http://www.kidney-international.
org
& 2011 International Society of Nephrology
Combination inhibition of the renin–angiotensin
system: is more better?
Michelle W. Krause1, Vivian A. Fonseca2 and Sudhir V. Shah1
1
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Central Arkansas Veterans
Healthcare System, Little Rock, Arkansas, USA and 2Department of Internal Medicine, Tulane University, New Orleans, Louisiana, USA
Angiotensin-converting enzyme inhibitors or angiotensin II
receptor blockers are considered the standard of care for
treatment of cardiovascular disease and chronic kidney
disease. Combination therapy with both angiotensin-
converting enzyme inhibitors and angiotensin II receptor
blockers effectively inhibits the renin–angiotensin system
as well as potentiates the vasodilatory effects of bradykinin.
It has been advocated that this dual blockade approach
theoretically should result in improved clinical outcomes in
both cardiovascular disease and chronic kidney disease.
Clinical trial evidence for the use of combination therapy with
angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers in cardiovascular disease has provided
conflicting results in hypertension, congestive heart failure,
and ischemic heart disease. Clinical trial evidence to support
combination therapy with angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers in chronic
kidney disease has largely been based on proteinuria
reduction as a surrogate marker for clinically meaningful
outcomes. Recent large-scale randomized clinical trials have
not been able to validate protection in halting progression
in chronic kidney disease with a dual blockade approach.
This review serves as an appraisal on the clinical evidence of
combination angiotensin-converting enzyme inhibition and
angiotensin II receptor blockade in both cardiovascular
disease and chronic kidney disease.
Kidney International (2011) 80, 245–255; doi:10.1038/ki.2011.142;
published online 1 June 2011
KEYWORDS: ACE inhibitors; angiotensin; cardiovascular disease;
chronic kidney disease
Correspondence: Michelle W. Krause, Division of Nephrology, Department
of Internal Medicine, University of Arkansas for Medical Sciences, Central
Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA.
E-mail: krausemichellew@uams.edu
Received 1 October 2010; revised 9 February 2011; accepted 22 March
2011; published online 1 June 2011
Kidney International (2011) 80, 245–255
review
A wealth of research and publications has ensued in the last
few decades describing the beneficial effects of inhibition of
the renin–angiotensin system in cardiovascular disease and
chronic kidney disease (CKD). Angiotensin-converting en-
zyme (ACE) inhibition has improved survival and reduced
morbidity in hypertension, congestive heart failure (CHF),
acute myocardial infarction, and halts progression in CKD.
Angiotensin receptor blockers (ARBs) have been shown to be
equally efficacious to ACE inhibition in both cardiovascular
disease and CKD populations. ACE inhibitors or ARBs are
considered the standard of care for treatment of hypertension
in diabetes mellitus and CKD, reducing proteinuria and CKD
progression, and improving outcomes in CHF and acute
myocardial infarction. As both of these classes of medications
were used in both cardiovascular disease and CKD, the theory
that ‘more is better’ ensued and dual blockade of the
renin–angiotensin system was advocated by many leading
physicians. This review serves as an appraisal on the clinical
evidence of combination ACE inhibition and angiotensin
receptor blockade (combination therapy) in both cardiovas-
cular disease and CKD.
The belief of impurities in the blood causing hypertension
dates back well over 2000 years in ancient Egypt and Asia.
The association between hypertension, cardiovascular dis-
ease, and kidney disease was first made by Richard Bright1 in
1836. Modern day hypertension was described by Frederick
Mahomed2 in 1872 with primitive sphygmography. Devel-
opment of the blood pressure cuff by Riva-Rocci3 in 1896 and
auscultation of blood flow with such a device by Nikolai
Korotkoff4 in 1905 pioneered research into the physiological
mechanisms of hypertension.
