Anti-Inflammatory Agents and Antioxidants as a Possible “Third Great Wave” in Cardiovascular Secondary Prevention

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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.

Section snippets

The First Wave: Treating Plaque and Plaque Rupture

A fascinating research study by Tuzcu et al2 examined the prevalence of coronary artery disease (CAD) using intravascular ultrasound (IVUS). They found that 85% of people aged >50 years had CAD, and at the other end of the spectrum, 17% of children aged 13–19 years had atherosclerosis. Interestingly, these patients were all heart donors—people who died from a sudden blow to the head, a motor vehicle accident, and so forth—presumably healthy people who were found to have a very high prevalence

The Second Wave of Cardiovascular Prevention: Managing Platelets

In addition to plaque stabilization and plaque regression strategies, the second of the 3 important pillars of cardiovascular prevention is the management of platelets.13 The data for aspirin show it is better than placebo, but interestingly, it does not show any clear dose-response effect.14 There has been recent publicity about aspirin resistance, and there are patients who take aspirin who still experience thrombotic events. Thus, although aspirin is beneficial, we can do better.15 A number

Medical Versus Invasive Therapy

A wealth of data exists supporting an early invasive approach in patients who demonstrate they have plaque rupture, as in ACS (not stable patients).22 Findings in randomized clinical trials and meta-analyses show there is a significant reduction in death or MI by taking patients to the catheterization laboratory to do angioplasty, stenting, or bypass surgery, versus using medications alone.23 Most studies show an early invasive approach is best, but it is a mistake to think of it as an

Inflammation: The Third Wave of Treatment?

Figure 427 depicts not only the science involved with pro- and anti-inflammatory markers and mediators, but also how the complex balance between them can be expressed by the philosophical concept of yin and yang, which might account for some of the contradictory results noted with markers of inflammation. Some studies show that a host of proinflammatory mediators that were initially believed to be simply markers of inflammation, such as C-reactive protein (CRP), are active participants in the

Conclusion

With LDL cholesterol, lower really is better, and with HDL cholesterol, higher should be better, but this still needs to be validated prospectively. That is, it still needs to be proved that increasing HDL with pharmacotherapy improves outcomes when a low LDL level has already been attained. Antiplatelet therapy (obviously monotherapy, primarily with aspirin) is indicated for low-risk patients, but dual antiplatelet therapy definitely has a role in high-risk patients, such as those with ACS

Author Disclosures

The author who contributed to this article has disclosed the following industry relationships:

Deepak L. Bhatt, MD, reports receiving research grants funded directly to the institution from Bristol-Myers Squibb, Eisai, Ethicon, sanofi-aventis, and The Medicines Company; honoraria (currently donated to nonprofits) from Astra Zeneca, Bristol-Myers Squibb, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Paringenix, PDL BioPharma, Inc., sanofi-aventis, Schering-Plough, The

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