Anti-inflammatory agents and antioxidants as a possible "third great wave" in cardiovascular secondary prevention.

There are 3 important factors that predispose patients to plaque rupture or recurrent events: plaque burden or multiple arterial plaques, the presence of persistent hyperreactive platelets, and ongoing vascular arterial inflammation. Successful therapeutic strategies focus on these predisposing factors, and the use of low-density lipoprotein-lowering medications (principally statins) and antiplatelet agents (principally aspirin) has had a major impact on the occurrence of cardiovascular outcomes and overall mortality over the last 2 decades. However, despite these interventions, a significant number of patients experience recurrent events or progression of disease. Novel compounds are being studied to determine, for example, whether an increase in high-density lipoprotein will provide additional risk reduction; to date, this has not proved to be sufficiently effective. Although early invasive management has been proved to be superior to medical therapy in patients with plaque rupture producing acute coronary syndromes, its superiority in patients with clinically stable obstructive disease has been questioned. Thus, the search for additional agents to improve the outcomes of patients with atherothrombotic disease continues. The importance of inflammation, a potentially critical element in the initiation, progression, and rupture of plaque, has become increasingly evident. In this supplement, the role of inflammation and its principal cause, oxidative stress, are analyzed as potential targets of pharmacologic therapy. The history of anti-inflammatory and antioxidant therapy in cardiovascular disease is critically examined. Finally, the whole process of contemporary drug discovery and development from lead rationale and identification through biologic screening and testing in animals and then humans is explored, using as an example the xanthophyll carotenoids, a class of potent antioxidants currently under investigation.