The renin–angiotensin system was first described by
Tigerstedt and Bergman5 in 1898, with the observation that
infusion of a substance termed ‘renin’ isolated from rabbit
kidneys induced hypertension. The importance of the kidney
in modulating hypertension was shown by the work of Harry
Goldblatt et al.6 in 1934 who demonstrated that renal
ischemia resulted in an animal model of hypertension. This
model, termed ‘Goldblatt hypertension’, supported Tigerstedt
and Bergman’s previous description of a vasopressor
substance released into the renal vein during periods of
renal ischemia. Frey and Krant discovered kallirein in 1926,7
and parallel groups of investigations led by Eduardo
245
review
Braun-Menendez and colleagues8 in Argentina and by Irving
Page and colleagues9 in Indianapolis in the 1930–1940s
demonstrated the pathway of renin activation to ‘hyperten-
sin’ and ‘angiotonin’ by a renin activator. In 1956, Skeggs
et al.10 discovered ACE and by 1961 the terminology of
‘hypertensin’ and ‘angiotonin’ was changed to angiotensino-
gen as the renin substrate and angiotensin as the active
metabolite.11
The renin–angiotensin system was further characterized
by efforts made by John Vane, Kevin Ng, Sergio Ferreira,
Ervin Erdös, and Mick Bakhle and others who described
conversion of angiotensin I to angiotensin II in the
pulmonary circulation through ACE with bradykinin in-
activation.12,13 A bradykinin-potentiating factor isolated
from pit viper venom (Bothrops jararac) resulted in ACE
inhibition and identified a novel mechanism in the treatment
of hypertension.12 Collaboration with research scientists at
Squibb and other experts in the field at that time led to the
formulation of the first oral ACE inhibitor, captopril. Under
the direction of John Laragh and colleagues,14 a clinical trial
for the treatment of hypertension with captopril was
conducted in 1978 and led to Food and Drug Administration
(FDA) approval of captopril for treatment of hypertension in
1981. Drug development in the discovery of angiotensin II
receptor blockers and direct renin inhibitors occurred during
the mid 1980s, but was limited by the use of peptide
compounds that had a short half-life and were not orally
bioavailable. It was not until 1982 that a group of scientists at
DuPont laboratories reviewed a US patent that described
imidazole derivates that demonstrated angiotensin II recep-
tor-blocking activity.15 Such imidazole derivates were highly
selective for the angiotensin II receptor, but required massive
doses for potency that the possibility of drug development
was abandoned in several laboratories. It was not until a
molecular change with the addition of a tetrazole group that
losartan was developed and ultimately approved as the first
ARB by the FDA in 1995. Finally, aliskiren, the first oral direct
inhibitor of renin, was developed and approved for treatment
of primary hypertension by the FDA in 2007.
DUAL BLOCKADE OF THE RENIN–ANGIOTENSIN SYSTEM AND
CARDIOVASCULAR DISEASE
Rationale
There are good theoretical reasons why complete inhibition
of the renin–angiotensin system should result in improved
clinical outcomes in cardiovascular disease. In addition to
blood pressure regulation and cardiac remodeling, angioten-
sin has been implicated in inflammation, oxidative stress,
atherosclerosis, and has proliferative effects through the AT2
receptor.16–19 ACE inhibitors block the conversion of
angiotensin I to angiotensin II and additionally inhibit
kininase II, potentiating the beneficial vasodilatory effects of
bradykinin and nitric oxide resulting in blood pressure
lowering.16–18 However, with ACE inhibitors alone, there is
incomplete inhibition of the renin–angiotensin system
because of ‘angiotensin escape’, which refers to production
246
MW Krause et al.: Combination inhibition of the renin–angiotensin system
Angiotensinogen
Renin Diect renin
ACE inhibitors
inhibitors
Angiotensin I
Bradykinin ‘Angiotensin escape’
Chymase
ACE Cathepsin G
Angiotensin II
Inactive
metabolites
Angiotensin II
receptor blockers
Angiotensin II receptor(s)
Figure 1 | The renin-angiotensin system. ACE, angiotensin
converting enzyme.
of angiotensin II through non-ACE pathways.17 Therefore,
combination therapy with inhibition of angiotensin II
formation through ACE with ACE inhibitors and blockade
of angiotensin II binding to the AT receptors with ARBs
provides a more complete blockade of the angiotensin effects.
One caveat in combination therapy is that ACE inhibitors
and ARBs increase renin stimulation. Renin has been
associated with increased risk for myocardial infarction and
stroke,20 and therefore combination therapy is not ‘complete’
inhibition of the renin–angiotensin system (Figure 1). The
following serves as a review of the clinical evidence for
combination therapy in the treatment of hypertension, CHF,
and ischemic heart disease.
