The New England Journal of Medicine

Original Article
Volume 345:1667-1675

December 6, 2001

Number 23
A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic
Heart Failure
Jay N. Cohn, M.D., Gianni Tognoni, M.D., for the Valsartan Heart Failure
Trial Investigators
ABSTRACT
Background Actions of angiotensin II may contribute to the progression of
heart failure despite treatment with currently recommended drugs. We
therefore evaluated the long-term effects of the addition of the
angiotensin-receptor blocker valsartan to standard therapy for heart
failure.
Methods A total of 5010 patients with heart failure of New York Heart
Association (NYHA) class II, III, or IV were randomly assigned to receive
160 mg of valsartan or placebo twice daily. The primary outcomes were
mortality and the combined end point of mortality and morbidity, defined as
the incidence of cardiac arrest with resuscitation, hospitalization for
heart failure, or receipt of intravenous inotropic or vasodilator therapy
for at least four hours.
Results Overall mortality was similar in the two groups. The incidence of
the combined end point, however, was 13.2 percent lower with valsartan than
with placebo (relative risk, 0.87; 97.5 percent confidence interval, 0.77 to
0.97; P=0.009), predominantly because of a lower number of patients
hospitalized for heart failure: 455 (18.2 percent) in the placebo group and
346 (13.8 percent) in the valsartan group (P<0.001). Treatment with
valsartan also resulted in significant improvements in NYHA class, ejection
fraction, signs and symptoms of heart failure, and quality of life as
compared with placebo (P<0.01). In a post hoc analysis of the combined end
point and mortality in subgroups defined according to base-line treatment
with angiotensin-converting–enzyme (ACE) inhibitors or beta-blockers,
valsartan had a favorable effect in patients receiving neither or one of
these types of drugs but an adverse effect in patients receiving both types
of drugs.
Conclusions Valsartan significantly reduces the combined end point of
mortality and morbidity and improves clinical signs and symptoms in patients
with heart failure, when added to prescribed therapy. However, the post hoc
observation of an adverse effect on mortality and morbidity in the subgroup
receiving valsartan, an ACE inhibitor, and a beta-blocker raises concern
about the potential safety of this specific combination.
  _____

