Author + information
- Robert J. MacFadyen, MD, PhD, FRCP⁎ ( and )
- Russell Davis, MD, MRCP
- ↵⁎University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, United Kingdom
Dr. Leier (1) has made a useful and provocative commentary on the work of Sliwa et al. (2). Clearly Dr. Leier is impressed by the principle of testing order effects in the management of systolic left ventricular (LV) dysfunction. This is a very wise and long overdue assessment although not performed in a double-blinded randomized crossover design that would be expected to characterize an order effect. It would be equally wise to retain balance in estimating the impact or generalizability of this work.
First, it is often forgotten that all modern studies in systolic failure involve structured addition of therapy to established treatments. Although we often focus on the added therapy we tend to ignore the baseline, which is constantly changing and makes proving efficacy of a new addition consequently more challenging. For example, all patients in the angiotensin-converting enzyme (ACE) inhibitor, ino-dilator, or vasodilator and digoxin systolic failure trials of the 1980s and 1990s were subjected to loop diuretic therapy, which has a powerful impact in stimulating the circulating and tissue-based (renin-angiotensin-aldosterone system). The well-characterized and accepted adverse effects of the changes caused by these treatments are balanced in the individual patient by the beneficial effect on fluid volume and loading. Although beta-blockade will suppress renin, it does so inefficiently compared to ACE inhibition. To presume that beta-blocker addition following an ACE inhibitor is the same as the addition of an ACE inhibitor after a beta-blocker is simply wrong. To suggest that beta-blockade should be given first and an ACE inhibitor not at all is equally wrong. To presume that an ACE inhibitor after a beta-blocker would be ineffectual or of little value from the limited work of Sliwa and colleagues is at best an overstatement.
Second, the patients in this study are likely to be Africans (a critical missing statement that avoided detection in the review process?). This patient group, in addition to being rarely studied, is at least well known to show reduced response to renin system blockade. Furthermore, the subjects are unusual in that they are all suggested to have idiopathic dilated cardiomyopathy. This would be rare in a Westernized cohort relevant to the U.S. or Europe.
We believe Dr. Leier should not fear for the efficacy of ACE inhibitor therapy in systolic LV dysfunction, although he is very correct to draw attention to the significance of order effects in therapeutics. These have been well recognized in cardiovascular pharmacology for over a century. A more temperate interpretation of Silwa’s study results would be that beta-blockade should be introduced in patients with systolic heart failure as soon as possible after diagnosis, and certainly without a six-month delay. Physicians might reasonably initiate a beta-blocker prior to an ACE inhibitor in those patients with euvolemic “dry” heart failure, and an ACE inhibitor first in those with persisting congestion, with plans to add a beta-blocker as soon as the congestion has resolved.
- American College of Cardiology Foundation
- Leier C.V.
- Silwa K.,
- Norton G.R.,
- Kone N.,
- et al.