ACE Inhibitors and ARBs— Should They be Used Together?
Abstract & Commentary
Synopsis: The resulting data demonstrated that losartan improved the peak aerobic capacity and relieved symptoms in patients with congestive heart failure who remained severely symptomatic despite treatment with optimal doses of ACE inhibitors, digoxin, and loop diuretics.
Source: Hamroff G, et al. Circulation 1999;99:990-992; Domanski M, et al. J Am Coll Cardiol 1999;33:588-604.
The study of left ventricular dysfunction (SOLVD) treatment trials1 and numerous other studies2,3 have clearly demonstrated that angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients with symptomatic heart failure. A second SOLVD prevention trial4 also concluded that ACE inhibitors reduce the combined incidence of death or hospitalization for heart failure in patients with symptomatic left ventricular dysfunction. Angiotensin II receptor blockers (ARBs) have been introduced only relatively recently and, therefore, outcome and efficacy studies have been limited; however, as indicated above, a large volume of data has been produced in studies using standard ACE inhibition therapy in congestive heart failure patients. As a result, most physicians currently use standard ACE inhibitor therapy for the treatment of patients with congestive heart failure whereas ACE II inhibitors have generally been used only in those individuals who have been unable to tolerate standard ACE inhibition therapy.
Marked elevations of angiotensin II, norepinephrine, and aldosterone plasma levels have been demonstrated to be associated with the progression of left ventricular dilatation in some patients with congestive heart failure even if they have been treated with recommended doses of ACE inhibitors, suggesting that long-term ACE inhibition may only partially suppress the activated renin-angiotensin system.4,5 Hamroff and associates6 from the Albert Einstein College of Medicine in New York performed a study in which they used an ARB (i.e., losartan) in patients with severe congestive heart failure who had been maximally treated with ACE inhibitors in addition to standard therapy. The study was undertaken to determine the effect of losartan vs. placebo on exercise capacity and functional class in patients with congestive heart failure who were severely symptomatic despite treatment with optimal doses of ACE inhibitors, digoxin, and diuretics. Peak oxygen uptake, clinical assessments, and laboratory evaluations were obtained weekly for one month and monthly thereafter. The resulting data demonstrated that losartan improved the peak aerobic capacity and relieved symptoms in patients with congestive heart failure who remained severely symptomatic despite treatment with optimal doses of ACE inhibitors, digoxin, and loop diuretics.
Comment by Harold L. Karpman, MD
Even though there were only 33 patients in Hamroff et al’s study, the results seemed to suggest that angiotensin II blockers significantly improved the clinical status of congestive heart failure patients who were already being treated with recommended doses of ACE inhibitors. This beneficial effect appears to be secondary to the fact that long-term ACE inhibition may suppress the activated renin-angiotensin system only incompletely; therefore, when an angiotensin II inhibitor is added to the therapeutic regimen, ACE suppression becomes complete or nearly complete, thereby improving the patient from a symptomatic point of view.
It is also interesting to note that a recently reported trial7 from the National Heart, Lung, and Blood Institute demonstrated that ACE inhibitors decrease the risk of death following a recent myocardial infarction (MI) by reducing cardiovascular mortality and that the reduction in sudden cardiac death with the addition of ACE inhibitors was an important component of this survival benefit. It will be interesting to see whether this positive result is even further improved in subsequent clinical trials by the addition of angiotensin II blockers since, if the addition of these agents to ACE blocking agents improves exercise capacity in patients with severe congestive heart failure, it is entirely possible that the other manifestations of symptomatic coronary artery disease (i.e., sudden cardiac death, recurrent MIs, etc.) may be affected similarly in a positive way.
The ACC/AHA guidelines for the management of patients with acute MI concluded that "all trials in which only oral ACE inhibitors were used demonstrated a benefit in mortality." It may be that we will soon be adding ARB to standard ACE inhibitor therapy in all or most patients who have suffered an acute MI or are afflicted with coronary artery disease whether symptomatic or not and/or those who suffer from congestive heart failure of any cause.
References
1. SOLVD Investigation. N Engl J Med 1991;325: 293-302.
2. Cohn JN, et al. N Engl J Med 1991;325:303-310.
3. CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-1435.
4. Rousseau MF, et al. Am J Cardiol 1994;73:488-493.
5. Francis GS, et al. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87(suppl V1):V1-40-V1-48.
6. Hamroff G, et al. Circulation 1999;99:990-992.
7. Domanski M, et al. J Am Coll Cardiol 1999;33: 588-604.
Which of the following elevated plasma levels have been demonstrated to be associated with the progression of left ventricular dilatation in some patients with congestive heart failure?
a. Angiotensin II
b. Norepinephrine
c. Aldosterone
d. All of the above
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