Pharmacotherapy for heart failure has advanced considerably in recent years
as clinical trials have demonstrated favorable long-term effects of
angiotensin-converting–enzyme (ACE) inhibitors 1
<http://content.nejm.org/cgi/content/full/345/23/#R1> , 2
<http://content.nejm.org/cgi/content/full/345/23/#R2> , 3
<http://content.nejm.org/cgi/content/full/345/23/#R3>  and beta-blockers 4
<http://content.nejm.org/cgi/content/full/345/23/#R4> , 5
<http://content.nejm.org/cgi/content/full/345/23/#R5> , 6
<http://content.nejm.org/cgi/content/full/345/23/#R6>  on morbidity and
mortality. Despite the use of these potent drugs, heart failure remains the
leading reason for hospitalization in the Medicare population, 7
<http://content.nejm.org/cgi/content/full/345/23/#R7>  mortality among
patients with heart failure is high, and the quality of life is low.
Angiotensin II, a potent vasoconstrictor and growth-stimulating hormone, may
contribute to the impairment of left ventricular function and the
progression of heart failure through increased impedance of left ventricular
emptying, 8 <http://content.nejm.org/cgi/content/full/345/23/#R8>  adverse
long-term structural effects on the heart and vasculature, 9
<http://content.nejm.org/cgi/content/full/345/23/#R9>  and potentially
deleterious activation of other neurohormonal agonists, including
norepinephrine, aldosterone, and endothelin. 10
<http://content.nejm.org/cgi/content/full/345/23/#R10>  Since previous
studies have shown that physiologically active levels of angiotensin II
persisted despite long-term therapy with an ACE inhibitor, 11
<http://content.nejm.org/cgi/content/full/345/23/#R11> , 12
<http://content.nejm.org/cgi/content/full/345/23/#R12>  we undertook a study
to determine whether the angiotensin-receptor blocker valsartan could
further reduce morbidity and mortality among patients who were already
receiving the pharmacologic therapy that was considered optimal by their
physicians. Descriptions of the rationale for and design of this trial have
been published elsewhere. 13
<http://content.nejm.org/cgi/content/full/345/23/#R13>
Methods
Study Design
The Valsartan Heart Failure Trial (Val-HeFT) was a randomized,
placebo-controlled, double-blind, parallel-group trial. Patients at 302
centers in 16 countries gave written informed consent for participation in
the trial, which was approved by the institutional review board at each
center. The investigation conformed to the principles of the Declaration of
Helsinki. Site monitoring, data collection, and data analysis were performed
by Novartis Pharmaceuticals. An independent end-points committee adjudicated
all reports of primary end points. An independent data and safety monitoring
board reviewed biannual interim analyses. The manuscript was prepared by the
authors and reviewed by the steering committee and the sponsor.
Eligibility
Men and women 18 years old or older with a history and clinical findings of
heart failure for at least three months before screening were eligible.
Patients had heart failure of New York Heart Association (NYHA) class II,
III, or IV and were clinically stable. To be eligible, they had to have been
receiving for at least two weeks a fixed-dose drug regimen that could
include ACE inhibitors, diuretics, digoxin, and beta-blockers. In addition,
they had to have documented left ventricular dysfunction with an ejection
fraction of less than 40 percent and left ventricular dilatation with an
echocardiographically measured short-axis internal dimension at end diastole
greater than 2.9 cm per square meter of body-surface area. Echocardiograms
were analyzed locally after the technical and reader quality at each center
had been validated by one of three core laboratories (in Los Angeles; Milan,
Italy; or Stockholm, Sweden) that also monitored quality control during the
study. Criteria for exclusion have been published previously. 13
<http://content.nejm.org/cgi/content/full/345/23/#R13>
Placebo Run-in Period
Patients were assessed for two to four weeks to confirm their eligibility,
clinical stability, and compliance while taking placebo in a single-blind
fashion twice daily. Base-line evaluations included laboratory tests for
hematologic variables and blood chemistry; urinalysis; echocardiography;
12-lead electrocardiography; and chest radiography. Quality of life was
assessed with the Minnesota Living with Heart Failure questionnaire, which
was administered to 60 percent of patients — that is, those in the United
States, the United Kingdom, Australia, and Italy.
Randomization and Dose Adjustment
Eligible patients, stratified according to whether or not they were
receiving a beta-blocker as background therapy, were randomly assigned to
receive oral valsartan or matching placebo. Stratification was performed to
ensure the equal distribution of patients receiving these drugs in the two
groups. Randomization occurred after the base-line eligibility data were
verified by the coordinating centers in Minneapolis and Milan. Valsartan was
initiated at a dose of 40 mg twice daily, and the dose was doubled every two
weeks until a target dose of 160 mg twice daily was reached. Placebo doses
were similarly adjusted. The criteria for increasing the dose included a
systolic blood pressure of 90 mm Hg or higher while the patient was
standing, the absence of symptoms of hypotension, and a serum creatinine
concentration of less than 2.0 mg per deciliter (177 µmol per liter) or no
more than 50 percent higher than the base-line concentration. Patients
returned for follow-up visits at two, four, and six months and every three
months thereafter.
Outcome Measures
The study was designed with two primary end points: mortality and the
combined end point of mortality and morbidity, which was defined as cardiac
arrest with resuscitation, hospitalization for heart failure, or
administration of intravenous inotropic or vasodilator drugs for four hours
or more without hospitalization. Secondary cardiovascular outcomes included
the changes from base line to the last available observation after treatment
had begun in ejection fraction, NYHA functional class, quality-of-life
scores, and signs and symptoms of heart failure.
Statistical Analysis
Statistical analyses were performed at an overall significance level of
0.05, adjusted for the two primary end points. Each primary end point was
tested at a two-sided significance level of 0.02532, on the basis of the
Dunn–Sidak inequality: {alpha}'=1–(1–{alpha})1/2. The significance level for
the analysis of the time to death was further adjusted for five biannual
interim analyses according to the O'Brien–Fleming alpha-spending function.
Therefore, the final analysis for the time to death was performed at a
two-sided significance level of 0.02.
The calculation of sample size was based on the time-to-death end point. The
number of deaths that would be required to detect, with 90 percent power, a
20 percent difference between the death rate with valsartan and that with
placebo (estimated at 12 percent per year) was calculated to be 906. We
planned to enroll 2500 patients per treatment group.
Comparisons of the primary end points between treatment groups were
performed by means of a log-rank test. To estimate the size of the effect,
we used a Cox regression model with prespecified base-line covariates,
including NYHA class, ejection fraction (above or below the median), cause
of heart failure (ischemic or nonischemic), age (younger than 65 years or 65
years old or older), ACE inhibitor use or nonuse, and beta-blocker use or
nonuse. Confidence intervals of 98 percent and 97.5 percent were calculated
for mortality and the combined end point of mortality and morbidity,
respectively. To estimate the size of the effect on the secondary end points
and in subgroups, relative risks with 95 percent confidence intervals were
calculated with the use of the Cox regression model.
Results
Of the 5010 patients who underwent randomization, 2511 were assigned to
receive valsartan and 2499 to receive placebo, all with background therapy
for heart failure. There were no clinically relevant differences in the
base-line characteristics of the two groups ( Table 1
<http://content.nejm.org/cgi/content/full/345/23/#T1> ). A description of
the base-line demographic characteristics of this diverse population has
been published previously. 14
<http://content.nejm.org/cgi/content/full/345/23/#R14>  At the time of
randomization, 93 percent of the patients were being treated with ACE
inhibitors. The average daily doses were 17 mg of enalapril, 19 mg of
lisinopril, 80 mg of captopril, 6 mg of ramipril, and 23 mg of quinapril.
Thirty-five percent of the patients were receiving beta-blockers (15 percent
were receiving carvedilol, 12 percent metoprolol, and 3 percent atenolol),
and randomization was stratified according to their use or nonuse; this
percentage remained stable throughout the study. Only 5 percent of the
patients were treated with spironolactone. The overall mean duration of
follow-up was 23 months (range, 0 to 38).


