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n engl j med
349;20
www.nejm.org november
13, 2003
The
new england journal
of
medicine
1963
editorials
Angiotensin-Receptor Blockade in Acute Myocardial
Infarction — A Matter of Dose
Douglas L. Mann, M.D., and Anita Deswal, M.D., M.P.H.
Beta-blockers, angiotensin-converting–enzyme
(ACE) inhibitors, and aldosterone antagonists have
been shown to reduce the overall risk of death as
well as the risk of major nonfatal cardiovascular
events when they are administered to patients with
acute myocardial infarction who also have left ven-
tricular systolic dysfunction, clinical evidence of
heart failure, or both.
1,2
However, there remains a
sizable subgroup of patients in whom clinical heart
failure worsens despite optimal medical therapy af-
ter acute myocardial infarction. Relevant to this dis-
cussion is the observation that ACE inhibitors block
only 13 percent of the total production of angioten-
sin II in the human heart
3
because of the existence
of ACE-independent pathways (e.g, chymase, ca-
thepsin, and kallikrein) that convert angiotensin I to
angiotensin II.
These observations provided the impetus for the
development of angiotensin-receptor antagonists
that offer more complete protection against angio-
tensin II by directly blocking the angiotensin type I
receptor. However, when this therapeutic approach
was tried in the Optimal Trial in Myocardial Infarc-
tion with the Angiotensin II Antagonist Losartan
(OPTIMAAL), in which the angiotensin-receptor an-
tagonist losartan (at a dose of 50 mg per day) was
compared with the ACE inhibitor captopril (at a dose
of 150 mg per day) in high-risk patients with acute
myocardial infarction,
4
there was a strong trend in
favor of captopril with respect to the primary end
point of death from any cause (P=0.07) and a signif-
icant difference in favor of captopril with respect to
the prespecified end point of death from cardiovas-
cular causes (P=0.03). Thus, the OPTIMAAL trial
raised important questions regarding the role of se-
lective angiotensin-receptor antagonism after acute
myocardial infarction.
The Valsartan in Acute Myocardial Infarction
(VALIANT) trial reported by Pfeffer et al. in this is-
sue of the
Journal
5
compared the effects of the angi-
otensin-receptor blocker valsartan, the ACE inhib-
itor captopril, and the combination of valsartan and
captopril in a population of high-risk patients with
clinical or radiologic evidence of heart failure, evi-
dence of left ventricular systolic dysfunction, or both
after acute myocardial infarction. A total of 14,808
patients underwent randomization in a 1:1:1 ratio
to receive valsartan (titrated to 160 mg twice daily),
captopril (titrated to 50 mg three times daily), or the
combination of valsartan (titrated to 80 mg twice
daily) and captopril (titrated to 50 mg three times
daily) beginning 12 hours to 10 days after a myocar-
dial infarction. The primary end point of the study
was death from any cause, and a prespecified analy-
sis was designed to demonstrate the noninferiority,
or equivalence, of valsartan to captopril in the event
that valsartan was not clearly shown to be superior
in the primary analysis.
During a median follow-up of 24.7 months,
mortality was 19.9 percent in the valsartan group,
19.5 percent in the captopril group, and 19.3 per-
cent in the valsartan-and-captopril group. The haz-
ard ratio for death in the valsartan group as com-
pared with the captopril group was 1.00 (97.5
percent confidence interval, 0.90 to 1.11; P=0.98),
and the hazard ratio for death in the valsartan-and-
captopril group as compared with the captopril
group was 0.98 (97.5 percent confidence interval,
0.89 to 1.09; P=0.73). The comparison of valsartan
with captopril showed that these two agents were
equivalent in terms of overall mortality and in terms
of the rate of the composite end point of fatal and
nonfatal cardiovascular events.
