Download Systematic Review of Combined Angiotensin

Systematic Review of Combined Angiotensin-Converting
Enzyme Inhibition and Angiotensin Receptor Blockade
in Hypertension
Timothy W.R. Doulton, Feng J. He, Graham A. MacGregor
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Abstract—Some evidence suggests that long-term angiotensin-converting enzyme (ACE) inhibition may become less
effective, thereby increasing angiotensin II levels, which could be inhibited by the addition of an angiotensin receptor
blocker. We conducted a meta-analysis of randomized trials with searches of MEDLINE, EMBASE, and Cochrane
databases. Overall, the combination of an ACE inhibitor and an angiotensin receptor blocker reduced ambulatory blood
pressure by 4.7/3.0 mm Hg (95% confidence interval [CI], 2.9 to 6.5/1.6 to 4.3) compared with ACE inhibitor
monotherapy and 3.8/2.9 mm Hg (2.4 to 5.3/0.4 to 5.4) compared with angiotensin receptor blocker monotherapy. Clinic
blood pressure was reduced by 3.8/2.7 mm Hg (0.9 to 6.7/0.8 to 4.6) and 3.7/2.3 mm Hg (0.4 to 6.9/0.2 to 4.4) compared
with ACE inhibitor and angiotensin receptor blocker, respectively. However, the majority of these studies used
submaximal doses or once-daily dosing of shorter-acting ACE inhibitors and, when a larger dose of shorter-acting ACE
inhibitor was given or a longer-acting ACE inhibitor was used, there was generally no additive effect of the angiotensin
receptor blocker on blood pressure. Proteinuria was reduced by the combination compared with ACE inhibitor and
angiotensin receptor blocker monotherapy, an effect that was independent of blood pressure in several studies,
suggesting that the combination could have benefits in proteinuric nephropathies. None of the studies was of sufficient
size and duration to determine whether there may be safety concerns. In conclusion, although there is a small additive
effect on blood pressure with an ACE inhibitor–angiotensin receptor blocker combination, the routine use of this
combination in uncomplicated hypertension is not recommended until more carefully controlled studies are performed.
(Hypertension. 2005;45:880-886.)
Key Words: angiotensin-converting enzyme 䡲 hypertension 䡲 meta-analysis 䡲 proteinuria 䡲 receptors, angiotensin
䡲 renin-angiotensin system
T
he renin-angiotensin system (RAS) plays an important role
in regulating blood pressure (BP).1,2 Both angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin II type 1
receptor blockers (ARBs) inhibit the RAS and have been shown
to be effective treatments for increased BP.3 At the same time,
they have other beneficial effects that may be independent of
their ability to lower BP, for example, reductions in the progression of nephropathy in diabetes mellitus (DM) and chronic renal
failure (CRF).4 – 6 Administration of ACEI causes plasma levels
of angiotensin II (Ang II) to become undetectable, whereas there
is some evidence that chronic administration of ACEI results in
partial escape, ie, there is incomplete suppression of Ang II
levels at peak, which may reduce the effectiveness of ACEI as
BP-lowering agents.7–9
Several studies have suggested that combining an ARB with
an ACEI may provide a more complete blockade of the RAS in
the treatment of diabetic and nondiabetic nephropathy and
essential hypertension; in particular, it may lower BP and
proteinuria further than monotherapy.10 –13 However, the major-
ity of these studies have used low doses of ACEI or shorteracting ACEI. Because BP has been measured in the majority of
the studies at trough, it is unclear whether this is a truly additive
effect or a pharmacodynamic interaction, in that ARBs are
generally longer-acting than ACEIs. There is some evidence to
suggest that in animal models, the combination of these two
drugs may be more likely to cause renal failure,14 and it is
unclear in humans whether this strategy is safe.
We undertook a review of the published literature to
ascertain the evidence for a greater decline in BP when
combining an ACEI and an ARB in the treatment of hypertension. At the same time, we looked at whether there was an
additive effect on proteinuria and reviewed the available
safety data for combination RAS blockade.
Methods
Literature Search
We developed a search strategy (Table I, please see http://hyper.
ahajournals.org) to identify randomized trials of combined RAS
Received January 27, 2005; first decision January 27, 2005; revision accepted February 28, 2005.