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Table 1. Base-Line Characteristics of the Patients According to Treatment
Group.

The target dose was achieved in 84 percent of the patients receiving
valsartan (mean dose, 254 mg) and 93 percent of those receiving placebo
(mean equivalent dose, 283 mg). Systolic blood pressure was reduced to a
greater extent with valsartan than placebo: at four months, it was reduced
by a mean (±SD) of 5.2±15.8 mm Hg in the valsartan group, as compared with
1.2±14.8 mm Hg in the placebo group, and at one year the reductions were
5.2±16.0 mm Hg and 1.3±15.9 mm Hg, respectively. The mean heart rate was
unchanged.
Primary End Points
Mortality was similar in the two treatment groups ( Figure 1
<http://content.nejm.org/cgi/content/full/345/23/#F1>  and Table 2
<http://content.nejm.org/cgi/content/full/345/23/#T2> ). The adjudicated
causes of death were also similar in the two treatment groups (there were
262 sudden deaths from cardiac causes in the valsartan group and 258 in the
placebo group, and there were 118 deaths due to heart failure in the
valsartan group and 125 in the placebo group).


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Figure 1. Kaplan–Meier Analysis of the Probability of Survival.



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Table 2. Incidence and Relative Risk of the Primary End Points.

The combined end point of mortality and morbidity was significantly reduced
among patients receiving valsartan as compared with those receiving placebo
(P=0.009) ( Figure 2
<http://content.nejm.org/cgi/content/full/345/23/#F2> ). The benefit
appeared early after randomization and increased throughout the trial. Among
the patients in the valsartan group, 723 (28.8 percent) reached the combined
end point, as compared with 801 patients (32.1 percent) in the placebo
group — a 13.2 percent reduction in risk with valsartan (relative risk,
0.87; 97.5 percent confidence interval, 0.77 to 0.97) ( Table 2
<http://content.nejm.org/cgi/content/full/345/23/#T2> ). The predominant
benefit in terms of the combined end point was a 24 percent reduction in the
rate of adjudicated hospitalizations for worsening heart failure as a first
event in those receiving valsartan (13.8 percent) as compared with those
receiving placebo (18.2 percent) (P<0.001) ( Table 2
<http://content.nejm.org/cgi/content/full/345/23/#T2> ).


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Figure 2. Kaplan–Meier Analysis of the Probability of Freedom from the
Combined End Point (Death from Any Cause, Cardiac Arrest with Resuscitation,
Hospitalization for Worsening Heart Failure, or Therapy with Intravenous
Inotropes or Vasodilators).

Secondary End Points
The risk of a hospitalization for heart failure (with censoring of the data
for patients who died) was reduced by 27.5 percent with valsartan (P<0.001).
There were 1189 nonadjudicated hospitalizations for heart failure in the
placebo group and 923 in the valsartan group (P=0.002). Since
hospitalizations for problems other than heart failure were unaffected, the
rate of hospitalizations for any cause was reduced similarly — by 250
events, from 3106 in the placebo group to 2856 in the valsartan group
(P=0.14). The mean change in ejection fraction from base line to the last
observation was 4.0 percent in the valsartan group and 3.2 percent in the
placebo group (P=0.001). More patients in the valsartan group than in the
placebo group had improvements in NYHA classification (23.1 percent vs. 20.7
percent) and fewer had worsening (10.1 percent vs. 12.8 percent) (P<0.001).
Similarly, dyspnea, fatigue, edema, and rales were more favorably affected
by valsartan than by placebo (P<0.01). Among the 1504 patients in the
valsartan group to whom the Minnesota Living with Heart Failure
questionnaire was administered, there was little change in scores from base
line to the end point, but among the 1506 such patients in the placebo
group, the mean score worsened by an average of 1.9 (P=0.005 for the
comparison between the treatment groups).
Subgroup Analyses
The beneficial effect of valsartan on the combined mortality–morbidity end
point was generally consistent among the predefined subgroups of patients.
Valsartan improved the outcome in young and old patients, men and women,
those with and without diabetes or coronary artery disease, those with
ejection fractions or left ventricular dimensions above and below the
median, and those with NYHA class II and class III or IV symptoms ( Figure 3
<http://content.nejm.org/cgi/content/full/345/23/#F3> ). In the small,
heterogeneous black population (which included 344 African-American and
South African patients), there was a wide confidence interval for relative
risk of the combined end point with valsartan that included 1.0 (relative
risk, 1.11; 95 percent confidence interval, 0.77 to 1.61).


