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Heart Failure Treatment: What Role for ARBs?

Heart Failure Treatment: What Role for ARBs?

Heart failure
(HF), the most
common Medicare
diagnosis related
has a significant and growing
impact on health care
resources. The incidence
of HF has tripled during the
last decade. Almost 5 million
Americans have HF, and an
estimated 500,000 new cases
are diagnosed yearly. The
lifetime risk of HF is about
20%.1 Drug therapy has improved
considerably in recent
years, but the magnitude
and severity of the
problem has created a need
for newer therapies-particularly
since HF is associated
with an increased risk of
sudden death and a diminished
quality of life.2


In chronic HF, activation
of neurohormonal
mechanisms promotes maladaptive
growth, remodeling,
and progressive myocardial
dysfunction. Angiotensin II is
a potent vasoconstrictor and
growth-stimulating hormone
that may contribute to impairment
of left ventricular
(LV) function and progression
of HF through such
mechanisms as:

  • Increased impedance of
    LV emptying.
  • Adverse long-term structural
    effects on the heart
    and vasculature.
  • Potentially harmful activation
    of other neurohormonal
    agonists, such as epinephrine,
    aldosterone, and


Physiologically active
levels of angiotensin II persist
despite long-term therapy
with angiotensin-converting
enzyme (ACE) inhibitors. Researchers therefore
sought to determine
whether the angiotensin II
receptor blocker (ARB) valsartan
could further reduce
mortality and morbidity
among patients already receiving
therapy considered optimal
by their physicians.

Details of the study.The Valsartan Heart Failure
Trial (Val-HeFT) was a randomized,
placebo-controlled, parallelgroup
study that recruited
5010 patients in 302 centers
in 16 countries.3 Participants
were clinically stable
adults with New York Heart
Association (NYHA) class
II, III, or IV HF who were
assigned to take valsartan,
160 mg, or placebo twice
daily. At the time of randomization,
93% of the patients
were taking ACE inhibitors;
35%, β-blockers; and 5%,
spironolactone. Patients
were followed for 2 years.

Total mortality was
similar in the 2 treatment
groups. The combined end
point of mortality and morbidity
was 13% lower in the
valsartan group than in the
placebo group (P = .009).
The incidence of hospitalization
for HF decreased by
27% (P < .001). The mean
improvement in ejection
fraction was 4% for those in
the valsartan group and
3.2% in the placebo group
(P = .001). More patients in
the valsartan group had improvements
in NYHA class,
and fewer had worsening.
There was a greater reduction
in dyspnea, fatigue,
edema, and rales in the valsartan-
treated group, and
less worsening in the measured
quality-of-life analysis
than in the placebo group.

Valsartan was associated
with improved outcome
in all age groups and both
sexes and in those with and
without diabetes or coronary
heart disease. Valsartan
was generally well tolerated:
the drug was discontinued
by 9.9%, compared
with 7.2% who discontinued
the placebo.3

A word of caution.Subgroup analysis seemed
to indicate that background
therapy with neurohormonal
inhibitors influenced the response
to valsartan. In the
226 patients who were not
taking either a β-blocker or
an ACE inhibitor, mortality
was reduced by 33% with valsartan
(P = .012). In the 366
patients who were not taking
ACE inhibitors (some of
whom were receiving β-
blockers), there was a 44%
reduction in the combined
end point of mortality and
morbidity and a 33% reduction
in mortality.3 In contrast,
there was a trend toward increased
mortality and morbidity
in the subgroup of patients
who were taking an
ACE inhibitor and a β-blocker
in addition to valsartan
(P = .10).3 Future trials will
determine whether multiple
neurohormonal blockade is
harmful in patients with HF.

Despite the known efficacy
of combined ACE
inhibitor and -blocker therapy
in HF, only one third of
the patients enrolled in the
Val-HeFT study were taking
drugs from both classes at
baseline. Current guidelines
recommend that an ACE
inhibitor and a β-blocker be
considered for every patient
with chronic HF, regardless
of disease severity (Table).1
Improved compliance with
the guidelines may reduce
the number of inadequately
treated patients.

  Table — Drugs and dosages used to treat chronic heart failure
in clinical trials
Drug   Starting dosage (mg/d) Target dosage (mg) Reduce symptoms Reduce HF events Improve survival

ACE inhibitors   +++ +++ +++
Captopril   6.25 - 12.5 50 tid

Enalapril   2.5 - 5 10 bid

Lisinopril   2.5 - 5 10 - 20 qd

Ramipril   1.25 - 2.5 10 qd

ARBs   ++ ++ +/-
Candesartan   4 16 qd

Losartan   25 50 qd

Valsartan   80 160 qd

ß-Blockers     +/++ +++ +++

Bisoprolol   1.25 10 qd

Carvedilol   3.125 - 6.25 25 - 50 bid

Metoprolol succinate   12.5 150 - 200 qd

Aldosterone antagonist       ++ +++ +++
Spironolactone   12.5 - 25 25 qd

Other       ++ ++ 0

Amlodipine   2.5 - 5 5 qd

Digoxin   0.125 0.125 qd

HF, heart failure; ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers.


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