From the Blood Pressure Unit, Department of Cardiac and Vascular Sciences, St. George’s Hospital Medical School, London, UK.
Correspondence to Professor Graham A. MacGregor, Blood Pressure Unit, Department of Vascular and Cardiovascular Sciences, St. George’s Hospital
Medical School, London, SW17 0RE, UK. E-mail [email protected]
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000161880.59963.da
880
Doulton et al
inhibition with an ACEI and ARB compared with monotherapy with
either class of drug from electronic databases: MEDLINE (1966 to
July 2004) and EMBASE (1988 to July 2004). We also searched the
Cochrane Library (The Cochrane Controlled Trials Register and the
Cochrane Database of Systematic Reviews) with the terms “ACE
inhibitor” and “angiotensin receptor” from 1995 to 2004. We
reviewed the reference lists of original and review articles to search
for further relevant trials. Searches were limited to English language.
TABLE 1.
Systematic Review of Combination ACEI–ARB
881
Inclusion and Exclusion Criteria
For inclusion, trials needed to satisfy the following criteria: (1)
participants were hypertensive (clinic sitting systolic BP [SBP]
ⱖ140 mm Hg and/or diastolic BP [DBP] ⱖ90 mm Hg; mean
ambulatory SBP ⱖ130 mm Hg or ambulatory DBP ⱖ85 mm Hg)3 or
the use of antihypertensive drugs; (2) changes in BP were a primary
or significant secondary outcome variable; and (3) allocations to trial
interventions were randomized.
Overview of Study Entry Criteria, Study Design, Demographic Details of Participants, and Baseline BP
Author, Year
Jacobsen, 200210
Entry Criteria
Study Design
Duration of
Intervention
n*
Age,
y
Baseline BP
Study Intervention†
Type 1 DM
Crossover
8 wk
21
45
156/87‡§
ACEI⫹Irbesartan 300 od
BP ⬎135/85
ACEI⫹placebo
⬎1 g proteinuria
Jacobsen,
200334
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Jacobsen,
200335
Type 1 DM
Cross-over
8 wk
24
42
131/74‡§
⬎300 mg proteinuria
Type 1 DM
Enalapril 40 od⫹Irbesartan 300 od
Enalapril 40 od⫹placebo
Cross-over
8 wk
20
43
141/81‡§
⬎300 mg proteinuria
Benazepril 20 od⫹Valsartan 80 od
Benazepril 20 od
Valsartan 80 od
Placebo
Mogensen, 200011
Type 2 DM
Parallel group
12 wk
⬍300 mg proteinuria
67
60
163/96‡
(197)
Lisinopril 20 od⫹Candesartan 16 od
Lisinopril 20 od⫹placebo
Candesartan 16 od⫹placebo
Rossing, 200236
Type 2 DM
Cross-over
8 wk
18
58
159/85‡§
BP⬎135/85
ACEI⫹Candesartan 8 od
ACEI⫹placebo
⬎1 g proteinuria
Rossing, 200329
Type 2 DM
Cross-over
8 wk
20
62
138/72§储
BP ⬎135/85
ACEI⫹Candesartan 16 od
ACEI⫹placebo
⬎300 mg proteinuria
Agarwal, 200137
CRF (DM/non-DM)
Cross-over
4 wk
17
53
156/88‡§
MABP¶ ⬎ 97
Lisinopril 40 od⫹Losartan 50 od
Lisinopril 40 od⫹placebo
⬎1 g proteinuria
Berger, 200217
Non-DM CRF
Cross-over
8 wk
12
52
128/79§储
⬎1g proteinuria
Ferrari, 200230
Nakao, 200312
Non-DM CRF
ACEI⫹candesartan 8 od
ACEI⫹placebo
Cross-over
6 wk
10
48
144/91‡
Fosinopril 20 od⫹Irbesartan 150 od
⬎140/90
Fosinopril 20 od (no placebo)
⬎1.5 g proteinuria
Irbesartan 150 od (no placebo)
Non-DM CRF
Parallel group
2.9 y
⬎300 mg proteinuria
99
45
130/75§储
(263)
Trandolapril 3 od⫹Losartan 100 daily
Trandolapril 3 od⫹placebo
Losartan 100 daily⫹placebo
Azizi, 200013
Essential hypertension
Parallel group
6 wk
DBP 95–115
60
NS
161/105‡
(177)
Enalapril 10 od⫹Losartan 50 od
Enalapril 10 od (no placebo)
Losartan 50 od (no placebo)
Stergiou, 200038
Essential hypertension
Cross-over
5 wk
20
49
150/100‡§
Ambulatory DBP ⬎85
Weir, 200139
Morgan, 200425
Benazepril 20 od⫹placebo
Essential hypertension
Parallel
DBP 95–115
group
Systolic hypertension
ambulatory SBP ⬎135
Cross-over
Older than 65 years
Benazepril 20 od⫹Valsartan 80 od
6 wk
23
48
146/97‡§
(81)
6 wk
23
Benazepril 20 od⫹Valsartan 160 od
Valsartan 320 od (no placebo)
76
160/88‡
Candesartan 16 od⫹Lisinopril 20 od
Lisinopril 20 od
Candesartan 16 od**
882
TABLE 1.
