Circ J 2004; 68: 361 – 366

Rationale for the Use of Combination Angiotensin-Converting

Enzyme Inhibitor and Angiotensin II Receptor
Blocker Therapy in Heart Failure

Yoshio Yasumura, MD; Kunio Miyatake, MD; Hiroshi Okamoto, MD; Takeshi Miyauchi, MD;
Masatoshi Kawana, MD; Takayoshi Tsutamoto, MD; Masafumi Kitakaze, MD;
Hiroaki Matsubara, MD; Hideyuki Takaoka, MD; Teisuke Anzai, MD; Hideo Himeno, MD;
Hiroyuki Yokoyama, MD; Koichi Yokoya, MD; Uichirou Shintani, MD; Katsuji Hashimoto, MD;
Yukihiro Koretsune, MD; Yukio Nakamura, MD; Katsuji Imai, MD; Shingo Maruyama, MD;
Yoshiko Masaoka, MD; Michihito Sekiya, MD; Teruo Shiraki, MD;
Hisanori Shinohara, MD; Keizaburo Ozono, MD; Tatsuru Matsuoka, MD;
Yuji Miyao, MD; Fumikazu Nomura, MD

Background The present multicenter study investigated whether the combination of angiotensin-converting
enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) is more beneficial for preventing left ven-
tricular remodeling and suppressing neurohumoral factors than either ACEI or ARB alone.
Methods and Results One hundred and six patients with mild-to-moderate congestive heart failure treated in
26 Japanese institutes were randomly assigned to the combination therapy or monotherapy. Changes in physical
activity (New York Heart Association functional classes, Specific Activity Scale (SAS)), concentrations of neu-
rohumoral factors (plasma renin activity, angiotensin II, aldosterone, and brain natriuretic peptide (BNP)), and
cardiac function for 6 months were compared between the 2 groups. It was found that the combination therapy,
which was administered at doses standard in Japan, increased the SAS score (4.5±1.5 to 4.9±1.5, p<0.05) and
decreased the plasma BNP concentration (183±163 to 135±118 pg/ml, p<0.05). In contrast, there were no
changes in SAS score (4.5±1.4 to 4.6±1.4, NS) or BNP concentration (156±157 to 151±185 pg/ml, NS) in the
patients receiving monotherapy.
Conclusions The results of the study demonstrate that the combination therapy, even at the standard doses for
Japan, improves physical activity and plasma BNP concentration more than the monotherapy. A larger study is
required to assess the effects of the combination therapy on major clinical outcomes. (Circ J 2004; 68: 361 –
366)
Key Words: Angiotensin converting enzyme inhibitor; Angiotensin II receptor blocker; Congestive heart failure

T
he combination of angiotensin II receptor blockers
(ARBs) and angiotensin-converting enzyme inhibi-
tors (ACEIs) has been reported to offer more
complete blockade of the effect of angiotensin II than treat-
ment with ACEI alone, while retaining the benefits of
bradykinin potentiation obtained from ACEI treatment.1,2 In
the clinical setting, the combination of ACEI and ARB is
more beneficial in preventing left ventricular remodeling
and decreasing the plasma concentrations of aldosterone
and brain natriuretic peptide (BNP) than either ACEI or
ARB alone.3,4 In addition, the combination therapy has
recently been proved to improve prognosis to a greater
extent than the monotherapy.4,5 However, the doses of
ACEI and ARB in large-scale trials performed in the USA
and Europe have been 3–4-fold higher than the standard
doses prescribed in Japan. The aim of this study was to
(Received November 13, 2003; revised manuscript received January
20, 2004; accepted January 27, 2004)
The institutes particpating in the study are listed in Appendix 1.
Mailing address: Kunio Miyatake, MD, Division of Cardiology,
Department of Medicine, National Cardiovascular Center, 5-7-1
Fujishirodai, Suita 565-8565, Japan. E-mail: kmiyatak@hsp.ncvc.
go.jp
investigate the effects of the combination of ACEI and
ARB at the standard doses prescribed in Japan on left ven-
tricular remodeling and neurohumoral factors in patients
with chronic heart failure.
Methods
Study Design
This is a multicenter, randomized, open-labeled trial to
compare the clinical effects of ACEI or ARB monotherapy
and their combination for 6 months. All the patients treated
in the 26 institutes gave their written informed consent to
participate in the trial, which was approved by the institu-
tional review board of the National Cardiovascular Center,
Osaka, Japan.
Eligibility
Men and women, 18 years old or older, with stable
chronic heart failure for at least 3 months before the screen-
ing were eligible to participate in this study. In addition,
they had to have documented left ventricular (LV) systolic
dysfunction with an LV ejection fraction (EF) equal to or
less than 45%, determined by echocardiography or LV ven-

