aspirin may also not be as effective at reducing blood clot risk. Combining aspirin with other NSAIDs has been shown to further increase the risk of gastrointestinal bleeding. Using aspirin in combination with clopidogrel or warfarin also increases the risk of upper gastrointestinal bleeding. Blockade of COX-1 by aspirin apparently results in the upregulation of COX-2 as part of a gastric defense. Several trials suggest that the simultaneous use of a COX-2 inhibitor with aspirin may increase the risk of gastrointestinal injury. However, currently available evidence has been unable to prove that this effect is consistently repeatable in everyday clinical practice. More dedicated research is required to provide greater clarity on the subject. Therefore, caution should be exercised if combining aspirin with any "natural" supplements with COX-2-inhibiting properties, such as garlic extracts, curcumin, bilberry, pine bark, ginkgo, fish oil, resveratrol, genistein, quercetin, resorcinol, and others. "Buffering" is an additional method that is used with the intention of mitigating gastrointestinal bleeding. Buffering agents are intended to work by preventing the aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed. Almost any buffering agent used in antacids can be used; Bufferin, for example, uses magnesium oxide. Other preparations use calcium carbonate. Gas-forming agents in effervescent tablet and powder formulations can also double as a buffering agent, one example being sodium bicarbonate, used in Alka-Seltzer. Taking vitamin C with aspirin has been investigated as a method of protecting the stomach lining. In trials vitamin C-releasing aspirin (ASA-VitC) or a buffered aspirin formulation containing vitamin C was found to cause less stomach damage than aspirin alone. Retinal vein occlusion It is a widespread habit among eye specialists (ophthalmologists) to prescribe aspirin as an add-on medication for patients with retinal vein occlusion (RVO), such as central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). The reason of this widespread use is the evidence of its proven effectiveness in major systemic venous thrombotic disorders, and it has been assumed that may be similarly beneficial in various types of retinal vein occlusion. However, a large-scale investigation based on data of nearly 700 patients showed "that aspirin or other antiplatelet aggregating agents or anticoagulants adversely influence the visual outcome in patients with CRVO and hemi-CRVO, without any evidence of protective or beneficial effect". Several expert groups, including the Royal College of Ophthalmologists, recommended against the use of antithrombotic