Hypertension
May 2005
Continued
*Number of participants receiving ACE–ARB combination; numbers in parentheses refer to total numbers of subjects in study in parallel group studies.
†Numerical values refer to drug doses administered (in mg).
‡Clinic (office) sitting BP.
§Baseline BP measured on antihypertensive medication.
¶Mean arterial blood pressure.
储24-hour mean ambulatory BP.
**Morgan et al25 also compared combination with candesartan 32 od and lisinopril 40 od; for the purposes of the meta-analysis, we compared doses of monotherapy
with the same doses administered in the combination.
ACEI indicates use of angiotensin-converting enzyme inhibitors (the dosages of which are given below); BP, blood pressure; CRF, chronic renal failure; daily,
administration of given amount in divided dosages during the day; DBP, diastolic blood pressure; DM, diabetes mellitus; od refers to once-daily administration; od,
administration of given amount as a single daily dose; SBP, systolic blood pressure.
Jacobsen 200210: enalapril 20 od (n⫽5); lisinopril 20 od (n⫽2); captopril unknown dose (n⫽15).
Rossing 200236: enalapril 40 od (n⫽17); lisinopril 40 od (n⫽2); captopril 150 daily (n⫽1).
Rossing 200329: enalapril 20 od (n⫽9); lisinopril 20 od (n⫽5); captopril 100 daily (n⫽4).
Berger 200217: enalapril 10 daily (n⫽5); ramipril 5 daily (n⫽3); quinalapril 10 daily (n⫽1); captopril 50 daily (n⫽1).
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Trials were excluded if: (1) participants were normotensive; (2)
changes in BP were not the main or a significant secondary outcome
variable, or were not reported; (3) allocation to trial interventions
were not randomized; and (4) significant alterations in number
and/or doses of concomitant antihypertensive medications were
allowed during the course of the trial, unless these were clearly
spread equally between study groups.
Data Extraction
Data were extracted independently by 2 of the authors (T.D., F.H.)
using a standard form. Relevant data recorded were characteristics of
the study, study design (parallel or crossover), type of the study
(open, single-blind, or double-blind), study duration, preintervention and postintervention results for BP and proteinuria
(when measured), and relevant safety data. For the purpose of pooled
analyses, statistics that could be used to estimate the variances of the
outcome measures were recorded.
Statistical Analysis
We calculated the treatment effect for SBP and DBP, which for
crossover trials was the difference in BP between the end of the
ACEI or ARB monotherapy (ie, control) period and the end of
the ACE–ARB combination period, and for parallel trials was the
difference between the 2 treatment groups in the change in BP from
baseline to the end of the treatment period. Treatment effects were
calculated for proteinuria in a similar manner. We also calculated the
variance of the treatment effect for SBP, DBP, and proteinuria from
standard deviations or standard errors of paired differences between
baseline and the end of follow-up for each group in a parallel trial15
or between the 2 treatment periods in a crossover trial, or, if these
statistics were not given, from confidence intervals, exact t or P
values. If the exact variance of paired difference was not derivable,
it was imputed either by inverting a boundary probability value (eg,
P⬍0.05 became P⫽0.05) or by assuming a correlation coefficient of
0.5 between the initial and final BP.16 Among the 14 trials included
in our meta-analysis, only 1 had to have variance imputed. Mean
effect sizes were calculated using random effects model on Cochrane
Collaboration Review Manager 4.2.1 software.