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Figure 3. Relative Risks and 95 Percent Confidence Intervals for the
Combined End Point, According to Demographic and Clinical Characteristics.
Patients found to be in New York Heart Association (NYHA) class I were not
included in the analysis of severity of disease. Two patients did not have
an ejection-fraction measurement at base line.

Background therapy with neurohormonal inhibitors appeared to influence the
response to valsartan ( Figure 4
<http://content.nejm.org/cgi/content/full/345/23/#F4> ). The patients were
divided into four subgroups on the basis of the use or nonuse of
ACE-inhibitor and beta-blocker therapy at base line. The global test for the
interaction between treatment and subgroup among the four subgroups was
statistically significant for mortality (P=0.009) and the combined end point
of mortality and morbidity (P=0.001). In the three groups receiving neither
drug or either ACE inhibitors or beta-blockers alone, there was a
significantly favorable effect of valsartan on the rate of the combined end
point (P=0.003, P=0.002, and P=0.037, respectively) and a favorable point
estimate of the odds ratio for death. Mortality was significantly reduced in
the 226 patients who were treated with neither an ACE inhibitor nor a
beta-blocker (P=0.012). Among those who were receiving both drugs at base
line, valsartan had an adverse effect on mortality (P=0.009) and was
associated with a trend toward an increase in the combined end point of
mortality and morbidity (P=0.10). Among all 366 patients who were not
receiving an ACE inhibitor, whether or not a beta-blocker had been
prescribed, there was a significantly lower risk of the combined end point
in the valsartan group than in the placebo group (relative risk, 0.56; 95
percent confidence interval, 0.39 to 0.81), as well as a lower risk of death
(relative risk, 0.67; 95 percent confidence interval, 0.42 to 1.06).


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Figure 4. Relative Risks and 95 Percent Confidence Intervals for the
Combined End Point (Death from Any Cause, Cardiac Arrest with Resuscitation,
Hospitalization for Worsening Heart Failure, or Therapy with Intravenous
Inotropes or Vasodilators), According to the Background Therapy at Base
Line, as Calculated by Means of a Cox Regression Model.
ACE denotes angiotensin-converting enzyme, + the use of the drug, and –
nonuse.