Circulation Journal Vol.68, April 2004

362 YASUMURA Y et al.

Table 1 Incidence of the Primary End-Points Study End-Points

Monotherapy (n) Combination therapy (n)
Total events 14 15
CHF 9 6
Death 1 1
Hypotension 1 7
Cough 2 1
Cerebral event 1 0
CHF, congestive heart failure.
triculography, and LV dilatation with LV end-diastolic
dimension (LVDd) equal to or greater than 55 mm deter-
mined by echocardiography.
The exclusion criteria included pregnancy, acute myo-
cardial infarction, unstable angina, cardiac surgery or per-
cutaneous transluminal angioplasty within the past 3
months, alcoholic cardiomyopathy, myocarditis, bradycar-
dia (heart rate (HR) <50 beats/min) or hypotension (systolic
blood pressure <90 mmHg), cerebral vascular accidents
within the past 3 months, clinically important renal (serum
creatinine >2.5 mg/dl), hepatic or hematological disorders,
any terminal disease with a life expectancy of less than 1
year, and noncompliance.
Randomization and Dose Adjustment
Patients who had not previously received ACEI or ARB
were prescribed one of these agents, which was titrated to
the initial dose before randomization. The initial target
dose was equal to or more than 5 mg/day of enalapril or
50 mg/day of losartan if possible. Judging from the doses
used in patients with hypertension, we considered that the
effect of 5 mg/day of enalapril is equivalent to that of 10 mg
of lisinopril, 2 mg/day of temocapril, 5 mg/day of imidapril,
25 mg/day of alacepril, 37.5 mg/day of captopril, and
1 mg/day of trandolapril. Similarly, the effect of 25 mg/day
of losartan was considered to be equivalent to that of
4 mg/day of candesartan or 40 mg/day of valsartan. When
judged to be in a clinically stable state with the initial dose
of ACEI or ARB, the patients were randomized to mono-
therapy or combination therapy. After randomization, the
initial dose was titrated up in the monotherapy and in the
combination therapy the added drug was titrated up as
much as possible. Other background medication remained
unchanged.
The primary end-points of this study were (1) cardiovas-
cular death or hospitalization because of heart failure, (2)
the additional administration of diuretic and/or inotropic
agent for worsening heart failure, and (3) withdrawal of the
ACEI or ARB because of the development of hypotension
or cough. Secondary end-points included changes in physi-
cal activity, LVDd, LV fractional shortening (FS), LVEF,
plasma renin activity (PRA) and the concentrations of
angiotensin II, aldosterone and BNP. Physical activity was
determined on the basis of New York Heart Association
(NYHA) functional class and the Specific Activity Scale
(SAS) questionnaire, which has been validated in patients
with congestive heart failure.6
Statistical Analyses
Values are presented as mean ± SD. Changes in NYHA
functional class were analyzed by Wilcoxon’s test. Changes
in SAS, LV function, and concentrations of neurohumoral
factors following the therapy were tested by Student paired
t-test. Significance was accepted for a value of p<0.05.
Results
One hundred and forty-seven patients were enrolled and
randomly assigned to the treatment groups. Twelve
patients, 1 from the monotherapy group and 11 from the
combination therapy group, dropped out, leaving 135 pa-
tients who could be followed for 6 months. Twenty-nine
patients experienced primary end-points (Table 1). There
were no significant differences in mortality and morbidity,
except for hypotension, between the 2 groups. Hypotension
occurred more frequently in the combination therapy group
than in the monotherapy group.
Functional capacity, cardiac function and neurohumoral
factors could be followed up in 106 patients. The clinical
background did not differ between the 2 groups (Table 2).
ACEI and ARB were prescribed for 65% and 35%, respec-
tively, of the patients undergoing monotherapy (Table 3)
and enalapril comprised 68% of the ACEI prescribed and
losartan comprised 75% of the ARB. The initial dose of
enalapril at randomization was 5.5±1.9 mg/day, which was
increased to 7.2±3.3 mg/day during the follow-up period.
The initial dose of losartan at randomization was 45.0±
10.4 mg/day, which was increased to 46.7±8.8 mg/day
during follow-up. For the combination therapy, ACEI and