Results
Searches by one of the authors (T.D.) of MEDLINE and
EMBASE databases, using the search strategy outlined with
secondary searches using the bibliographies of relevant articles, identified 1632 publications. A search of the Cochrane
Library produced 986 further publications. In total, 2618
potentially relevant publications were identified and screened
for retrieval. Of these, 2598 were excluded on the basis of
title or abstract, because the publications were not randomized trials of an ACEI–ARB combination in hypertensive
patients. Twenty potentially appropriate trials were retrieved
for more detailed evaluation, resulting in 14 that were
considered appropriate for inclusion in this meta-analysis.
Four studies were undertaken in patients with uncomplicated essential or isolated systolic hypertension, 4 in patients
with CRF, and 3 each in patients with type 1 and type 2 DM.
Ten studies were crossover designs and 4 were parallel group
studies. Allocation to trial medication was open in 2 studies,
single-blinded in 1 other, and the remaining 11 studies were
double-blinded. In total, 434 subjects received combination
ACEI–ARB therapy. The mean age of participants was 52
years (range, 42 to 76) and 71% were male. In 10 studies in
which patients had an ACEI and/or ARB added to existing
antihypertensive medication, the mean baseline BP or on
placebo (the latter in the case of studies in which no baseline
BP was provided) was 148/88 mm Hg (range, 131 to 159/74
to 100 mm Hg) for clinic BP (n⫽7) and 132/75 mm Hg
(range, 128 to 138/72 to 79 mm Hg) for 24-hour ambulatory
BP (n⫽3). In 4 studies in which antihypertensive medication
had been withdrawn, clinic BP at randomization was 157/
95 mm Hg (range, 144 to 162/88 to 105). An ACEI–ARB
combination was compared with ACEI monotherapy in 13
studies, and with ARB monotherapy in 7 studies. Study
characteristics are summarized in Table 1.
Effects on BP
The combination of an ACEI and ARB reduced 24-hour
ambulatory BP by 4.7/3.0 mm Hg (95% confidence interval
[CI] 2.9 to 6.5/1.6 to 4.3) when compared with ACEI
monotherapy, and by 3.8/2.9 mm Hg (95% CI, 2.4 to 5.3/0.4
to 5.4) when compared with ARB monotherapy (Figures 1
and 2, respectively). Clinic BP (sitting or supine) was reduced
by 3.8/2.7 mm Hg (95% CI, 0.9 to 6.7/0.8 to 4.6) and
3.7/2.3 mm Hg (95% CI, 0.4 to 6.9/0.2 to 4.4) versus ACEI
and ARB monotherapy, respectively (Figures 1 and 2).
However, the majority of studies used submaximal doses or
once-daily dosing of shorter-acting ACEI, and in the 1 study
in which a longer-acting ACEI (trandolapril) was used, there
was no additive effect on BP when an ARB was added.12
Further analysis according to whether the participants had
essential hypertension, DM, or CRF was undertaken. Because
the results of the overall analysis showed that reductions in
ambulatory and clinic BP were similar, we combined ambu-
Doulton et al
Systematic Review of Combination ACEI–ARB
883
Figure 1. Net change in ambulatory SBP
and clinic SBP for ACE–ARB combination versus ACEI alone, both in diagrammatic and numerical format (mm Hg,
95% CI). The overall effect represents
the pooled estimate of mean net change
in SBP for ambulatory and clinic measurements, respectively. (n)⫽reference
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latory and clinic measurements for this analysis by using
ambulatory BP results; if these were unavailable, clinic BP
results (but not both) were used. Because of the small
numbers of studies in which combination therapy was compared with ARB monotherapy (n⫽7; hypertension 3, diabetes
3; CRF 1), we only looked at the combination compared with
ACEI monotherapy. In participants with essential or isolated
systolic hypertension, BP was reduced by 4.0/2.3 mm Hg
(95% CI, 1.9 to 6.0/0.2 to 4.4) and in those with DM the
reduction was 6.8/4.7 mm Hg (95% CI, 4.4 to 9.2/3.3 to 6.0).
There was no reduction in BP in participants with CRF
(0.7/0.4 mm Hg; 95% CI, ⫺0.6 to 1.3/⫺1.2 to 2.7).
