Therapy and prevention 439 Lack of effect on coronary atherosclerotic disease biomarkers with modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type-1 receptor blocker, and the combination James P. Tsikouris a , Craig D. Cox b , Jan S. Simoni b , Charles F. Seifert b , Miranda C. Peek b and Gary E. Meyerrose b Background Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, used alone or in combination, have been shown to improve outcomes in certain populations, primarily when administered in high doses. For stable coronary atherosclerotic disease, however, the relative physiologic effect of these therapies is unclear. Furthermore, because of the notorious subtarget dosing of such agents in clinical practice, we explored the influence of a modest dosing of an angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blockers, and the combination on common biologic markers of coronary atherosclerotic disease. Methods This randomized, cross-over study enrolled stable coronary atherosclerotic disease patients (n = 20), each receiving three treatments: candesartan 16 mg daily, ramipril 5 mg daily, and candesartan 8 mg plus ramipril 2.5mg daily. Treatments were administered for 2 weeks with a 2-week washout. Blood samples were collected before and after each treatment. Markers of endothelial function, fibrinolytic balance, and vascular inflammation were measured. Results No significant differences were observed in the pretreatment concentrations of angiotensin-converting enzyme or of any measured biologic marker. Relative to pretreatment levels, candesartan alone was the only therapy to exhibit an action on any measured biomarker – a trend toward increased nitric oxide concentrations (P = 0.054). Otherwise, no effects on biologic markers were observed with the treatments. Conclusion This study of various methods of the renin–angiotensin system inhibition in stable coronary atherosclerotic disease patients demonstrates negligible effects of a modest dosing of ramipril and the combination of ramipril plus candesartan on common biologic markers of coronary atherosclerotic disease. Candesartan at modest doses may favorably influence endothelial function. Overall, however, the results indicate that the commonly practiced subtarget dosing of such treatments provides little, if any, benefit pertaining to key physiologic components of coronary atherosclerotic disease. Coron Artery Dis 17:439–445  c 2006 Lippincott Williams & Wilkins. Coronary Artery Disease 2006, 17:439–445 Keywords: angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, coronary artery disease a University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania and b Texas Tech University Health Sciences Center, Lubbock,Texas, USA Correspondence and requests for reprints to Gary E. Meyerrose, MD, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9410, Lubbock, TX 79430, USA Tel: +1 806 743 3155; fax: +1 806 743 3148; e-mail: gary.meyerrose@ttuhsc.edu Sponsorship: This study was funded by the American College of Clinical Pharmacy Research Institute, AstraZeneca Cardiovascular Research Award. Received 13 December 2005 Revised 14 February 2006 Accepted 16 February 2006 Introduction Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs), used alone or in combination, have been studied and shown to improve outcomes for certain cardiovascular conditions [1–6]. In the setting of stable coronary atherosclerotic disease (CAD), a condition that affects more that 16 million Americans [7], however, only ACE inhibitors have been systematically studied and shown to benefit these patients [8–10]. As ACE inhibitors and ARBs display pharmacologic actions at different levels of the renin– angiotensin system (RAS), it is important to directly compare the effects of such agents administered alone or in combination to evaluate the relative benefit pertaining to worsening CAD. From a physiologic perspective, atherosclerotic severity can be evaluated by the measurement of common biologic markers of the disease. Specifically, increased activity of the RAS adversely influences ischemic cardiovascular event risk [11,12], which may be mediated by the key components of atherosclerotic disease, 0954-6928  c 2006 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.