Table 2 Baseline Characteristics of the Patients According to Treatment Group

Monotherapy Combination therapy p value

Total number 57 49
Male (%) 77 84 NS
Age (years) 65±11 65±12 NS
New/old 11/46 9/40 NS
HR (beats/min) 76±10 72±15 NS
SBP (mmHg) 128±19 121±16 NS
Primary cause of HF
IHD (n, %) 24 (42) 22 (45) NS
DCM (n, %) 31 (54) 19 (39) NS
Other (n, %) 2 (4) 8 (16) NS
Medications
β-blocker (n, %) 28 (49) 22 (45) NS
Aldosterone (n, %) 22 (39) 18 (37) NS

new, new administration of ACEI and/or ARB; old, patients prescribed with ACE or ARB before this study; HR, heart rate; SBP,
systolic blood pressure; HF, heart failure; IHD, ischemic heart disease; DCM, dilated cardiomyopathy.

Circulation Journal Vol.68, April 2004

ACEI/ARB Combination Therapy 363

Table 3 Ratio and Dose of Each ACEI or ARB Used at Randomization and During Follow-up Period (Monotherapy)
Randomization Follow-up
n (%) Dose (mg/day) n (%) Dose (mg/day)
ACEI 37 (100) 37 (100)
Enalapril 25 (68) 5.5±1.9 25 (68) 7.2±3.3
Lisinopril 1 (3) 20 1 (3) 20
Temocapril 3 (8) 2 3 (8) 2
Imidapril 3 (8) 5 3 (8) 5
Alacepril 2 (5) 25 2 (5) 25
Captopril 0 (0) – 0 (0) –
Trandolapril 3 (8) 1 3 (8) 1
ARB 20 (100) 20 (100)
Losartan 15 (75) 45.0±10.4 15 (75) 46.7±8.8
Valsartan 2 (20) 80 2 (20) 80
Candesartan 3 (15) 6.7±2.3 3 (15) 6.7±2.3

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.

Table 4 Ratio and Dose of Each ACEI or ARB Used at Randomization and During Follow-up Period
(Combination Therapy)
Randomization Follow-up
n (%) Dose (mg/day) n (%) Dose (mg/day)
ACEI 36 (100) 49 (100)
Enalapril 27 (75) 5.2±1.5 35 (71) 5.4±1.8
Lisinopril 2 (5) 15 3 (6) 11.7±7.6
Temocapril 0 (0) – 0 (0) –
Imidapril 6 (17) 5.4±2.5 9 (18) 5.0±2.2
Alacepril 0 (0) – 1 (2) 25
Captopril 1 (3) 25 1 (2) 25
Trandolapril 0 (0) – 0 (0) –
ARB 13 (100) 49 (100)
Losartan 11 (85) 45.5±10.1 35 (71) 44.3±10.7
Valsartan 0 (0) – 6 (12) 56.7±26.6
Candesartan 2 (15) 4 8 (16) 5.5±2.1
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.