Safety
Valsartan therapy was generally well tolerated. Adverse events leading to
the discontinuation of the drug occurred in 249 of the patients receiving
valsartan (9.9 percent) and 181 patients receiving placebo (7.2 percent)
(P<0.001). The adverse events leading to discontinuation and occurring in
more than 1 percent of the patients in the valsartan group included
dizziness (in 1.6 percent of the patients and 0.4 percent of those in the
placebo group; P<0.001), hypotension (1.3 percent and 0.8 percent,
respectively; P=0.124), and renal impairment (1.1 percent and 0.2 percent,
P<0.001). Overall, the mean change from base line in the blood urea nitrogen
concentration was an increase of 5.9 mg per deciliter (2.1 mmol per liter)
with valsartan and an increase of 3.3 mg per deciliter (9.2 mmol per liter)
with placebo (P<0.001). The mean change in the serum creatinine
concentration was an increase of 0.18 mg per deciliter (15.9 µmol per liter)
with valsartan and an increase of 0.10 mg per deciliter (8.8 µmol per liter)
with placebo (P<0.001). The mean change in the serum potassium concentration
was an increase of 0.12 mmol per liter with valsartan and a decrease of 0.07
mmol per liter with placebo (P<0.001).
Discussion
Our study was designed to assess the efficacy of the angiotensin-receptor
blocker valsartan when added to prescribed therapy for heart failure. The
benefit in terms of morbidity and mortality was achieved in a population in
which 93 percent of patients were treated with an ACE inhibitor and 35
percent were treated with a beta-blocker. The outcomes suggest that even
with the use of currently prescribed therapy, angiotensin contributes to
morbidity but not mortality in patients with heart failure. An unexpected
finding emerged, however, from a post hoc analysis of the data on
concomitant therapy. Within the 30 percent of the population that was being
treated with both an ACE inhibitor and a beta-blocker at base line, there
was a significant adverse effect of valsartan on mortality and a nearly
significant adverse effect on morbidity. Clarification of whether this
finding represents a true interaction or is attributable to chance must
await the outcome of ongoing trials evaluating the combination of an
angiotensin-receptor blocker with an ACE inhibitor and a beta-blocker. Since
only 5 percent of the patients in the trial were receiving spironolactone,
an aldosterone-receptor blocker, 15
<http://content.nejm.org/cgi/content/full/345/23/#R15>  we cannot assess the
efficacy or safety of valsartan when given in combination with
spironolactone.
The protocol was designed with two primary end points and appropriate
statistical adjustment. Although mortality was similar in the two treatment
groups, a significant favorable effect of valsartan on cardiovascular
morbidity was evident, primarily as a result of a 24 percent reduction in
adjudicated (first) hospitalizations for heart failure and a similar
reduction in all nonadjudicated (subsequent) hospitalizations for heart
failure. The favorable effect was achieved with a target dose of 160 mg
twice daily; this dose was chosen because of its hemodynamic and hormonal
effects, which were documented in a pilot study involving patients who were
receiving ACE-inhibitor therapy. 16
<http://content.nejm.org/cgi/content/full/345/23/#R16>  The dose was well
tolerated; most patients achieved the target dose, and side effects were
only slightly more prevalent than in the placebo group.
This study differed from previous trials of angiotensin-receptor blockers in
heart failure, such as the Losartan Heart Failure Survival Study 17
<http://content.nejm.org/cgi/content/full/345/23/#R17>  and the Randomized
Evaluation of Strategies for Left Ventricular Dysfunction, 18
<http://content.nejm.org/cgi/content/full/345/23/#R18>  in terms of the high
dose we used, our large sample size, and the use of valsartan as a balanced,
placebo-controlled add-on to background therapy.
The reduction in cardiovascular morbidity has relevance for the economic
burden of heart failure on the health care system. In addition, the moderate
but statistically significant benefit in terms of the secondary end points —
NYHA class, quality of life, signs and symptoms of heart failure, and left
ventricular ejection fraction — is consistent with an overall incremental
benefit of valsartan for patients with heart failure who are receiving
medical therapy.
The negative effect of angiotensin II on heart failure could be mediated
through a vasoconstrictor-induced increase in blood pressure or a direct
effect on cardiac and vascular tissues. Since systolic blood pressure was an
average of 5 mm Hg lower in patients who were randomly assigned to receive
