Correspondence
Valsartan in Chronic Heart Failure
N Engl J Med 2002; 346:1173-1174April 11, 2002
- Article
To the Editor:
Cohn and Tognoni (Dec. 6 issue)1 found that the angiotensin-receptor blocker valsartan reduced the combined end point of mortality and morbidity and improved clinical signs and symptoms in patients with heart failure when it was added to prescribed therapy. However, an adverse effect on mortality and morbidity was observed in a subgroup receiving valsartan, an angiotensin-converting–enzyme (ACE) inhibitor, and a beta-blocker. In the overall study, adverse events leading to the discontinuation of valsartan included dizziness, hypotension, and renal impairment, but hypotension was not significantly more frequent in the valsartan group than in the placebo group. The authors state that “extensive blockade of multiple neurohumoral systems in patients with heart failure could be deleterious.” Clinicians should keep this possibility in mind when they are considering the use of vasodilator therapy, since hypotension reduces perfusion pressure to the brain and heart, resulting in cerebral and myocardial damage. Was there a significant incidence of hypotension and cerebral and myocardial damage in the subgroup, which led to an increase in mortality?
1 ReferencesFrancis J. Haddy, M.D., Ph.D.
211 Second St. NW, 1607, Rochester, MN 55901-2896
tbhaddy@aol.com 1
Cohn JN ,Tognoni G . A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675
Full Text | Web of Science | Medline
To the Editor:
Cohn and Tognoni report that the addition of valsartan to standard therapy for heart failure reduced the combined end point of mortality and morbidity in all patients except those who were receiving both an ACE inhibitor and a beta-blocker at base line; in this subgroup, mortality was significantly increased. The authors acknowledge that extensive blockade of multiple neurohormonal systems in patients with heart failure could be deleterious.
My colleagues and I recently reported that beta-blockade reduces angiotensin II levels in patients with heart failure who are receiving ACE inhibitors.1 Our findings are consistent with the well-described ability of beta-blockade to reduce renin secretion.2 Thus, the combination of ACE inhibition, beta-blockade, and angiotensin-receptor blockade represents triple inhibition of the renin–angiotensin system. Studies in animals indicate that extensive blockade of the renin–angiotensin system has deleterious effects, particularly in the presence of sodium depletion.3,4 Whereas single or double blockade of the renin–angiotensin system (with the use of either ACE inhibition and beta-blockade or ACE inhibition and angiotensin-receptor blockade) is beneficial in patients with heart failure, triple blockade may be deleterious. The risk of harm may be increased by sodium depletion resulting from diuretic therapy. Measurement of angiotensin II levels may provide a means to identify patients who have little to gain — and who may be harmed — by the addition of an angiotensin-receptor blocker to their heart-failure regimen.
4 ReferencesDuncan John Campbell, M.D., Ph.D.
St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia
j.campbell@medicine. unimelb. edu. au 1
Campbell DJ ,Aggarwal A ,Esler M ,Kaye D . β-Blockers, angiotensin II, and ACE inhibitors in patients with heart failure. Lancet 2001;358:1609-1610
CrossRef | Web of Science | Medline2
Buhler FR ,Laragh JH ,Baer L ,Vaughan ED Jr ,Brunner HR . Propranolol inhibition of renin secretion: a specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. N Engl J Med 1972;287:1209-1214
Full Text | Web of Science | Medline3
Menard J ,Campbell DJ ,Azizi M ,Gonzales MF . Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats. Circulation 1997;96:3072-3078
Web of Science | Medline4
Griffiths CD ,Morgan TO ,Delbridge LM . Effects of combined administration of ACE inhibitor and angiotensin II receptor antagonist are prevented by a high NaCl intake. J Hypertens 2001;19:2087-2095
CrossRef | Web of Science | Medline
To the Editor:
There are two problems with the conclusion of Cohn and Tognoni that valsartan improves outcomes in patients with chronic heart failure. First, since the average dose of standard therapy with ACE inhibitors in the base-line population was quite low, it is not logical to conclude that the benefits noted in the valsartan group were due to valsartan. It has been well demonstrated that ACE inhibitors are frequently underused in patients with heart failure and that the doses prescribed are too small.1 Furthermore, a 1999 study demonstrated that 30 mg of lisinopril daily was superior to a daily dose of 5 to 10 mg in reducing the risk of death and hospitalization,2 yet the average dose of lisinopril in the current study was only 19 mg daily. Until valsartan is evaluated in a study of patients with heart failure in which appropriately therapeutic doses of ACE inhibitors are used, it remains in question whether the benefits noted are specific to valsartan or would be equal or inferior to those obtained with higher doses of ACE inhibitors.
