Antiangiogenic and anti-inflammatory drugs: are they safe?

Since Rofecoxib (Vioxx) was withdrawn from the worldwide market based on the safety findings of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, the uncertainty around the cardiovascular safety of NSAIDs and COX-2 inhibitors remains and leaves practitioners with difficult management decisions for the hundreds of millions of patients worldwide who continue to require pain-relieving therapy to maintain an acceptable quality of life.

Importantly, the Food and Drug Administration recently summarized a statement that in various controlled clinical trials the cardiovascular risks of COX-2 selective drugs have been indistinguishable from non-selective NSAIDs, thus also raising serious questions about the safety of the latter. As such, the FDA mandated a “boxed warning” for COX-2 selective inhibitors and traditional NSAIDs alike in view of the potential of these agents to increase adverse cardiovascular outcomes. Unfortunately, none of the reported randomised trials undertaken with NSAIDs and COX-2 selective inhibitors have thus far been specifically designed to examine cardiovascular outcomes. Thus, the current situation is one of classic ‘equipoise’. Adequately powered, independently run randomized clinical trials prospectively designed to capture cardiovascular outcomes are urgently needed.

In order to address at least some of the remaining clinically important questions concerning anti-inflammatory drugs, the PRECISION – Prospective Randomised Evaluation of Celecoxib Integrated Safety vs. Ibuprofen and Naproxen - trial in more than 20000 patients with osteoarthritis is now under way. Until trials like these are completed, careful risk benefit analysis needs to be undertaken for all anti-inflammatory agents regarding their potential gastrointestinal benefit, which in many cases remains yet to be definitely established, versus potential increase in cardiovascular risk, hypertension and its clinical sequels in particular.

Similarly, safety concerns exist for novel anti-VEGF therapies that have shown to effectively delay vision loss in patients with age-related neovascular macular degeneration (AMD), the most important cause of blindness in the Western world. Although the pathophysiology of AMD is still poorly understood, it is increasingly clear that vascular endothelial growth factor (VEGF) plays an important role in the promotion of neovascularization and vessel leakage that leads to loss of central vision. Therefore, intravitreal anti-VEGF therapy is currently the primary therapy for neovascular AMD. Currently, the most common therapeutic agents are ranibizumab, bevacizumab and pegaptanib which differ in their selectivity for VEGF. However, their well-documented efficacy in treating wet AMD may come at the cost of cardiovascular safety, as VEGF, mostly through its downstream mediator NO, exerts essential physiological functions in maintaining vascular integrity. Since breakdown of the blood-ocular barrier is common in AMD, repeated intravitreal anti-VEGF therapy may lead to clinically relevant systemic VEGF inhibition, possibly resulting in serious long-term cardio- and cerebrovascular adverse events. Unfortunately, the number of cardiovascular events in these AMD trials without pre specified cardiovascular safety endpoints are too small to provide any clinical relevant evidence of safety.

Only adequately powered randomized clinical trials prospectively addressing cardiovascular safety will provide the evidence of whether the proven benefits of VEGF antagonism in the eye may come at the cost of potential systemic, particularly adverse cardiovascular events. Until this trial evidence becomes available, ophthalmologists and cardiologists should synchronize their efforts to reduce the cardiovascular burden of patients with wet AMD.