Effects on Proteinuria
Eight trials reported data on proteinuria, albuminuria, or
urinary albumin creatinine ratio (UACR) that was suitable
for analysis. For simplicity, when we refer to “proteinuria”
hereafter, we are referring to albuminuria, proteinuria, or
UACR. Because the treatment effect was expressed in
terms of percentage changes in “proteinuria” in all of the
trials included, we have combined these different methods
of expressing urinary protein excretion for the purposes of
the meta-analysis. Two trials reported effects on proteinuria but could not be included in the analysis because of
insufficient provision of data, with attempts to contact the
Figure 2. Net change in ambulatory SBP
and clinic SBP for ACE–ARB combination versus ARB alone, both in diagrammatic and numerical format (mm Hg,
95% CI). The overall effect represents
the pooled estimate of mean net change
in SBP for ambulatory and clinic measurements, respectively. (n)⫽reference
884
Hypertension
TABLE 2.
May 2005
Safety Data
Mean Change in Serum/
Plasma Potassium,
mmol/L
Significant
Hyperkalemia,
n*
Change in
Renal Function
关Parameter Measured兴†
Change in Hb,
mmol/L
Withdrawal From
Study Because
of AE (n) 关Event兴‡
⫹0.3
NS
⫹0.3
4
1
1
NS§ 关EDTA-GFR兴
NS 关EDTA-GFR兴
—
NS
⫺0.4
⫺0.4 (P⬍0.05 vs ACEI only)
1 关hyperkalemia兴
None
None
Rossing, 200236
Rossing, 200329
Agarwal, 200137
Berger, 200217
Ferrari, 200230
Nakao, 200312
⫹0.3 (?P⬍0.05)
NS
NS
NS
NS
NS
—
“No change”
NS
—
NS
⫺4.4 mL/min 关CrCl兴
⫺5 mL/min 关EDTA-GFR兴
NS 关EDTA-GFR兴
NS 关SCr兴
NS 关SCr兴
NS 关CrCl兴
“No significant acute
deterioration in
renal function”
“No change”
NS 关SCr兴
—
NS 关SCr兴
—
—
—
NS
—
—
—
Azizi, 200013
Stergiou, 200038
Weir, 200139
Morgan, 200425
—
None
None
—
—
2
7/88 vs 8/86
in ACE group vs 4/89
in ARB group.
—
None
—
4 vs 1 and 2 on monotherapy
?1 关dizziness兴
1 关nausea兴
None
None
None
None
18 关various reasons兴
vs 19 in ACEI group.
vs 11 in ARB group
—
None
—
None
Author, Year
Jacobsen, 200210
Jacobsen, 200334
Jacobsen, 200335
Mogensen, 200011
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—
—
—
—
*Significant hyperkalemia is defined in all studies as serum potassium ⬎5.0 to ⬎5.2 mmol/L in subjects receiving combination ACE–ARB, when stated, except
for Nakao et al,12 who do not define “significant hyperkalemia.”
†EDTA-GFR: glomerular filtration rate determined by standard 51Cr-EDTA isotope techniques; CrCl, creatinine clearance; SCr, serum creatinine concentration.
‡Attributable to a participant receiving combination ACEI-ARB; reporting of side effects such as cough varied widely between different studies and so these data
could not be analyzed in a meaningful manner.
§NS indicates no significant difference between study groups (P⬎0.05, where given).
authors for further information being unsuccessful.12,17
The combination of an ACEI and ARB reduced proteinuria
by 30% (95% CI, 23% to 37%) compared with monotherapy with an ACE inhibitor, and by 39% (95% CI, 31%
to 48%) compared with ARB monotherapy.
Safety Data
In the majority of the studies reviewed, there were no
significant changes in serum potassium or hemoglobin. A
large acute deterioration in renal function was reported in just
1 patient in the 14 studies reviewed, and this did not
necessitate renal replacement therapy or result in significant
morbidity for that individual. In 3 studies, a small increase of
serum potassium (0.3 mmol/L) was reported, and significant
hyperkalemia was reported in 19 individuals receiving both
an ACEI and an ARB, out of a total of 434 participants. Six
episodes of hyperkalemia occurred in diabetic participants
(3.5%) and 9 episodes occurred in participants with nondiabetic CRF (6.5%). Further details of safety data can be found
in Table 2.