Hypertension
One of the early treatment trials in hypertension with
combination therapy was published in 2000 by Azizi et al.,21
who reported that combination of losartan and enalapril
compared with monotherapy with either agent alone had a
greater diastolic blood pressure lowering at study clinic visits
but did not show a significant difference in the 24-h mean
ambulatory blood pressure. A series of other trials of
combination therapy for hypertension were published
between 2000 and 2005 but were limited by small sample
sizes, lack of pre-defined hard clinical end points, use of non-
generalizable subject populations, short durations of follow-
up, or suboptimal drug dosing regimens.22–24 In 2001, Weir
et al.25 reported in 6465 hypertensive subjects that the most
significant blood pressure-lowering effects were seen with
candesartan and diuretics, followed by candesartan and
calcium antagonists, candesartan and b-blockers, and the
least effective combination was with candesartan and ACE
inhibitors. This trial confirmed the results of the AURA
(Atacand Under Real-life Aspects) study that candesartan was
an effective anti-hypertensive agent in primary hypertension;
however, when added on to other classes of antihypertensive
medications, combination of ACE inhibitors and ARBs had
the weakest effect.26 The AMAZE (A Multicenter trial using
Kidney International (2011) 80, 245–255
MW Krause et al.: Combination inhibition of the renin–angiotensin system
Atacand and Zestril versus zestril to Evaluate the effects on
lowering blood pressure) trials included two randomized,
multi-centered, double-blind controlled investigations com-
paring the combination of lisinopril and candesartan versus
maximizing the dose of lisinopril alone.27 The results of the
studies provided conflicting data with one of the cohorts
demonstrating that combination therapy was superior,
whereas the second cohort could not corroborate the
same results.
A meta-analysis published in 2005 by Doulton et al.28
summarized the evidence of combination therapy as
compared with monotherapy for the treatment of hyperten-
sion. A series of 14 publications met the author’s inclusion
criteria of hypertensive subjects, having blood pressure
control as an outcome measure and requiring that the trial
design include randomization. The results showed that blood
pressure reductions were modest with combination therapy
as compared with monotherapy and achieved statistical
significance; however, the authors concluded that the impact
on clinical outcomes was likely to be minor and therefore
were unable to recommend combination therapy over other
drug regimens.
The ONTARGET (The ONgoing Telmisartan Alone and in
combination with Ramipril Global End point Trial) trial was
a landmark trial of combination therapy in high-risk subjects
with cardiovascular disease or diabetes mellitus without
CHF.29 A total of 25,620 subjects underwent randomization
into three double-blind treatment arms of ramipril (10 mg
daily), telmisartan (80 mg daily), or the combination of
telmisartan and ramipril daily. The primary outcomes of this
investigation were twofold: first to determine non-inferiority
of telmisartan compared with ramipril and second to
investigate whether combination therapy was superior to
ramipril alone in a composite end point of death from
cardiovascular causes, myocardial infarction, stroke, or
hospitalization for heart failure. Approximately 69% of those
enrolled in the study had baseline primary hypertension. All
three treatment groups demonstrated effective lowering of
blood pressure that was persistent throughout the study, and
in the combination group, there was a greater reduction in
blood pressure as compared with the single treatment arms.