Second, and of more concern, is the post hoc finding that the addition of valsartan to a regimen of an ACE inhibitor and a beta-blocker significantly increased the risk of death and nonsignificantly increased the risk of the combined end point of mortality and morbidity. Among patients who were already receiving appropriate treatment, the outcome was better if placebo was given than if valsartan was given.
2 ReferencesWilliam E. Cayley, Jr., M.D.
Eau Claire Family Medicine, Eau Claire, WI 54701
bcayley@yahoo.com 1
Bungard TJ ,McAlister FA ,Johnson JA ,Tsuyuki RT . Underutilisation of ACE inhibitors in patients with congestive heart failure. Drugs 2001;61:2021-2033
CrossRef | Web of Science | Medline2
Packer M ,Poole-Wilson PA ,Armstrong PW , et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100:2312-2318
Web of Science | Medline
To the Editor:
The results reported by Cohn and Tognoni indicate a lack of effect of valsartan on mortality in the population studied but a small reduction in the rate of a first adverse event. Although the results of subgroup analyses should be treated with great caution, differences in mortality are noteworthy. We were therefore surprised that the significant increase in mortality with valsartan therapy, as compared with placebo, in the subgroup that was receiving both beta-blockers and ACE inhibitors (mortality rates, 16.2 percent and 11.9 percent, respectively) was presented only in the form of a relative risk and received only brief mention. It is difficult to understand why an absolute difference in mortality of 4.3 percent, meaning that 1 extra death occurred for every 23 patients in this subgroup who received valsartan, is worthy of such little comment and presented only in terms of relative risk. We believe that this result is by far the most important finding of the subgroup analyses and must be a cause for concern, given the current trend in many clinical trials involving patients with heart failure to use combination therapy to disable the renin–angiotensin–aldosterone–sympathetic nervous system.
J. Colin Forfar, M.D., Ph.D.
Shahzad Munir, M.B., Ch.B.
John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
colin.forfar@orh. nhs. uk Author/Editor Response
The authors reply:
To the Editor: The issue of the possible adverse effect of combined therapy with an ACE inhibitor, a beta-blocker, and an angiotensin-receptor blocker, mentioned by Drs. Haddy and Campbell, is one that has concerned us as well. Valsartan lowered blood pressure to a similar degree in all subgroups, although the group treated with an ACE inhibitor and a beta-blocker had a slightly lower blood pressure at base line. We did not find a greater incidence of symptoms of hypotension or end-organ damage in this subgroup.
Dr. Campbell's reaffirmation of the renin-inhibiting effect of beta-blockers provides an attractive hypothesis that potent renin–angiotensin blockade is the culprit, but the physiological mechanism of this as yet unconfirmed adverse effect remains unclear. The results of other ongoing clinical trials in which large numbers of patients are receiving the three-drug combination for various cardiovascular diseases may help to determine whether the interaction is real.
Dr. Cayley and Drs. Forfar and Munir question our interpretation of the results of the trial. Although the average dose of ACE inhibitors prescribed to our patients was remarkably close to the doses used in previous clinical trials and not “quite low,” as characterized by Dr. Cayley, we agree that higher doses might have provided greater benefit. We disagree, however, with his characterization of an appropriate dose of an ACE inhibitor. Successful trials have targeted the equivalent of 20 mg of lisinopril daily, and the 1999 trial to which he referred unfortunately provided no evidence that a 30-mg dose is better than a 20-mg dose.1 We have not suggested that the efficacy of valsartan is unique, but the efficacy of higher doses of an ACE inhibitor has not been evaluated in this context.
We emphasized in the article the potential adverse effect of high-dose valsartan in patients who were already receiving an ACE inhibitor and a beta-blocker, but we must stress again the danger of placing too much confidence in the results of a post hoc subgroup analysis. The adverse effect on mortality of the triple-inhibitor regimen certainly warrants our attention, but the overall design and the protocol-driven results of the trial — a 13.2 percent reduction in the combined end point of mortality and morbidity — must take precedence.2
2 ReferencesJay N. Cohn, M.D.
University of Minnesota Medical School, Minneapolis, MN 55455
cohnx001@umn.edu Gianni Tognoni, M.D.
Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy1
Nicklas JM ,Cohn JN ,Pitt B . What does ATLAS really tell us about “high“ dose angiotensin-converting enzyme inhibition in heart failure? J Card Fail 2000;6:165-168
CrossRef | Web of Science | Medline2
Wedel H ,Demets D ,Deedwania P , et al. Challenges of subgroup analyses in multinational clinical trials: experiences from the MERIT-HF trial. Am Heart J 2001;142:502-511
CrossRef | Web of Science | Medline
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Renke Maas, Rainer H Böger. (2003) Antihypertensive therapy: special focus on drug interactions. Expert Opinion on Drug Safety 2:6, 549-579
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