valsartan than in those assigned to receive placebo, a hemodynamic mechanism
may account, at least in part, for the observed benefit. Nonetheless, the
growth-promoting and apoptotic effects of angiotensin II have been well
demonstrated 9 <http://content.nejm.org/cgi/content/full/345/23/#R9> , 19
<http://content.nejm.org/cgi/content/full/345/23/#R19>  and may contribute
to the structural remodeling that promotes the progression of heart failure.
20 <http://content.nejm.org/cgi/content/full/345/23/#R20> , 21
<http://content.nejm.org/cgi/content/full/345/23/#R21> , 22
<http://content.nejm.org/cgi/content/full/345/23/#R22> , 23
<http://content.nejm.org/cgi/content/full/345/23/#R23> , 24
<http://content.nejm.org/cgi/content/full/345/23/#R24>  A long-term increase
in the ejection fraction has been identified as a marker of regression of
left ventricular remodeling that is manifested as reduced chamber volume. 25
<http://content.nejm.org/cgi/content/full/345/23/#R25> , 26
<http://content.nejm.org/cgi/content/full/345/23/#R26>  This structural
effect has been associated with an improvement in survival. 27
<http://content.nejm.org/cgi/content/full/345/23/#R27> , 28
<http://content.nejm.org/cgi/content/full/345/23/#R28>  In our study, the
increase in the ejection fraction was more moderate than in previous trials
of ACE inhibitors and beta-blockers and was not associated with reduced
mortality. The absence of a more robust effect may be related to the
effectiveness of the other therapy received by the patients (annual
mortality in the placebo group was 9 percent, rather than the predicted 12
percent).
Subgroup analysis is used in large-scale trials to confirm the
generalizability of the findings or, if inconsistencies are observed, to
generate hypotheses about subgroup responses to be tested in subsequent
studies. In our study, subgroups defined on the basis of demographic
characteristics or base-line clinical characteristics generally had
responses that were similar to those in the study population as a whole.
Background neurohormonal-inhibitor therapy, however, appeared to influence
the outcome. Since this background therapy was not controlled and patients
were only partially stratified according to its presence or absence at
randomization (according to the use of beta-blockers but not ACE
inhibitors), the data generated by this analysis must be interpreted with
caution. Nonetheless, in the small subgroup of patients (7 percent) who were
not being treated with an ACE inhibitor, there was a 44.0 percent reduction
in the combined end point of mortality and morbidity and a 33.1 percent
reduction in mortality.
The point estimate of the odds ratio favored valsartan in all subgroups
except the subgroup of patients who were being treated with both an ACE
inhibitor and a beta-blocker at base line. As previously noted, the apparent
adverse effect of valsartan in this subgroup leads to the hypothesis that
the extensive blockade of multiple neurohormonal systems in patients with
heart failure could be deleterious. Recent clinical-trial experience with
moxonidine, 29 <http://content.nejm.org/cgi/content/full/345/23/#R29>
endothelin-receptor antagonists, and cytokine inhibitors 30
<http://content.nejm.org/cgi/content/full/345/23/#R30>  is consistent with
this hypothesis. Several trials involving substantial numbers of patients
who are receiving these three classes of neurohormonal inhibitors are
ongoing and can be expected to provide additional data relevant to this
safety concern.
Although current guidelines recommend ACE inhibitors and beta-blockers as
standard therapy for heart failure because of their demonstrated benefit in
terms of mortality, only one third of the patients enrolled in our study
were receiving both classes of drugs. Furthermore, patients who were already
being treated with angiotensin-receptor blockers, which are widely
prescribed for patients who are intolerant of ACE inhibitors, were excluded
from the study. Improved compliance with the guidelines may reduce the
number of inadequately treated patients. Nonetheless, the benefit of
valsartan in terms of the combined end point of mortality and morbidity that
was found in all subgroups except that receiving both ACE inhibitors and
beta-blockers suggests that the drug could have a role in the management of
the syndrome.
<http://weeklybriefings.org/feature.asp?strXmlDoc=3452303>
Supported by a grant from Novartis Pharma, Basel, Switzerland. Drs. Cohn and
Tognoni have had research support and consultation arrangements with
Novartis Pharmaceuticals, the sponsor of this study.
Presented in part at the American Heart Association meeting, New Orleans,
November 12–15, 2000.
* The investigators are listed in the Appendix.
<http://content.nejm.org/cgi/content/full/345/23/#RFN1>