Surprisingly, the beneficial effect of blood pressure lowering
did not result in greater protection that has been shown in
other cardiovascular studies. For the composite outcomes of
death from cardiovascular causes, myocardial infarction,
stroke, or hospitalization for heart failure, combination
therapy did not demonstrate a significant benefit over
monotherapy (relative risk 0.98 (0.90, 1.07)). On review of
the adverse events, combination therapy was associated with
significantly greater episodes of hypotensive symptoms,
syncopal events, diarrhea, kidney impairment, and hyperka-
lemia. The increased risk of these adverse events and the lack
of benefit on the clinical composite outcomes of this study
led investigators to conclude that combination therapy is not
warranted for this patient population. Criticisms of this study
validly point out that using combination therapy for 30% of
Kidney International (2011) 80, 245–255
review
the study population that was normotensive contributed to
excess syncopal and hypotensive events and likely increased
the cardiovascular events in this trial. This is in keeping with
previous studies, which have suggested that reducing blood
pressure is associated with a J-curve in which lower blood
pressures are associated with increased cardiovascular
events.30,31 In all practically, enrolling normotensive subjects
in a dual anti-hypertensive clinical trial targeted at drug
dosing rather than at blood pressure should have raised
concern. Despite criticisms of the trial design, the results of
the ONTARGET trial resulted in leading investigators along
with the Canadian Hypertensive Education Program and the
Canadian Heart and Stroke Foundation in 2009 to strongly
advise discontinuation of combination therapy in the
treatment of hypertensive patients.32,33
Congestive heart failure
If there is a lack of superiority established thus far with the
use of combination therapy in hypertension (Table 1) or in a
high-risk cardiovascular population, are there other cardio-
vascular disease states such as CHF or myocardial infarction
in which combination therapy may be effective? Several
clinical trials have been performed to address these popula-
tions, including RESOLVD (Randomized Evaluation of
Strategies for Left Ventricular Dysfunction), Val-HeFT
(VALsartan Heart Failure Trial), and the CHARM (Cande-
sartan in Heart failure: Assessment of Reduction in Mortality
and morbidity) studies.34–38 RESOLVD was a pilot study
published in 1999 to study the effects of candesartan and
enalapril as compared with candesartan alone or enalapril
alone in symptomatic subjects with NYHA (New York Heart
Association) Class II–IV CHF with a reduced ejection
fraction.31 The authors concluded that there was a benefit
of combination therapy on left ventricular remodeling based
on measurements of left ventricular systolic and diastolic
volumes but lacked meaningful clinical end points in the
study. The Val-HeFT trial was a multi-centered randomized
double-blind placebo-controlled trial of 5010 subjects with
CHF as defined by NYHA Class II–IV with reduced ejection
fraction.32 Valsartan was compared with standard CHF
therapy, with the majority of subjects receiving ACE
inhibitors. The results revealed that there was no significant
benefit with valsartan for mortality (relative risk 1.02 (0.88,
1.18)); however, a benefit was seen in the composite end
points of mortality and morbidity (relative risk 0.87 (0.77,
0.97)). Further evidence suggested benefit for the use of
combination therapy for treatment of CHF with the
publication of the CHARM studies (Table 2). The CHARM
studies were a series of three clinical trials evaluating the
effects of candesartan on subjects with CHF intolerant to
ACE inhibitors (CHARM-Alternative trial),36 on subjects
currently on ACE inhibitors with a preserved ejection
fraction (CHARM-Preserved trial),37 and on subjects cur-
rently on ACE inhibitors with a reduced ejection fraction
(CHARM-Added trial).38 On the basis of these study results,
Practice Guidelines from both Europe and the United States
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review MW Krause et al.: Combination inhibition of the renin–angiotensin system

Table 1 | Clinical trials for dual therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in
the treatment of hypertension
Study Design Inclusion criteria Sample size Intervention Outcome Results
21
Azizi et al. Double-blind, Essential 177 Losartan and 24-h Ambulatory BP Ambulatory BP: no difference
randomized hypertension enalapril and clinic BP Clinic BP: versus losartan 3.2
( 0.7, 5.7) versus enalapril 4.0
( 1.5, 6.4)
Stergiou et al.22 Cross-over DBP4100 mm Hg 20 Valsartan and 24-h Ambulatory BP SBP: 6.8± 9.7
benazepril DBP: 4.9±6.8
Weir et al.23 Open label, Hypertensive 88 Valsartan and Change in BP SBP: 2.4
randomized pilot African Americans benazepril DBP: 1.7
(P-value NS)
Morgan et al.24 Double-blind Systolic 23 Candesartan and 24-h Ambulatory BP versus candesartan alone 6.4
cross-over hypertension in the lisinopril versus (P=0.0003)
elderly over the age monotherapy versus lisinopril alone 3.3
of 65 years (P=0.003)
Weir et al.25 Open label Essential 6465 Candesartan and Change in trough SBP: 16.4
clinical experience hypertension or other ACE inhibitors sitting BP DBP: 10.4
isolated systolic P-value o0.05
hypertension
Schulte et al.26 Open label Primary 4531 Candesartan and Change in sitting clinic DBP: 14.9
non-randomized hypertension other ACE inhibitors BP
27
Izzo et al. Double-blind, Essential Cohort 1: 537 Candesartan and Mean change in BP Cohort 1: 2.39 ( 3.86, 0.92)
randomized hypertension Cohort 2: 555 lisinopril Cohort 2: 1.21 ( 2.57, 0.16)
28
Doulton et al. Meta-analysis HTN subjects with 434 ACE inhibitor 24-h Ambulatory and versus ACE inhibitor alone
BP as outcome and ARB clinic blood pressure ambulatory BP: 4.7 ( 6.50, 2.87)
variable and Clinic BP: 3.8 ( 6.74, 0.94)
randomization versus ARB alone ambulatory
BP: 3.8 ( 5.29, 2.35)
Clinic BP: 3.7 ( 6.92, 0.39)
ONTARGET Double-blind, High-risk vascular 25,620 Telmisartan and CV death, myocardial versus ramipril
Investigators29 randomized disease or diabetes ramipril infarction, stroke, SBP: 2.4
mellitus with hospitalization for CHF DBP: 1.4
preserved ejection
fraction
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CHF, congestive heart failure; CV, cardiovascular; DBP, diastolic
blood pressure; HTN, hypertension; NS, non-significant; SBP, systolic blood pressure.