Compliance and Publication Bias
Compliance with study medications was determined by tablet
count in 7 studies and was generally reported to be ⬎90%
with no differences between treatment groups in individual
studies. In 2 further studies compliance was assessed, although how this was achieved was not stated, and in 5
remaining studies no information about compliance was
provided.
Funnel plots were drawn to determine publication bias by
plotting the net change in systolic BP against the reciprocal of
the standard error of change in systolic BP.18 The graphical
plots for comparisons with both ACEI and ARB were
asymmetrical, suggesting under-reporting of trials showing
no additive effect with the combination.
Discussion
The results of this meta-analysis suggest that the combination
of an ACEI and ARB reduces BP by ⬇4/3 mm Hg when
compared with an ACEI or ARB administered as monotherapy. However, we were unable to determine whether this
modest additive effect on BP was caused by a synergistic
action of the ACEI–ARB combination, because of the way in
which the majority of included studies had been designed. It
is likely that any additive effect is attributable to an interaction between these two classes of drugs with different
pharmacokinetic properties because studies measuring the
peak/trough ratios of RAS blocking agents (ie, comparing the
BP-lowering effect of an agent at peak and at the end-ofdosing interval) have shown higher ratios in ARBs compared
with ACEI.19 –21 In other words, an ARB administered once
daily will generally lower BP significantly for 24 hours or
more, whereas most ACEIs need to be administered at least
twice daily to achieve the same effect.22–24 Ideally, studies
comparing an ACEI–ARB combination against monotherapy
should be designed to demonstrate a reduction in BP at peak,
ie, showing a true additive effect, as well as at trough, which
by itself may simply represent a pharmacological interaction
of the two drug classes. In our opinion, appropriately designed studies would show that combined RAS blockade
confers little advantage over monotherapy with an ACEI or
ARB as far as additive effects on BP are concerned, and a
number of strands of existing evidence lend support to this
view. First, the COOPERATE study, which used the longest
Doulton et al
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acting ACEI trandolapril, showed no additional reduction in
trough BP with combination therapy compared with monotherapy.12 Second, Morgan et al found that a combination of
candesartan 16 mg plus lisinopril 20 mg (both once daily) had
an additive effect on clinic BP only when compared with
monotherapy with lisinopril 20 mg, but not when compared
with lisinopril 40 mg or candesartan 16 mg or 32 mg.25
Finally, Forclaz et al have shown, in normotensive individuals, that a supramaximal dose of losartan achieves equivalent
RAS inhibition to a combination of losartan plus lisinopril,
particularly if the former is administered twice daily.26
In addition to concerns relating to dosage and dosage
intervals, it should be emphasized that these studies were
generally of short duration (4 to 8 weeks). With long-term
ACE inhibition, loss of negative feedback of Ang II on the
juxtaglomerular apparatus may result in reactive hyperreninemia and increased angiotensin I generation.9 Furthermore, there is some evidence to suggest that angiotensin I
may be converted to Ang II by ACE-independent enzymatic
pathways such as chymase.27,28 Consequently, chronic ACE
inhibition may not result in complete suppression of Ang II
levels,7 and so it is possible that the combination of an ACEI
and ARB might be more effective than monotherapy when
administered for longer periods than generally used in these
studies. However, it should be noted that the study of longest
duration showed no difference between monotherapy and
combination groups.12
Combined RAS blockade reduced proteinuria by 30% and
39% compared with monotherapy with ACEIs and ARBs,
respectively. One of the trials that could not be included in
our meta-analysis of proteinuria reduction was designed to
assess to effects of combined RAS blockade on progression
of nondiabetic proteinuric chronic renal failure, in addition to
reductions in proteinuria.12 After a mean follow-up period of
2.9 years, 11% of subjects receiving combination therapy
reached the combined primary endpoint of doubling of serum
creatinine or end-stage renal failure, compared with 23% on
monotherapy with an ACEI or ARB (hazard ratio, 0.38 and
0.4 for combination versus ACEI and ARB, respectively),
and proteinuria was reduced by 43%. Reductions in proteinuria were observed in diabetic nephropathy and nondiabetic
chronic renal failure and were independent of BP reductions
in 3 studies.12,29,30 This latter finding is consistent with
meta-analyses examining renoprotective effects of ACEI