Adverse events were less common with mono-
Downloaded from www.nejm.org by DR JOHN FJ BAYLISS on November 15, 2003.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
The
new england journal
of
medicine
1964
n engl j med
349;20
www.nejm.org november
13, 2003
therapy than with combination therapy, with hypo-
tension and renal dysfunction being more common
in the valsartan group and cough, rash, and taste
disturbance being more common in the captopril
group. Taken together, the results of this well-
designed and carefully performed study show that
320 mg of valsartan per day is as effective as a dose
of captopril that has been shown to be superior to
placebo in reducing morbidity and mortality among
high-risk patients with acute myocardial infarction.
1
The study by Pfeffer et al. also addressed the im-
portant question of whether more complete block-
ade of the renin–angiotensin system with the use of
valsartan and captopril is more effective than the use
of captopril alone. In contrast to two recently report-
ed trials involving patients with heart failure, in
which combination therapy with ACE inhibitors and
angiotensin-receptor blockers was shown to be ben-
eficial in terms of cardiovascular morbidity
6
and
mortality,
7
the study by Pfeffer et al. showed that
combination therapy resulted in an increase in the
rate of adverse events without improving overall
survival.
This trial serves as an important (and painful)
reminder that, in the treatment of high-risk patients
with cardiovascular disease, choosing the appropri-
ate dose of a therapeutic agent is perhaps just as im-
portant as choosing the right agent. That is, when
50 mg of losartan per day was compared with 150
mg of captopril per day in the OPTIMAAL trial, cap-
topril was shown to be superior, and when similar
doses of captopril and losartan were compared in
patients with moderate-to-severe heart failure in the
Evaluation of Losartan in the Elderly II trial, the re-
sults similarly favored captopril.
8
In contrast, in two
recently reported clinical trials in which the investi-
gators were allowed to increase the dose of losartan
gradually to 100 mg per day, there was a significant
reduction in the incidence of heart failure among
high-risk patients
9,10
; this finding raises the impor-
tant question of whether higher doses of losartan
might have been more effective in reducing the rates
of cardiovascular events in the OPTIMAAL trial.
The issue of proper doses is also germane to the
question of whether the effects of valsartan can
be interpreted as a “class effect” of angiotensin-
receptor blockers. Aside from the obvious differ-
ences in pharmacologic profiles among the angi-
otensin-receptor blockers, the most compelling
argument for not making assumptions regarding
class effects is underscored by the different clinical
outcomes in the OPTIMAAL and VALIANT trials, in
which the determination of the correct dose of an
angiotensin-receptor antagonist became a matter of
life and death.
How will the results of the study by Pfeffer et al.
affect the care of high-risk patients after acute my-
ocardial infarction? Given that valsartan was as ef-
fective as captopril in reducing the rates of death and
other cardiovascular events, the ultimate question
raised by this trial is whether high-risk patients
should receive ACE inhibitors or angiotensin-recep-
tor blockers after acute myocardial infarction.
Pfeffer et al. conclude the report on their landmark
study by stating that “the choice between these alter-
native treatments will depend on cumulative clinical
experience, tolerability, safety, convenience, and
cost.”
The tolerability and safety of valsartan and capto-
pril are both good for high-risk patients with acute
myocardial infarction. Given that ACE inhibitors
have been shown to reduce the risks of death and
nonfatal cardiovascular events after acute myocar-
dial infarction in 100,000 patients, whereas the clin-
ical experience with angiotensin-receptor blockers
has been more limited, and given that, in the United
States, the cost of using valsartan at the doses used
in the study by Pfeffer et al. is approximately four to
six times as high as the cost of using generic capto-
pril at the doses used in this study, ACE inhibitors
remain the logical first-line therapy for high-risk pa-
tients after acute myocardial infarction. However,
for those patients who cannot tolerate ACE inhibi-
tors, the good news provided by the current trial is
that there is now a safe and equally effective alterna-
tive strategy that will reduce the risks of death and
adverse cardiovascular events among patients who
have had an acute myocardial infarction.