Source Information
From the Cardiovascular Division, Department of Medicine, University of
Minnesota Medical School, Minneapolis (J.N.C.); and the Mario Negri
Institute, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto
Miocardico, Milan, Italy (G.T.).
Address reprint requests to Dr. Cohn at the Cardiovascular Division, Mayo
Mail Code 508, University of Minnesota Medical School, 420 Delaware St., SE,
Minneapolis, MN 55455.
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Appendix
The Valsartan Heart Failure Trial Investigators included the following: in
the United States: Alabama — R. Bourge, D. Calhoun, B. Foley, L. Lowe, S.
Oparil, G. Perry, B. Rayburn, B. Sanders; Arizona — J.E. Boulet, J.
Christensen, P. Fenster, S. Heumiller, R. Lee, P. McGowan, J. Ohm, R.
Siegel, T. Struiksma; California — J.W. Allen, J. Backman, P. Coleman, D.
Costello, T.A. Cox, P. Deedwania, L. Defensor, G. Dennish, W.A. Edmiston, D.
Everitt, S. Fabbri, C. Faulkner, J. Gilbert, J.I. Gorwit, S. Harte, L.A.
Hawkins, J. Hemphill, J.T. Heywood, B. Jackson, B. Jaski, S. Khan, D.
McAdams, P. Pak, N. Parker, R. Shabetai, H. Shively, J. Sklar, L. Sprinkle,
R. Stein, P. Waack, R. Wadlington, R. Wright, L.G. Yellen; Connecticut — S.
Carolan, I.S. Cohen, M.B. Fowler, M. Martin-O'Brien, A. Mullin, T. Ramahi,
K. Rholfs; District of Columbia — D.J. Diver, N. Douglas-Kersellious, D.
Lee, S. Singh; Florida — J. Anderson, J. Bauerlein, M. Bayer, G. Cintron, S.
Brenner, C. Davenport, S.L. Duncan, P. Green, T.C. Hilton, H. Karunaratne,
A. Kinsella, G. Lamas, M. Mayor, M. McIvor, M.R. Milunski, M.A. Nocero, J.
O'Bryan, J. Reddinger, D. Samada, C.R. Stastny, M. Taylor, H. Tee, J.L.
Walker, V. Wilson; Georgia — S. Beer, A. Carr, J. Grace, J. Guidot, S. Holt,
K. Taylor, W.R. Taylor, P. Yaun; Illinois — K. Furlong, M. Johnson, R. Lang,
H. Loeb; Indiana — J. Becker, J. Birt, L. Ford; Iowa — R. Oren, P. Scovall,
W. Wickemeyer, N. Young; Kansas — M. Bowles; Kentucky — K. Doerschuk, S.
Wagner; Louisiana — B. Iteld; Maryland — L. Black, S. Gottlieb, S.O.
Gottlieb, N. Greenberg, D. Lowry; Massachusetts — A. Burger, M. Burger, K.
Coleman, M. Criasia, W. Dec, C. Haggan, T. Meyer, M. Motta, P. Shrewe, J.
Smith; Michigan — P.A. Kaminski, D. Langholtz, A.B. Levine, T.B. Levine, J.
Nicklas, R. Rose; Minnesota — I. Anand, S. Berg, A. Holmstrom, B. Merkle, L.
Miller; Missouri — K. Aggarwal, E. Geltman, M. Gilbert, B. Lee, C. Hinden,
D. Yip; Nevada — A. Cason-Pitcher, R. Croke, A. Steljes; New Jersey — R.
Berkowitz, H.S. Ribner, J. Strobeck, P. Tabachnik, M.J. Zucker; New Mexico —
M. Conway, P. Doherty, R. Dubroff, S. Justice; New York — M. Applegate, L.
Baruch, C. Buchholz-Varley, J. Cappelli, M.E. Coglianese, J. Corbelli, T.
Costantino, M.A. Goodman, S. Graham, V. Hart, M. Kukin, O. Ocampo, W.
Orlowski, P. Patacsil, N. Schulhoff, P. Stein, R.M. Steingart, B.H. Sung,
M.F. Wilson; North Carolina — R. Bilbro, F. Cobb, G. Dodson, D. Framm, K.
Harshaw-Ellis, M. Higginbotham, B. Kuzil, G. Weidner; Ohio — D.J. Kereiakes,
R. Lengerich, L.L. Wohlford; Oklahoma — J. Anderson, J. Cook, M. Dickson,
R.D. Ensley, S. Jameson, J. Kalbfleisch, C. Melson-Alsip, D. Simmons;
Oregon — R. Hershberger, L. Keilson; Pennsylvania — M. Amidi, M. Bell, J.
Boehmer, E. Loh, P.J. Mather, S. Rubin, R. Shannon, I. Smith, R.
Weller-Moore, S. Worley; Rhode Island — A. Sadaniantz; South Carolina — J.
Evans, G. Hendrix; Tennessee — L. Chismark, W.G. Friesen, S. Gubin, L.
Howerton, J. Jeanes, F. McGrew, J. Osborn, K.B. Ramanathan, R. Smith;
Texas — N. Baradhi, L.A. Campos, R. Carney, S.E. El Hafi, R. Gammon, J.D.
Jackman, C. Janes, D. McCarroll, F. Navetta, M. Rotman, A. Smith; Utah —
J.J. Perry; Virginia — J. Bergin, J. Herre, J. O'Brien; Washington — B.
Crane, D. Fishbein, J. Forster, M. Hall; Wisconsin — C.V. Hughes, J.
Hosenpud, R. Siegel, C.R. Vander Ark, P.A. Wiederholt; outside the United
States: Australia — J. Amerena, I. Button, R. Calvert, M. Croot, P. Garrahy,
C. Hall, H. Hankey, D. Hogan, D. Hollens-Riley, J. Horowitz, L. Howes, B.
Jackson, I. Jeffrey, J. Karrasch, S. Leslie, H. Krum, L. Martin, B. Singh,
P. Taverner, A. Thomson, P. Thompson; Belgium — S. Degré, P. De Vusser, W.
Droogné, P. Noyens, A.Z.J. Palfijn, A. Strijckmans, J. Vanhaecke, W. Van
Mieghem, J. Vanwelden; Czech Republic — R. Cifkova, J. Gregor, J. Simon, J.
Toman, J. Vojacek, J. Widimsky; Denmark — O. Gøtzsche, T. Haghfelt, P.
Hildebrandt, E. Kassis, T. Toftegaard Nielsen; Finland — E. Engblom, J.