monotherapy in patients with nondiabetic renal disease,
which have concluded that there is benefit of ACE inhibition
beyond that attributable to BP-lowering.6,31 The antiproteinuric effect of an ACEI–ARB combination implies a synergistic action of these agents that is specific to the intrarenal
RAS and occurs at plasma concentrations of ACEI or ARB
below levels affecting systemic BP. There are data from
animal studies supporting this hypothesis,32 but it is unclear
from current evidence in humans whether higher doses of
ACEI or ARB administered as monotherapy might have
equivalent antiproteinuric effects to combination therapy. For
example, lisinopril up to a dose of 40 mg daily reduces
proteinuria in a stepwise fashion, but whether dosage increments beyond 40 mg would decrease proteinuria further is
unknown.33 In contrast, trandolapril was found to have a
Systematic Review of Combination ACEI–ARB
885
maximal antiproteinuric effect at 3 mg daily during dosetitration studies up to 6 mg daily, whereas combination
therapy (trandolapril and losartan) effected a further significant reduction in proteinuria compared with ACEI alone
administered at the maximal antiproteinuric dose.12 Further
research is needed to determine the optimal antiproteinuric
doses of ACEI or ARB when administered as monotherapy,
and to explain why combination blockade appears to have a
synergistic effect specifically on the intrarenal RAS.
A major theoretical concern when co-administering ACEI
and ARB would be the precipitation of acute renal failure or
acute-on-chronic renal failure, and the occurrence of hyperkalemia. In fact, the incidence of these events in the studies
reviewed in this article was extremely low, as indicated in
Table 2. However, perhaps with the exception of the study by
Nakao et al, none of these studies was of sufficient size and
duration to properly assess the safety of combining ACEI and
ARB.12 There is evidence from animal studies that maximal
RAS blockade results in death in salt-depleted rats,14 and it is
likely that humans co-prescribed an ACEI and ARB would be
at risk for acute renal failure if they became salt- and
volume-depleted. Therefore, until further studies are undertaken with adequate patient numbers and duration of
follow-up to determine the safety of combination RAS
blockade, patients on this treatment regime should have close
monitoring of renal function and electrolytes, particularly if
also receiving diuretics.
When stated, compliance with study medications appeared
to be good and, with 1 exception,11 the remaining 5 studies
that did not provide information on compliance were small
(n⫽67, 17, 12, 10, and 23, respectively). Therefore, it is
unlikely that inadequate compliance within the studies reviewed will have biased the overall result of our analysis.
Conversely, our finding of a possible publication bias suggests that the true additive effect of an ACE–ARB combination may be ⬍4/3 mm Hg we have found in this analysis.
Perspectives
This meta-analysis has found that an ACEI–ARB combination has a small additive effect on BP in hypertensive
individuals compared with ACEI or ARB monotherapy. This
additive effect is of questionable clinical significance and,
furthermore, may simply be a consequence of the design of
individual studies rather than representing a true additive
effect of the combination. Further research, ideally comparing combination therapy with maximal or supramaximal
licensed doses of ACEIs and/or ARBs, is therefore required
to determine whether the addition of an ARB to an ACEI (or
vice versa) is genuinely effective and safe in individuals with
essential hypertension. We have shown that a combination of
ACEI and ARB results in a clinically significant reduction in
proteinuria in patients with chronic kidney disease and
diabetic nephropathy already receiving an ACEI or ARB, and
other studies have shown reductions in the progression of
proteinuric CRF.12 A combination of an ACEI and ARB may
therefore be useful in hypertensive patients with CRF and
proteinuria, with the caveat that renal function and electrolyte
balance is carefully monitored. Further studies are required to
demonstrate that short-term reductions in proteinuria associ-
886
Hypertension
May 2005
ated with an ACE–ARB combination in individuals with
hypertension and diabetic nephropathy translate into reductions in clinical endpoints, before such a regime can be
routinely recommended in this population.
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Systematic Review of Combined Angiotensin-Converting Enzyme Inhibition and
Angiotensin Receptor Blockade in Hypertension
Timothy W.R. Doulton, Feng J. He and Graham A. MacGregor
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Hypertension. 2005;45:880-886; originally published online April 4, 2005;
doi: 10.1161/01.HYP.0000161880.59963.da
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