IVAN data mined for insights on intravitreal anti-VEGF systemic safety

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Analyses of data from the Inhibition of VEGF in Age-related Choroidal Neovascularisation trial conducted to explore relationships between temporal changes in serum VEGF and safety events showed that at 1 year, a larger fall from baseline serum VEGF was associated with a lower hazard of death.

Dr. Chakravarthy

By Cheryl Guttman Krader; Reviewed by Usha Chakravarthy, MD

Belfast, Ireland-Determination of the systemic safety profiles of intravitreal anti-vascular endothelial growth factor (VEGF) therapy is an area of ongoing research.

To that end, investigators from the Inhibition of VEGF in Age-related Choroidal Neovascularisation (IVAN) trial undertook analyses of data from their study to explore potential associations between serum VEGF and various safety outcomes.

Usha Chakravarthy, MD, in looking at research for whether change in serum VEGF from baseline to month 12 or average serum VEGF-calculated as the mean of the baseline and month 12 values-predicted the frequency of:

• Arterio-thrombotic events (ATEs) and/or heart failure (events that have been associated with systemically administered anti-VEGF drugs);

• Other serious adverse events (SAEs) not previously associated with VEGF, or

• Gastrointestinal (GI) events.

The analyses found that having a larger fall from baseline serum VEGF was associated with a lower hazard of death. In addition, higher average serum VEGF was associated with a marginally increased risk of ATEs. No other associations were found between decrease in serum VEGF or average serum VEGF and any of the safety endpoints analyzed.

“Our findings offer fascinating insights into the mechanisms that underlie the systemic effects of these local therapies,” said Dr. Chakravarthy, lead investigator, IVAN trial, and professor of ophthalmology and vision sciences, The Queen’s University of Belfast, Northern Ireland.

“Neutralizing VEGF cannot be good for the vasculature, and hence there is concern that anti-VEGF therapy may induce thrombogenesis,” Dr. Chakravarthy said. “However, too much VEGF in cancer patients is a marker for poor prognosis, and our finding associating larger falls in serum VEGF with a lower hazard of death is similar to the observation in cancer trials with bevacizumab where higher serum VEGF was associated with higher mortality.”

Study analyses

The study included data from 530 IVAN study participants who had serum VEGF measured at baseline and month 12. The laboratory that conducted the serum analyses was masked to all patient clinical information. The analyses of occurrence of SAEs were performed with a mixed effects logistic regression, center fitted as a random effect. Analyses of time to death were performed with Cox proportional hazards regression center-fitted as a frailty term. Serum VEGF levels and age were analyzed as linear variables, but the validity of the models was tested with fractional polynomials.

There were no significant differences in mean serum VEGF levels at baseline comparing the ranibizumab and bevacizumab arms or the continuous and discontinuous arms, indicating the groups were well-balanced for this parameter. After 1 year, serum VEGF was significantly lower with bevacizumab treatment compared with ranibizumab and with continuous versus discontinuous treatment.

Analyses were also conducted to examine potential relationships between the different safety outcomes and drug (ranibizumab or bevacizumab), treatment regimen (continuous or discontinuous), age (patients categorized into age groups by decade of life), and gender. Their results showed several significant associations with age.

Specifically, for each 10-year increase in age, the hazard of death increased 4-fold , the hazard of an ATE/heart failure increased 2.6-fold, and the hazard of both any other SAE not previously linked to VEGF and of all SAEs combined increased~40%. The only other significant association found was a 3.5-fold higher hazard of death in the discontinuous versus continuous arm.

“These data indicate continuous therapy is a safer option,” Dr. Chakravarthy said.

Usha Chakravarthy, MD, PhD

E: u.chakravarthy@qub.ac.uk

This article was adapted from Dr. Chakravarthy’s presentation at the 2014 annual meeting of the Association for Vision in Research and Ophthalmology. Dr. Chakravarthy has no relevant financial interests to disclose.