Research Article Differences in mean and variability of heart rate and ambulatory rate-pressure product when valsartan or carvedilol is added to lisinopril Joseph L. Izzo Jr., MD * , Siva H. Yedlapati, MBBS, Sheikh M. Faheem, MBBS, Usman Younus, MBBS, and Peter J. Osmond, MS Department of Medicine, State University of New York at Buffalo, Erie County Medical Center, Buffalo, NY Manuscript received June 12, 2012 and accepted August 23, 2012 Abstract Guidelines recommend combining b-blockers and angiotensin-converting enzyme (ACE) inhibitors in high-risk heart disease but not in the initial treatment of hypertension. The mechanism of this benefit has not been determined. After 3 weeks of lisinopril (L, 40 mg/day) run-in, 30 subjects entered a single-blinded, forced-titration, crossover study in which carvedilol (C, 20 then 40 mg/ day) or a control renin-angiotensin blocker, valsartan (V, 160 then 320 mg/day) were added to L. Ambulatory blood pressure (ABP) and heart rate monitoring was performed at the end of each period. Rate-pressure product (RPP, systolic BP  heart rate, an indicator of cardiac oxygen consumption) was measured over 24 hours, daytime (6 AM to midnight), and nighttime (midnight to 6 AM) periods. Variability (standard deviation and range) of RPP, BP, and heart ratewas also investigated. After 4 weeks, mean 24-hour systolic BP was about 8 mm Hg lower when either Vor C was added to L (P < .01 each). Heart rate was consistently lower with C (8 beats/min over 24 hours, P < .000) but was slightly increased with V (about 2 beats/min, P ¼ NS). Consequently, C lowered RPP to a greater degree than Vover 24 hours (about 8% vs. 2%, P < .000) and during daytime and nighttime periods (P < .000 each). In addition, RPP variability (SD but not range) was consistently lower on C than V. When added to L, C reduces the mean and variability (SD) of 24-hour heart rate and cardiac workload to a greater degree than valsartan. These effects may contribute to the outcome benefits observed with b-blocker–ACE inhibitor combinations. JAm Soc Hypertens 2012;6(6):399–404. Ó 2012 American Society of Hypertension. All rights reserved. Keywords: Blood pressure; blood pressure variability; carvedilol; heart rate; lisinopril; rate-pressure product; valsartan. Introduction Optimal ‘‘broad-spectrum’’ antihypertensive combina- tions usually include agents with diverse mechanisms of action, most often a blocker of the renin-angiotensin (RAS) system and either a thiazide-type diuretic or a calcium-channel blocker. 1,2 Combining either an angio- tensin receptor blocker (ARB) or a b-blocker with an angiotensin-converting enzyme (ACE) inhibitor may inten- sify the degree of ‘‘total RAS inhibition,’’ 3 but neither an ARB nor a b-blocker tends to decrease blood pressure (BP) to a great degree when added to an ACE inhibitor. 4–6 Because the principal goal of antihypertensive therapy is to lower cardiovascular disease (CVD) risk, the combina- tion drugs that are chosen should also have enhanced risk reduction profiles. For example, ACE inhibitor/ARB combinations do not confer additional CVD protection compared with ACE inhibition alone, 1,5,7,8 perhaps because of the closely related mechanisms of action of the two drug classes. Yet other combinations have differential effects on CVD risk. Despite similar achieved BP values, ACE inhib- itor/dihydropyridine combination therapy lowers CVD events more than ACE inhibitor/thiazide therapy. 9 b-blocker drugs lower heart rate, cardiac workload, 10 and excessive heart rate or BP variability, 11 so it is possible this class offers additional hemodynamic benefits over ACE inhibition alone. No hypertension trials have directly tested whether there are incremental outcome benefits of J.L.I. received research support from GlaxoSmithKline (the sponsor) but retained full control over the design, execution, and analysis of the protocol and was solely responsible for writing and publishing the manuscript without external assistance or modification by the sponsor. The study was funded in its entirety by GlaxoSmithKline and the authors wish to acknowledge the support of MaryAnn Lucas, MD. P.J.O. was responsible for all technical aspects of the study. ClinTrials#: NCT00657241. *Corresponding author: Joseph L. Izzo Jr., MD, Department of Medicine, 462 Grider St., Buffalo, NY 14216. Tel: (716) 898-5625. E-mail: jizzo@buffalo.edu 1933-1711/$ - see front matter Ó 2012 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2012.08.007 Journal of the American Society of Hypertension 6(6) (2012) 399–404