Effect of Combining Extended-Release Carvedilol and Lisinopril in Hypertension: Results of the COSMOS Study


  • John M. Flack MD, MPH, FAHA, FACP, FACSG

    1. From the Division of Translational Research and Clinical Epidemiology, Department of Medicine, Wayne State University, Detroit Medical Center, Detroit, MI
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John M. Flack, MD, MPH, Division of Translational Research and Clinical Epidemiology, Department of Medicine, Wayne State University, Detroit, MI
E-mail: jflack@med.wayne.edu

Bakris and colleagues1 report the results of a 6-week, randomized, double-blind, factorial trial in patients with stage 1 or 2 hypertension, contrasting the blood pressure (BP)–lowering effect of carvedilol extended-release (CR) and lisinopril monotherapy as well as 9 combination doses to determine whether at least one combination dose lowered BP more than its components. The co-primary end points were change from baseline in 24-hour ambulatory diastolic BP (DBP) and change from baseline in trough DBP. None of the combination therapies were superior to their monotherapy components. Because the 24-hour ambulatory DBP change was not significant, trough DBP differences were not formally tested for statistical significance. Interestingly, high-dose combination groups showed greater change from baseline in 24-hour ambulatory DBP, but not trough DBP, relative to high-dose monotherapy with carvedilol CR (80 mg/d) and lisinopril (40 mg/d). Office cuff BP readings were not used in any of the reported analyses.

Several studies2,3 have reported incremental BP lowering with the combination of a β-blocker and an angiotensin-converting enzyme (ACE) inhibitor. Alternatively, the CLEVER study4 showed that the combination of a β-blocker and an ACE inhibitor provided no greater BP lowering than simply up-titrating lisinopril, an ACE inhibitor with a flat dose-response curve, to a higher dose. This might logically be explained by the fact that these 2 drug classes owe at least a portion of their antihypertensive effect to modulation of renin angiotensin system (RAS) activity. In all likelihood, the addition of either a diuretic or possibly even a dihydropyridine calcium antagonist to either carvedilol or lisinopril or their combination would have lowered BP much more impressively than what was observed in the Coreg and Lisinopril Combination Therapy in Hypertensive Subjects (COSMOS) study. The clinician will, however, find the combined prescription of a β-blocker and an ACE inhibitor useful in routine clinical practice. For example, the combination of a β-blocker and ACE inhibitor is often prescribed in patients with heart failure with or without hypertension and/or CKD.

It is unlikely that the variability in the magnitude of the BP-lowering effect observed with combined use of β-blockers and ACE inhibitors can be explained by the use of different types of β-blockers. Accordingly, there do not appear to be clinically meaningful differences in the magnitude of BP lowering observed with traditional β-blockers, α-/β-blockers, or vasodilating β-blockers (nebivolol), although there is a small possibility of an unknown interaction between β-blocker type with ACE inhibitors. What is more likely is that the varied BP lowering of this combination simply reflects random variation around a rather modest incremental BP-lowering effect. On the other hand, all β-blockers are not created equal because the metabolic,5,6 side effect, and hemodynamic profiles vary markedly between β-blocker types.

Although incremental BP lowering can be obtained with the combination of a β-blocker and an ACE inhibitor, the magnitude of BP reduction is rather modest. Moreover, the BP-lowering effect of the combination used in the COSMOS study was not sustained throughout the 24-hour dosing interval. Accordingly, the potential benefits of this combination do not relate to its BP-lowering prowess. Thus, it seems highly doubtful that this single-pill combination will ever be developed for the general hypertension market. On the other hand, this combination would be of considerable utility for heart failure patients in whom β-blockers and ACE inhibitors are indicated.

Finally, the authors are to be commended for the expedient publication of an essentially negative study. Publication of only positive studies distorts the published literature in a highly insidious and misleading way. As important as it is to know what works, it is equally as important to understand what does not.