Hartikainen, S. Majahalme, M. Niemelä, K. Peuhkurinen, M. Pietilä, J.
Taurio, L.M. Voipio-Pulkki; France — P. Lechat, M. Baudet, M. Bory, A.
Cohen, P. Coumel, M. Dahan, J.M. Davy, Y.M. Frances, M. Galinier, M.
Guediche, G. Jarry, J.P. Ollivier, L. Slimane, M. Zaouali; Germany — C.
Bergmeier, K.O. Bischoff, C.G. Brilla, J. Cyran, W.G. Daniel, M. Dürsch, E.
Fleck, L. Goedel-Meinen, R. Griebenow, R. Hambrecht, M. Hamel, K.H. Hauff,
G. Haustein, C. Helzer-Arbeiter, D. Hey, T. Hoefs, M. Hofmann, T. Kleemann,
D. Koch, N. Kokott, T. Langenickel, E. Lopez, T. Matthes, V. Mitrovic, E.
Mueser, K.H. Munderloh, S. Philipp, V. Regitz-Zagrosek, A. Rouwen, R.
Rummel, A. Schmidt, J. Senges, K. Stumpe, H. Topp, C. Weiler, R.
Willenbrock, S. Winkler; Hungary — M. Csanady, I. Edes, K. Farkas, C.
Farsang, T. Forster, T. Fulop, A. Janosi, L. Mezei, M. Nemeth, E. Palkovi,
E. Szigeti; Italy — M.C. Albanese, G. Alunni, G. Ansalone, B. Aloisi, I.
Belloni, R. Belluschi, D. Bertoli, I. Bisceglia, G.M. Boffa, E. Bosi, A.
Branzi, E. Butti, L. Cacciavillani, C. Campana, S. Capomolla, G.
Castiglioni, A. Cavalli, V. Ceci, E. Cerè, V. Cirrincione, F. Cobelli, G.
Corsini, A.L. Cuzzato, F. De Santis, G. Di Pasquale, M. Farruggio, C.
Fresco, G. Ferrari, G. Filorizzo, G. Foti, A. Fraticelli, F.A. Galati, K.
Ghebremarian-Tesfau, F. Giancotti, P. Giannuzzi, G. Gibelli, A. Giordano, E.
Giovannini, S. Gramenzi, F. Ingrillì, S. Lombroso, F. Longaro, L. Magliani,
C. Manes, R. Mangia, G. Misuraca, R. Mocchegiani, A.P. Morciano, G. Occhi,
M. Olivieri, M. Palvarini, R. Panciarola, L. Pasetti, S. Pede, R. Pedretti,
G.P. Perini, F. Perticone, G. Pettinati, F. Plastina, M. Porcu, C.
Porcellati, F. Pozzar, G. Pulignano, C. Rapezzi, F. Rusconi, A. Sanna, M.
Santini, V. Santoro, S. Scalvini, F. Scapellato, A.M. Schillaci, C.
Schweiger, G. Sinagra, D. Staniscia, P. Tanzi, L. Tavazzi, E. Uslenghi, G.
Ventura, A. Vetrano, E. Zanelli; the Netherlands — M. Baselier, P. Bruels,
P.W.F. Bruggink, F. Den Hartog, P. Dunselman, P. Fels, G. Geurts, H.
Groeneveld, B. Hamer, N. Holwerda, J. Kragten, G. Laarman, J. Levert, A.
Liem, P. Lindner, H.R. Michels, G. Paulussen, J.L. Posma, H.J. Schaafsma,
W.M. Siesverda, L.C. Slegers, P. van der Burgh, E.C.M. van der Velden,
A.J.J. van Es, L. van Kempen, H. van Kesteren, R. van Rijswijk, P. van
Rossum, D.J. Heijden, J.C.L. Wesdorp, A. Willems, A. Withagen; Norway — M.
Bjurstroem, A. Hervold, T.O. Klemsdal, K. Knutsen, T. Lappegaard, S.
Solheim, S. Toft, K.V. Tuseth, A. Westheim, T. Wessel-Aas; South Africa —
L.J. Burgess, P.J. Commerford, Y. Govender, E. Klug, P. Manga, F. Maritz,
D.P. Naidoo, L. Opie, H.W. Prozesky, D. Smith; Spain — A. Aguilar Llopis, E.
Asin Cardiel, V. Barrios Alonso, A. Bayes De Luna, J. Bayon Fernandez, J.L.
Diago Torrent, E. Galve Basilio, M. Gil De La Peña, M. Gómez Gerboles, E.
Homs Espinach, I. Iglesias Garriz, J. Julia Gibergans, A. López Granados, A.
Mallol Kirchner, N. Manito Lorite, R. Masia Martorell, J. Orus, J. Padro
Dalmau, F. Pérez Villa, J. Roca Elias, E. Roig Minguell, J. Soler Soler, F.
Valles Belsue; Sweden — A. Andersson, H. Brodersson, S. Ekdahl, J. Ellström,
S. Hansen, J. Herlitz, L. Hjelmaeus, C. Höglund, B. Karlsson, P. Katzman, L.
Ljungdahl, M. Lundblad, H. Tygesen, C. Wettervik, L. Winberg; United
Kingdom — A. Baksi, A. Blackwell, C. Cope, D. Connelly, T.R. Cripps, G.
Dadahl, M.K. Ghosh, S. Gibbs, S. Gupta, M.E. Heber, P.J.B. Hubner, G.D.
Johnston, N. Jones, J. Kooner, R. Levy, D. Lubel, P. Nicholls, A. Rozkovec,
P. Schofield, E. Smith, I.B. Squire, L.B. Tan, C. Welsh, S. Williams;
Executive Committee — J.N. Cohn (chair), G. Tognoni (co-chair), R.D. Glazer,
D. Spormann; Steering Committee — J.N. Cohn (chair), G. Tognoni (co-chair),
H. Krum, J. Vanhaecke, J. Widimsky, T. Haghfelt, S. Majahalme, P. Lechat, K.
Stumpe, L. Tan, C. Farsang, L. Tavazzi, N.J. Holwerda, A. Westheim, L. Opie,
A. Bayes de Luna, C. Höglund, I. Anand; Study Coordination Centers — S.
Ziesche, R. Latini, A.P. Maggioni; End-Point Committee — P. Carson (chair),
C. Opasich, M. Scherillo, G. Sinagra, A. Volpe, C. O'Connor, I. Piña, F.
Tristani, L.W. Stevenson; Data Safety Monitoring Board — W. Parmley (chair),
M. Bobbio, D.J. van Veldhuisen, J. Abrams, D. DeMets; Echo Core Laboratory —
M. Wong, C. Höglund, L. Staszewsky, A. Volpi; Neurohormone Laboratory — D.
Judd, R. Latini, S. Masson.




Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.