Table 2 | Summary of the results of the CHARM studies (The effect of candesartan with chronic heart failure on standard-of-
care congestive heart failure therapy)
CHARM studies Study population Sample size Intervention Outcome Results

CHARM-Alternative trial CHF with NYHA II–IV, 2028 Candesartan 32 mg Cardiovascular death or HR 0.70 (0.60, 0.81),
intolerant of ACE inhibitors daily versus placebo hospitalization for CHF P-value o0.0001
CHARM-Preserved trial CHF with NYHA II–IV, 3023 Candesartan 32 mg Cardiovascular death or HR 0.86 (0.74, 1.0),
preserved ejection fraction daily versus placebo hospitalization for CHF P-value=0.051
CHARM-Added trial CHF with NYHA II–IV, reduced 2548 Candesartan 32 mg Cardiovascular death or HR 0.85 (0.75, 0.96),
ejection fraction of p40% daily versus placebo hospitalization for CHF P-value=0.01
Abbreviations: ACE, angiotensin-converting enzyme inhibitor; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity; CHF, congestive
heart failure; HR, hazard ratio; NYHA, New York Heart Association.
See references Granger et al.36; Yusuf et al.37; and McMurray et al.38

suggest recommendations for the use of combination therapy
in CHF. The European guidelines recommend that an ARB is
indicated in CHF with ejection fraction p40% if there are
CHF symptoms on optimal standard-of-care therapy
with ACE inhibitors (class of recommendation 1, level of
evidence A).39 The United States guidelines are slightly
different, and in the most recent 2009 update, recommenda-
tions suggest that an ARB added to an ACE inhibitor may be
considered in symptomatic CHF but should not be used with
other aldosterone antagonists (class II recommendation, level
of evidence B).40 The difference in the two guidelines focused
on the strength of the evidence for a lack of all-cause
mortality benefit demonstrated in the combination therapy
treatment groups in the aforementioned clinical trials.35–38
Ischemic heart disease
Clinical trials examining the efficacy of combination therapy
as compared with monotherapy are limited in subjects with
ischemic heart disease. In 2003, the VALIANT (VALsartan in
Acute myocardial INfarction) trial showed that in subjects
with acute myocardial infarction with left ventricular
dysfunction, there was no difference in mortality or in the
secondary end points of death by cardiovascular causes,
recurrent myocardial infarction, or hospitalization for CHF
in the combination of valsartan and captopril as compared
with captopril alone.41 There is a paucity of clinical trials
examining the effects of combination therapy for myocardial
infarction with preserved left ventricular function, and in a
recent systematic review, the only clinical trial that was able

248 Kidney International (2011) 80, 245–255

MW Krause et al.: Combination inhibition of the renin–angiotensin system
to be included was the ONTARGET trial.29,42 The authors
reiterated the previously published ONTARGET study
conclusions that there was no benefit for combination
therapy on reducing the risk of mortality or other
cardiovascular outcomes for myocardial infarction with
preserved ejection fraction and that there may be harm with
the increased risk of adverse events in the combination
therapy group.
Summary of the evidence for dual blockade of the
renin–angiotensin system and cardiovascular disease
At this time, there is no compelling evidence to recommend
the use of combination therapy simply for the treatment of
hypertension. Combination therapy does not change all-
cause mortality in CHF; however, clinical evidence supports
that combination therapy may be considered for those with
symptomatic CHF with reduced ejection fraction to reduce
cardiovascular death and hospitalizations. There is no benefit
of combination therapy for acute myocardial infarction with
reduced or preserved left ventricular function.