Fig 1. Changes in NYHA functional classes (Left), and SAS (Right) at 6 months compared with those at 0 month. cont,
0 month; 6Mo, 6 months after the therapy; NS, not significant.

ARB were prescribed for 73% and 27%, respectively, of pa-
tients at the time of randomization (Table 4) and enalapril
(5.4±1.8 mg/day) comprised 71% of the ACEI and losartan
(44.3±10.7 mg/day) was 71% of the ARB. Although the
NYHA functional class did not change in either group, the
SAS improved significantly only in the combination thera-
py group (Fig 1).
LVDd decreased, and FS and LVEF increased signifi-
cantly to the same degree in both groups (Fig 2), but the
PRA and the concentrations of angiotensin and aldosterone

Circulation Journal Vol.68, April 2004

364 YASUMURA Y et al.

Fig 2. Changes in left ventricular diastolic dimension (LVDd), fractional shortening (FS) and ejection fraction (EF) at 6
months compared with those at 0 month. cont, 0 month; 6Mo, 6 months after the therapy.

Fig 3. Changes in left ventricular diastolic dimension (LVDd), fractional shortening (FS) and ejection fraction (EF) at 6
months compared with those at 0 month. cont, 0 month; 6Mo, 6 months after the therapy; PRA, plasma renin activity.

did not change after the therapy (Fig 3). Although the
plasma BNP concentration did not change in the monother-
apy group (156±157 to 151±185 pg/ml), it decreased in the
combination therapy group (183±163 to 135±118 pg/ml,
p<0.05) (Fig 4). This decrease in the plasma BNP concen-
tration was observed only in patients with non-ischemic
heart diseases (203±117 to 134±123 pg/ml, n=27, p<0.01),
not in those patients with ischemic heart diseases (IHDs)
(159±143 to 138±115, n=22, NS).
In the combination therapy group, β-blocker had been
administered to 22 patients; that is, 22 patients had triple
combination therapy of ACEI, ARB andβ-blocker and 27
patients had double combination therapy of ACEI and
ARB. The EF increased significantly with both double
(34±7 to 43±11%, p<0.01) and triple combination therapies
(34±7 to 38±11%, p<0.05), but the plasma BNP concentra-
tion decreased only with the double therapy (180±176 to
129±122 pg/ml, p<0.01 vs 186±150 to 144±116 pg/ml for
the triple combination therapy, NS).
Discussion
We found that the combination of ACEI and ARB
therapy for 6 months at doses which are standard in Japan,
improved the symptoms of chronic heart failure and de-
creased the plasma BNP concentration to a greater extent

