Age-Related Macular Degeneration and Cardiovascular Disease

Tien Y Wong, MD, PhD
Professor, Department of Ophthalmology
Centre for Eye Research Australia
University of Melbourne
Royal Victorian Eye and Ear Hospital
East Melbourne, Australia

Age-related macular degeneration (AMD) is the leading cause of vision loss in the developed world. In the last three years, a new class of pharmaceuticals based on suppression of vascular endothelial growth factor (VEGF) — anti-VEGF agents — has been introduced for the treatment of "wet" or neovascular AMD, the most visually disabling form of AMD. In 2006, landmark clinical trial results were published showing that monthly intravitreal injections of ranibizumab (Lucentis, Genentech/Novartis) prevented vision loss in about 95% of patients and, in many cases, significantly improved the visual acuity of patients with neovascular AMD.^1,2 Another agent, bevacizumab (Avastin, Genentech) is used as "off-label" therapy for neovascular AMD.

A major concern regarding these new treatments is whether there are any major adverse cardiovascular effects associated with intravitreal injection of anti-VEGF agents.³ There are three questions of interest: first, does the presence of AMD increase the risk of cardiovascular disease (CVD)? Second, does anti-VEGF therapy further increase this risk? Third, should anti-VEGF therapy be administered differently in people with AMD and concomitant CVD risk factors?

Does the presence of AMD increase the risk of cardiovascular disease?
A number of epidemiological studies have now provided fairly convincing evidence that AMD is associated with an increased risk of CVD events, independent of traditional CVD risk factors like smoking and hypertension. The Atherosclerosis Risk in Communities study showed that persons with early AMD had double the risk of incident stroke over 10 years, while those with late AMD (geographic atrophy or neovascularization) had triple the risk of incident coronary heart disease (CHD).^4,5 Similar findings were reported from a survey of 1.4 million Medicare enrollees which found a 20-30% higher risk of stroke and CHD over 2 years.^6,7 The Australian Blue Mountains Eye Study reported a two-fold higher risk of CHD in persons with early AMD over 11 years, although this was only present in those below 75 years of age.⁸ Data submitted for publication from the Cardiovascular Health Study also support an increased risk of CHD in persons with early AMD.(Wong, unpublished data).

The relationship of CVD and AMD also applies in reverse, in that all of the traditional cardiovascular risk factors, such as smoking and hypertension, have also been linked with increased risk of AMD.^9,10 These findings support a "common soil" hypothesis which postulates that both AMD and CVD share common antecedents such as vascular inflammation, smoking, hypertension and genetic susceptibility.¹¹ It is worthwhile noting that polymorphisms in the complement factor H (CFH) gene have been implicated in AMD¹² and, in some studies, in CHD.¹³

Does anti-VEGF therapy increase the risk of cardiovascular disease in patients with AMD?
The issue of increased CVD risk with anti-VEGF agents arose from theoretical concerns that chronic inhibition of VEGF may impair some of this growth factor's essential functions such as the formation of collaterals in the myocardium,¹⁴ and the increased risk of arterial and venous thromboembolism with intravenous bevacizumab in patients with cancer.^15,16 Anti-VEGF agents are detectable in the systemic circulation to varying degrees.^17-19

Initial concerns were raised when a post-hoc analyses of the MARINA and ANCHOR trials found an increased rate of non-ocular hemorrhage (e.g. cerebral, gastrointestinal) with ranibizumab²⁰ and an interim analysis of the SAILOR trial reported increased risk of stroke with higher dose of ranibizumab.²¹ However, subsequent analyses at the completion of SAILOR and a meta-analysis of ranibizumab AMD trials showed no significant increased risk of CVD (although, as described below, there is a suggestion of a trend towards an increased risk of stroke in persons with a history of stroke or arrhythmias treated with higher ranibizumab doses).²²

Should anti-VEGF therapy be administered differently in people with AMD and concomitant CVD risk factors?
While these data are reassuring and establish the systemic safety of ranibizumab for the majority of patients, a few areas of uncertainty remain. In certain subgroups, mainly persons wtih prior stroke and persons with a history of arrhythmia, stroke risk was higher in those treated with higher doses of ranibizumab.²² This brings us to the third issue of differential treatment in persons with concomitant cardiovascular risk factors. Should a person with prior history of stroke and/or arrhythmias not receive ranibizumab, or receive a reduced dosing schedule? The increased risk in these subgroups was 3 to 4 fold higher, but the number of events was very small, and the differences were not statistically significant and could have occurred by chance, especially as the other subgroups examined (e.g. those with existing CHD, hypertension, diabetes) had no increased risk.²² If the increased risk is real, this would impact on the substantial proportion of patients with late AMD and CVD (up to 30% in the Blue Mountains Eye Study).²³ If so, what are the best treatment options for them? Pegaptanib has a relatively good safety profile, but significantly reduced efficacy compared to ranibizumab;³ pegaptanib in combination with photodynamic therapy and intravitreal steroid (triple therapy) may be an option.²⁴

The situation with persons taking bevacizumab, who comprise an even larger group than those receiving ranibizumab worldwide, is more uncertain. The theoretical risk of CVD risk with bevacizumab is higher as the agent remains in the systemic circulation longer than ranibizumab and is known to cause thrombosis at high concentrations in certain patients with cancer, but clinical safety data are sparse.^15,16,19 The limited data available comes from self-reported case series and suggests no increased risk.²⁵ The NIH is sponsoring a head to head trial comparing ranibizumab and bevacizumab (CATT) which will hopefully provide more reliable data on the systemic safety of bevacizumab.

In conclusion, AMD and CVD are closely linked, with the presence of one disease conferring increased risk of developing the other. The issue has taken on new clinical relevance as anti-VEGF agents for AMD become more widespread and concerns are raised regarding whether these agents may increase CVD risk. All trials to date show ranibizumab to be safe, except possibly in persons with a history of stroke or arrhythmias where there is a suggestion of a trend towards an increased risk of stroke with higher ranibizumab doses. It is unclear what options are best for this high risk group. Clearly, further research into the systemic risks of ranibizumab and other anti-VEGF agents in susceptible individuals with existing CVD is needed.

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