DUAL BLOCKADE OF THE RENIN–ANGIOTENSIN SYSTEM AND
CKD
Rationale
Blockade of the renin–angiotensin system with either ACE
inhibitors or ARBs has been shown in numerous studies to
improve outcomes in CKD beyond their effects on lowering
systemic blood pressure. Although the precise mechanism is
not known, the additional beneficial effects have been
attributed to preferentially lowering intra-glomerular pres-
sure through effects on the efferent arteriole resulting in
reduction in proteinuria, blocking of mediators of inflam-
mation, inhibiting oxidative stress, and eventually preventing
fibrosis and renal scarring.43–45 Dual blockade of the
renin–angiotensin system with ACE inhibitors and ARBs
has been postulated to improve clinical outcomes in CKD
superior to monotherapy by greater reduction in proteinuria,
which is a risk factor for CKD progression and end-stage
kidney disease (ESKD). The remainder of this review focuses
on the clinical evidence of combination therapy in both
diabetic and non-diabetic kidney disease.
Diabetic kidney disease
Diabetes mellitus is the leading cause of CKD and ESKD in
the United States. Numerous randomized clinical trials have
demonstrated the benefit of ACE inhibitors or ARBs in
albuminuria reduction and in slowing CKD progression in
diabetic nephropathy.46–50 The concept of dual blockade of
the renin–angiotensin system with combination therapy was
advanced in the late 1990s and early 2000s, with several small
clinical trials suggesting renoprotection in diabetics with both
microalbuminuria and overt nephropathy. One of the largest
of these early clinical trials was performed by Mogensen
et al.51 with the publication of the CALM (The Candesartan
And Lisinopril Microalbuminuria) study. At 12 weeks,
combination therapy with candesartan and lisinopril was
Kidney International (2011) 80, 245–255
review
more effective than monotherapy in blood pressure lowering
and reducing albuminuria. However, this trial was criticized
by the use of suboptimal drug doses that were not applicable
to clinical practice. In a subsequent trial, Rossing et al.52
added candesartan to maximal doses of an ACE inhibitor in
type 2 diabetic subjects and demonstrated that there was
additional blood pressure lowering and proteinuria reduction
with combination therapy as compared with monotherapy.
An insignificant decline in glomerular filtration rate (GFR)
was also noted in the combination treatment group.
Although this trial used drug dosing that was more applicable
to clinical practice, it was still limited by a small sample size
of 20 subjects and short duration of 8 weeks follow-up.
Similar results have been demonstrated for combination
therapy in type 1 diabetics. In a small clinical trial of 20
subjects, the combination of benazepril and valsartan was
more effective in reducing blood pressure and albuminuria at
8 weeks compared with monotherapy and confirmed the
CALM study results.53 However, it is noteworthy that there
was a significant decline in the GFR in the combination
group of 10 ml/min per 1.73 m2 as compared with the
monotherapy groups that was reversible once therapy was
discontinued. These studies were again criticized for using
suboptimal dosing regimens for both ACE inhibitors and
ARBs. Jacobsen et al.54 reported results of a small clinical trial
in type 1 diabetics with hypertension and nephropathy, who
had a maximum dose of irbesartan added to maximal doses
of enalapril. At 8 weeks, there were significant reductions in
blood pressure and in proteinuria excretion in the combina-
tion therapy group than in the enalapril only group; however,
long-term follow-up was not reported.