Circulation Journal Vol.68, April 2004

ACEI/ARB Combination Therapy
than monotherapy with either ACEI or ARB.
The percentage of IHDs as the primary cause of conges-
tive heart failure in this study was approximately 45%,
which was less than in the RESOLVD pilot study (≈70%).3
Therefore, care must be taken when comparing the results
of the present study with those of studies performed in
Western countries. Indeed, the plasma BNP concentration
decreased only in the non-IHD group receiving the combi-
nation therapy in the present study.
β-blocker was used in approximately 45% of patients in
the present study, compared with 15% in the RESOLVD
pilot study,3 35% in the Val-HeFT4 and 55% in the
CHARM Added trial.5 The triple combination therapy of
ACEI, ARB andβ-blocker could not decrease the plasma
BNP concentration whereas the double combination thera-
py withoutβ-blocker significantly decreased it. Because the
plasma BNP concentration can be used as a surrogate
marker for prognosis,7,8 our results suggest that we do not
necessarily have to prescribe ARB to patients receiving
both ACEI andβ-blocker. The loss of clinical benefit with
the triple combination therapy was also observed in the
Val-HeFT.4 Because β-blocker therapy should have had a
beneficial effect on neurohumoral factors in the triple
combination therapy before the time of randomization, the
further benefit from adding ACEI or ARB may have been
too small to register. In contrast, the greatest benefit of LV
reverse remodeling was noted with the triple combination
of enalapril, metoprolol, and candesartan in the RESOLVD
study.3 As well as the effect of reverse remodeling, can-
desartan administered in combination with ACEI and β-
blocker improved the clinical outcome in the CHARM
Added trial.5 Valsartan was used in Val-HeFT, candesartan
in CHARM and mainly losartan in the present study. The
apparent difference among these studies may be explained
by the particular type or dose of ARB used.
In the RESOLVD pilot study, the combination therapy
caused the greatest decrease in the aldosterone concen-
tration and the greatest increase in renin, which indicates
complete blockade of the renin – angiotensin aldosterone
system (RAAS).3 This suggests that the mechanisms by
which ACEI and ARB block the RAAS axis may be both
independent and complementary. In the present study, PRA
and the angiotensin II and aldosterone concentrations did
not change in either group, which indicates that the doses
administered in this study were too small to completely
suppress the RAAS. However, the combination therapy did
decrease the plasma BNP concentration, which is a surro-
gate marker of prognosis of chronic heart failure.7 There-
fore, ARB can be added for the management of patients
with congestive heart failure receiving ACEI.
Cardiac function assessed on the basis of LVDd, FS and
LVEF improved with both monotherapy and combination
therapy in this study. In contrast toβ-blocker therapy, the
degree of reverse remodeling following the administration
of ACEI or ARB alone has been reported as small.9,10
Valsartan added to ACEI was also reported to reverse LV
remodeling.11 Our results indicating that the degree of
reverse remodeling was similar between the monotherapy
and the combination therapy are consistent with the results
of the Val-HeFT.11
Study Limitations
The superiority of the combination therapy over the
monotherapy in this study may come from the inadequate
doses of ACEI or ARB in the monotherapy. It is true that
Circulation Journal Vol.68, April 2004
365
Fig 4. Changes in plasma BNP level at 6 month compared with that
at 0 month. cont, 0 month; 6Mo, 6 months after the therapy.
the dose of ACEI or ARB was slightly larger in the mono-
therapy than in the combination therapy, but the doses used
in the monotherapy may be insufficient to suppress the
RAAS compared with the doses used in the combination
therapy. We could have compared the degree of RAAS
suppression between the 2 groups if the changes in blood
pressure were able to be compared. However, the changes
in PRA, angiotensin II and aldosterone concentrations for
6 months did not differ between the 2 groups.
Because of the limited sample size, the results of this
study must be carefully interpreted. However, the trend in
the changes in the RAAS and BNP 6 months after therapy
is consistent with the results of the multicenter, double-
blind, randomized, parallel, placebo-controlled trial of the
RESOLVD pilot study.3
In conclusion, the present study demonstrated that