Dr. Mann reports having received lecture and consulting fees
from AstraZeneca and lecture fees from Novartis.
From the Medical Care Line, Houston Veterans Affairs Medical
Center, and the Winters Center for Heart Failure Research, Baylor
College of Medicine — both in Houston.
1.
Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on
mortality and morbidity in patients with left ventricular dysfunction
after myocardial infarction. N Engl J Med 1992;327:669-77.
2.
Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldos-
terone blocker, in patients with left ventricular dysfunction after
myocardial infarction. N Engl J Med 2003;348:1309-21. [Erratum,
N Engl J Med 2003;348:2271.]
3.
Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angio-
tensin II-forming pathways in normal and failing human hearts.
Circ Res 1990;66:883-90.
4.
Dickstein K, Kjekshus J. Effects of losartan and captopril on
mortality and morbidity in high-risk patients after acute myocar-
dial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:
752-60.
5.
Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, capto-
Downloaded from www.nejm.org by DR JOHN FJ BAYLISS on November 15, 2003.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
n engl j med
349;20
www.nejm.org november
13, 2003
editorials
1965
pril, or both in myocardial infarction complicated by heart failure,
left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-
906.
6.
Cohn JN, Tognoni G. A randomized trial of the angiotensin-
receptor blocker valsartan in chronic heart failure. N Engl J Med
2001;345:1667-75.
7.
McMurray JJ, Ostergren J, Swedberg K, et al. Effects of cande-
sartan in patients with chronic heart failure and reduced left-ventric-
ular systolic function taking angiotensin-converting-enzyme inhib-
itors: the CHARM-Added trial. Lancet 2003;362:767-71.
8.
Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan com-
pared with captopril on mortality in patients with symptomatic
heart failure: randomised trial — the Losartan Heart Failure Survival
Study ELITE II. Lancet 2000;355:1582-7.
9.
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan
on renal and cardiovascular outcomes in patients with type 2 diabe-
tes and nephropathy. N Engl J Med 2001;345:861-9.
10.
Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular mor-
bidity and mortality in the Losartan Intervention For Endpoint re-
duction in hypertension study (LIFE): a randomised trial against
atenolol. Lancet 2002;359:995-1003.
Copyright © 2003 Massachusetts Medical Society.
Removal of Expression of Concern: Schiffl H, et al.
Daily Hemodialysis and the Outcome of Acute Renal Failure.
N Engl J Med 2002;346:305-10.
Jeffrey M. Drazen, M.D., Julie R. Ingelfinger, M.D., and Gregory D. Curfman, M.D.
In the issue of January 31, 2002, we published a
study by Helmut Schiffl, M.D., Susanne M. Lang,
M.D., and Rainald Fischer, M.D.
1
It came to our at-
tention, through communication with Klaus Peter,
Dean of the Medical Faculty at Ludwig Maximilians
University in Munich, Germany, that there was an
ongoing investigation into potential scientific mis-
conduct in the performance of the study. We there-
fore published an expression of concern.
2
We have
now received a note from Dr. Peter concerning that
investigation that reads, in part, as follows:
“This is to inform you that the office of the rec-
tor of the university has informed us that the perma-
nent commission of evaluation of scientific mis-
conduct has concluded that no conclusive proof of
scientific misconduct exists and has therefore closed
the investigation.”
Accordingly, the
Journal
is officially removing its
expression of concern.
1.
Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the out-
come of acute renal failure. N Engl J Med 2002;346:305-310.
2.
Drazen JM, Ingelfinger JR, Curfman GD. Expression of con-
cern: Schiffl H, et al. Daily hemodialysis and the outcome of acute
renal failure. N Engl J Med 2002;346:305-10. N Engl J Med 2003;
348:2137.
Copyright © 2003 Massachusetts Medical Society.
Downloaded from www.nejm.org by DR JOHN FJ BAYLISS on November 15, 2003.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
