Antiplatelet Drugs May Increase Retinal Bleeding in Wet AMD

Laird Harrison

February 17, 2016

Anticoagulant and antiplatelet drugs may increase the risk for retinal or subretinal bleeding by 50% in people who have a combination of neovascular age-related macular degeneration (nAMD) and hypertension, researchers say.

If further research confirms the finding of a new post hoc data analysis, clinicians will have to weigh the risk for retinal hemorrhage against the risk for stroke and heart attack, first author Gui-shuang Ying, PhD, told Medscape Medical News.

"They have to balance out which is the higher risk and which is the more severe disease," said Dr Ying, an associate professor of biostatistics at the University of Pennsylvania in Philadelphia.

Dr Ying and colleagues published their findings in the February issue of Ophthalmology.

The number of older adults is increasing in the United States, and there is a high prevalence of cardiovascular diseases treated with antiplatelet and anticoagulant drugs as well as a high prevalence of nAMD in this population, the researchers note.

Previous studies examining the effects of these drugs on ocular hemorrhage have reached conflicting conclusions, they write. In an effort to shed light on the question, they analyzed data from the Comparisons of AMD Treatments Trials (CATT). In this study, researchers randomly assigned participants from 43 centers in the United States to receive ranibizumab monthly, bevacizumab monthly, ranibizumab as needed, and bevacizumab as needed.

The participants were 50 years of age or older with untreated active choroidal neovascularization from nAMD in the study eye and visual acuity between 20/25 and 20/320 on electronic visual acuity testing. They excluded eyes with current vitreous hemorrhage or diabetic retinopathy that might require medical or surgical intervention during the 2-year trial follow-up.

The participants provided information about cardiovascular disease and hypertension at baseline. They provided information about the use of antiplatelet and anticoagulant drugs at baseline and every 4 weeks.

The investigators obtained stereoscopic color photographs and fluorescein angiograms of the macula at baseline and at 1 and 2 years of follow-up.

The researchers defined baseline hypertension as systolic blood pressure at least 160 mm Hg, diastolic blood pressure at least 95 mm Hg, or a reported history of hypertension.

Among 1165 participants with gradable fundus photographs, 608 (52.2%) used one or more antiplatelet or anticoagulant drugs at baseline, including 514 (44.1%) with antiplatelet drugs only, 77 (6.6%) with anticoagulant drugs only, and 17 (1.5%) with both types of medication.

The most frequently used of these drugs were aspirin (69.4%), warfarin (14.7%), and clopidogrel (11.4%). At enrollment, the median duration of antiplatelet or anticoagulant use was 6.6 years.

At baseline, 724 (62.1%) of the participants with gradable photographs had retinal or subretinal hemorrhage. Of these, 84.4% were 1 disc area (DA) or less, 8.1% were 1 to 2 DAs, and 7.5% were more than 2 DAs.

The participants with hemorrhages at baseline were older on average and had slightly lower mean diastolic blood pressure, but they had a similar history of cardiovascular disease, hypertension, diabetes, osteoarthritis, and rheumatoid arthritis.

Of the 608 participants taking antiplatelet or anticoagulant drugs, 64.5% had retinal or subretinal hemorrhage. In comparison, 59.6% of 507 participants who did not take antiplatelet or anticoagulant drugs had such hemorrhages. The difference was not statistically significant (adjusted odds ratio [aOR], 1.23; 95% confidence interval, 0.97 - 1.56; P = .09).

Adjusting for age, sex, smoking status, history of cardiovascular disease, and choroid neovascularization only reduced the strength of the association (aOR, 1.18; 95% confidence interval, 0.91 - 1.51; P = .21).

Likewise, the researchers did not find a statistically significant association between hemorrhage and either antiplatelet or anticoagulant classes of drugs considered separately, or between hemorrhages and any particular drug of these classes. That did not change when the researchers looked at the dose or duration of the anticoagulant or antiplatelet use.

However, when the researchers restricted their analysis to participants with hypertension at baseline, 66.8% of those who took antiplatelet or anticoagulant medications had subretinal or retinal hemorrhages compared with 56.4% of those who did not take the medications. This difference was statistically significant (aOR, 1.48; P = .01).

Looking specifically at the class of medication, the researchers found that participants with hypertension who took antiplatelets had a statistically significant increased risk for subretinal or retinal hemorrhages (P = .02), but those who took anticoagulants did not (P = .42). When analyzed by medication type, the risk was specifically seen among aspirin users (aOR, 1.5; P = .01) and clopidogrel users (aOR, 2.4; P = .01).

Antiplatelet and anticoagulant use was not associated with the size of retinal or subretinal hemorrhage at baseline, nor with new or recurrent retinal or subretinal hemorrhages, even among patients with hypertension. Nor was anticoagulant or antiplatelet use associated with an increased risk for hemorrhage among those participants with normal blood pressure.

The investigators did not analyze the relationship of antivascular endothelial growth factor treatments to hemorrhages.

Some previous studies have produced similar results, whereas others have either found an association between subretinal and retinal hemorrhage in all patients with nAMD who took antiplatelet and anticoagulant drugs or have not found an association at all.

One explanation for the different results in this study could be the exclusion of patients with vitreous hemorrhage and patients with visual acuity less than 20/320, the researchers speculate.

The study confirms the importance of checking whether patients' blood pressure is under control when they are diagnosed with nAMD, Pravin U. Dugel, MD, who was not associated with the study, told Medscape Medical News.

Clinicians should also inform patients that they may run an increased risk for retinal or subretinal bleeding when they have nAMD and hypertension, said Dr Dugel, a managing partner of Retinal Consultants of Arizona in Phoenix, Arizona, and a clinical professor of ophthalmology at the University of Southern California Eye Institute, Keck School of Medicine, University of Southern California in Los Angeles.

In general, however, he would not advise patients to stop taking prescribed anticoagulant or antiplatelet medications because the risk from a stroke or heart attack is greater than the risk from an ocular hemorrhage. And that is probably the approach most other ophthalmologists are taking, he said.

"There are some studies that change our treatment strategy," he said. "This is not such a study. I think this study is very much in line with what we're doing. It is an important reaffirmation of current treatment patterns."

The study was supported by the National Eye Institute. The authors have disclosed no relevant financial relationships. Dr Dugel reports financial relationships with many ophthalmologic product companies and stock ownership in Alimera, Macusight, Ophthotech, and Digisight.

Ophthalmology. 2016;123:352-360. Abstract

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