ACEI/ARB combination therapy, even when administered
at the standard doses prescribed in Japan, improves physi-
cal activity and BNP concentration to a greater extent than
either ACEI or ARB alone.
Acknowledgment
This study was supported by a Research Grants for Cardiovascular
Disease (12A-1) from the Ministry of Health, Labor and Welfare, Japan.
References
1. Baruch L, Anand I, Cohen IS, Ziesche S, Judd D, Cohn JN for the
Vasodilator Heart Failure Trial (V-HeFT) Study Group. Augmented
short- and long-term hemodynamic and hormonal effects of an
angiotensin receptor blocker added to angiotensin converting
enzyme inhibitor therapy in patients with heart failure. Circulation
1999; 99: 2658 – 2664.
2. Carson PE. Rationale for the use of combination angiotensin-con-
verting enzyme inhibitor/angiotensin II receptor blocker therapy in
heart failure. Am Heart J 2000; 140: 361 – 366.
3. McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield
J, et al for RESOLVD Pilot Study Investigators. Comparison of
candesartan, enalapril, and their combination in congestive heart
failure: Randomized evaluation of strategies for left ventricular
dysfunction (RESOLVD) pilot study. Circulation 1999; 100: 1056 –
1064.
4. Cohn JN, Tognori G for the Valsartan Heart Failure Trial Investiga-
tors. A randomized trial of the angiotensin-receptor blocker valsartan
in chronic heart failure. N Engl J Med 2001; 345: 1667 – 1675.
5. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P,
366
Michelson EL, et al for the CHARM Investigators and Committees.
Effects of candesartan in patients with chronic heart failure and
reduced left-ventricular systolic function taking angiotensin convert-
ing-enzyme inhibitors: The CHARM-Added trial. Lancet 2003; 362:
767 – 771.
6. Sasayama S, Asanoi H, Ishizuka S, Miyagi K. Evaluation of func-
tional capacity of patients with congestive heart failure. In: Yasuda
H, Kawaguchi H, editors. New aspects in the treatment of failing
heart. Tokyo: Springer-Verlag; 1992; 113 – 117.
7. Tsutamoto T, Wada A, Mabuchi N, Hayashi M, Tsutsui T, Ohnishi
M, et al. High levels of brain natriuretic peptide and interleukin-6
after optimized treatment for heart failure are independent risk
factors for morbidity and mortality in patients with congestive heart
failure. J Am Coll Cardiol 2000; 36: 1587 – 1593.
8. Eichhorn E. Prognosis determination in heart failure. Am J Med
2001; 110: 14S – 36S.
9. Eichhorn EJ, Bristow MR. Medical therapy can improve the biologi-
cal properties of the chronically failing heart: A new era in the treat-
ment of heart failure. Circulation 1996; 94: 2285 – 2296.
10. LeJemtel TH, Galveo M, Sonnenblick EH. Beta-adrenergic blockade
reverses, while ACE inhibition attenuates, left ventricular remodel-
ing in patients with chronic heart failure. Heart Failure 1998; 14:
57 – 63.
11. Wong M, Staszewsky L, Latini R, Barlera S, Volpi A, Chiang Y, et
al for the Val-HeFT trial investigators. Valsartan benefits left ven-
tricular structure and function in heart failure: Val-HeFT echocardio-
YASUMURA Y et al.
graphic study. J Am Coll Cardiol 2002; 40: 970 – 975.
Appendix 1
Principal Investigator: Kunio Miyatake, MD.
Participating Institutes
Division of Cardiology, Department of Medicine; National Cardiovascular
Center: Department of Cardiovascular Medicine; Hokkaido University
Graduate School of Medicine; Department of Internal Medicine, Universi-
ty of Tsukuba: Department of Cardiology; The Heart Institute of Japan,
Tokyo Women’s University; Department of Cardiovascular and Respirato-
ry Medicine; Shiga University of Medical Science; Division of Cardiolo-
gy, Department of Medicine, National Cardiovascular Center; Department
of Cardiovascular Medicine, Kyoto Prefectural University of Medicine;
Department of Cardiovascular Medicine, University of Kobe; National
Hakodate Hospital; National Sagamihara Hospital; National Tokyo
Medical Center; Division of Cardiology, Tohsei National Hospital;
National Toyohashi-Higashi Hospital; National Mie Chuo Hospital;
Cardiovascular Division, Osaka National Hospita; Department of Cardiol-
ogy, Kanazawa National Hospital; Osaka Minami National Hospita;
Himeji National Hospital; National Okayama Medical Cente; Ehime
National Hospital; Iwakuni National Hospital; National Zentsuji Hospita;
Department of Cardiology, National Kyushu Medical Center; National
Hospital, Kyushu Cardiovascular Center; Division of Cardiovascular Cen-
ter, Kumamoto National Hospita; National Hospital, Kure Medical Center.
Circulation Journal Vol.68, April 2004