hemorrhagic events are known to be potential adverse events associated with systemically administered VEGF inhibitors. For this reason, we provided a complete list of all the nonocular hemorrhagic events reported at 2 years in the MARINA trial and at 1 year in the ANCHOR trial in the Supplementary Appendixes available online with the articles. Although the post hoc statistical analysis performed by Gillies and Wong is not ideal (e.g., pooling 1-year and 2-year incidence rates), we acknowledge that the apparent trend, which was noted in our articles, merits further investigation. We expect that better estimates of the rates of adverse events that are potentially associated with VEGF inhibition will be available with continued follow-up of patients receiving anti-VEGF agents by intraocular injection.

We recognize the importance of post-marketing surveillance to determine the long-term safety of any newly marketed therapy, and for that reason, we are monitoring the safety of ranibizumab for up to 5 years in a long-term extension study (the HORIZON trial) that follows the patients who participated in the MARINA and ANCHOR trials. The safety of ranibizumab is also being monitored in other ongoing trials, such as the phase IIIb SAILOR (Safety Assessment of Intravitreal Lucentis for Age-Related Macular Degeneration) study, which enrolled more than 4000 patients with choroidal neovascularization secondary to age-related macular degeneration, as well as through the Food and Drug Administration's Adverse Event Reporting System.

Philip J. Rosenfeld, M.D., Ph.D.
Bascom Palmer Eye Institute, Miami, FL 33136

David M. Brown, M.D.
Vitreoretinal Consultants, Houston, TX 77030

Susan Schneider, M.D.
Genentech, South San Francisco, CA 94080

for the MARINA and ANCHOR Study Groups

4 References

1. 1

   Bubbage RR, Xu X, Zlateva G, Knight T, Goss TF. Clinical characteristics and impact of neovascular age-related macular degeneration on medical status, daily living, functioning, and health resource utilization: a survey of five countries. Presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, FL, May 1, 2006.
   

2. 2

   Scott IU, Mo J, Klein R, et al. Association between neovascular age-related macular degeneration and incident myocardial infarction. Presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, FL, May 1, 2006.
   

3. 3

   Ianchulev T, Alexander S, Werther W, Linde-Zwirble W. Annual rates of cardiovascular events in Medicare neovascular age-related macular degeneration patients. Presented at the Annual Meeting of the American Society of Retinal Specialists (ASRS), Cannes, France, September 11, 2006.
   

4. 4

   West ES, Werther W, Napalkov P, Francom S, Butler S, Shams N. Myocardial infarction and cerebrovascular accident rates in patients with neovascular age-related macular degeneration in a healthcare claims database. Presented at the Annual Meeting of the American Society of Retinal Specialists (ASRS), Cannes, France, September 11, 2006.
   

Citing Articles (11)

Citing Articles

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   Paul Mitchell. (2011) A systematic review of the efficacy and safety outcomes of anti-VEGF agents used for treating neovascular age-related macular degeneration: comparison of ranibizumab and bevacizumab. Current Medical Research and Opinion 27:7, 1465-1475
   CrossRef

2. 2

   Norbert Bornfeld. (2011) Epimacular brachytherapy — old ghost or new age?. Graefe's Archive for Clinical and Experimental Ophthalmology 249:4, 471-473
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   Ângela M. Carneiro, Daniel Barthelmes, Manuel S. Falcão, Luis S. Mendonça, Sofia L. Fonseca, Rita M. Gonçalves, Fernando Faria-Correia, Fernando M. Falcão-Reis. (2011) Arterial Thromboembolic Events in Patients with Exudative Age-Related Macular Degeneration Treated with Intravitreal Bevacizumab or Ranibizumab. Ophthalmologica 225:4, 211-221
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4. 4

   Yihai Cao. (2010) Angiogenesis: What can it offer for future medicine?. Experimental Cell Research 316:8, 1304-1308
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5. 5

   S Jyothi, H Chowdhury, M Elagouz, S Sivaprasad. (2010) Intravitreal bevacizumab (Avastin) for age-related macular degeneration: a critical analysis of literature. Eye 24:5, 816-824
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6. 6

   Robert A. Weale. (2009) A note on age-related comorbidity. Archives of Gerontology and Geriatrics 49:1, 93-97
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7. 7

   Pedro R. Moreno, Javier Sanz, Valentin Fuster. (2009) Promoting Mechanisms of Vascular Health. Journal of the American College of Cardiology 53:25, 2315-2323
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8. 8

   Focke Ziemssen, Salvatore Grisanti, Karl Ulrich Bartz-Schmidt, Martin S. Spitzer. (2009) Off-Label Use of Bevacizumab for the Treatment of Age-Related Macular Degeneration. Drugs & Aging 26:4, 295-320
   CrossRef

9. 9

   V. Biousse, M.-G. Bousser, A. Gaudric. (2008) Dégénérescence maculaire liée à l’âge et risque d’accident vasculaire cérébral. Journal Français d'Ophtalmologie 31:1, 111-125
   CrossRef

10. 10

    Rakesh K Jain, Aloke V Finn, Frank D Kolodgie, Herman K Gold, Renu Virmani. (2007) Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nature Clinical Practice Cardiovascular Medicine 4:9, 491-502
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11. 11

    Timothy W. Olsen. (2007) Treatment of Exudative Age-related Macular Degeneration: Many Factors to Consider. American Journal of Ophthalmology 144:2, 281-283
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