A meta-analysis of the clinical trials for combination
therapy in diabetic subjects was published in 2007 by
Jennings et al. 55 This analysis included 10 trials with 156
subjects receiving combination therapy. The results demon-
strated that combination therapy was more effective in
reducing proteinuria; however, there was a decrease in
estimated GFR (eGFR) and a trend toward increased
creatinine in the combination group. The authors concluded
that recommendation for widespread use of combination
therapy for diabetic nephropathy is limited by using
proteinuria as a surrogate marker for kidney outcomes, and
lack of hard clinical end points such as morality or
cardiovascular events in the active treatment groups. In
attempts to address issues of short follow-up times and small
sample sizes, the CALM II trial and the IMPROVE
(Irbesartan in the Management of PRoteinuric patients at
high risk for Vascular Events) trial were performed to
examine the effects of combination therapy on albuminuria
reduction and blood pressure control over a longer treatment
time56 and in larger populations.57 In the CALM II trial, the
combination of candesartan and lisinopril was compared
with uptitration of lisinopril alone in hypertensive diabetic
subjects. In contrast to the CALM study, at the end of 12
months, there was no significant difference in blood pressure
lowering or albuminuria excretion in the combination group
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as compared with lisinopril alone. In the IMPROVE trial, 405
hypertensive subjects with microalbuminuria at high cardi-
ovascular risk previously on ACE inhibitors were randomized
to combination therapy with irbesartan and ramipril versus
ramipril alone. No significant difference was demonstrated in
the combination therapy as compared with ramipril, despite
lower blood pressures in the combination arm. In a
subanalysis of those with albumin excretion rates of
X200 mg/min, there was a trend toward benefit with
combination therapy as compared with ramipril, but this
analysis was significantly underpowered to adequately
address the use of combination therapy in macroalbuminur-
ia. These results mirrored previous hypertension studies that
combination therapy has not been proven to be superior to
maximal doses of monotherapy,27 and raise the question that
if blood pressure is similar in the treatment groups, is there a
demonstrable renoprotective effect unique to ACE inhibitors
and ARBs in CKD? This was brought into question with the
publication of a meta-analysis by Casas et al.,58 in 2005, who
reported that there was no added benefit of ACE inhibitors or
ARBs in doubling of the serum creatinine or progression to
ESKD in diabetic subjects compared with other anti-
hypertensive medications independent of their blood pres-
sure-lowering effects.
Despite the lack of supporting clinical evidence of benefit
with clinically meaningful outcomes, the use of combination
therapy for diabetic kidney disease became a widespread
practice among many nephrologists and other treating
physicians in the community. Concerns regarding the safety
of combination therapy arose with the publication of the
ONTARGET study29 specifically with regard to kidney
outcomes.59 Pre-specified analyses of the ONTARGET trial
were performed to determine the effects of combination
therapy on a primary composite outcome of dialysis,
doubling of serum creatinine, or death, and second by
changes in surrogate markers of kidney disease by decline in
eGFR and change in albuminuria as measured by urinary
albumin-to-creatinine ratios. Despite a reduction in albumi-
nuria, there was an increased number of primary events with
combination therapy (hazard ratio 1.09 (1.01, 1.18)).
Combination therapy also increased the risk for dialysis or
doubling of serum creatinine (hazard ratio 1.24 (1.01, 1.51)).
The authors concluded that there was no benefit of
combination therapy on kidney outcomes, and in fact,
combination therapy led to overall harm. The results of this
trial led to widespread criticisms of the study design and
flaws in the interpretation of the results.60–62 Such criticisms
include a lack of standardization of creatinine, single
measurements of both creatinine and urinary albumin-to-
creatinine ratios at study visits, and the use of eGFR based on
the Modification of Diet in Renal Disease study equation that
is not validated in populations with eGFR 460 ml/min per
1.73 m2 or in older subjects that were included in this
trial.63,64 Moreover, the early decline in eGFR in combination
therapy was an anticipated hemodynamic effect that has been
demonstrated in other clinical trials,65 and if taken into
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MW Krause et al.: Combination inhibition of the renin–angiotensin system
consideration in the statistical analysis, then there was no
significant difference in eGFR decline with combination
therapy as compared with monotherapy. In addition,
criticisms accurately state that the need for dialysis was
largely for acute dialysis and not for progression to ESKD. If
acute dialysis was excluded from study analyses, then there
was no difference in combination therapy as compared with
monotherapy. However, it should be noted that although
acute dialysis should not be included as events for dialysis
that implies ESKD, acute kidney injury requiring dialysis is
not benign. Acute kidney injury is associated with significant
morbidity and mortality and even if kidney function
recovers, acute kidney injury is one of the greatest risk
factors for the development of CKD and progression to
ESKD especially in an elderly population.66 Therefore, any
dialysis places an individual at risk, and exclusion of these
events in attempts to justify the use of combination therapy for
CKD needs to be carefully considered. If one interprets the
ONTARGET trial with the flaws and criticisms for kidney
outcomes, then the best interpretation is that there is no
additional benefit with combination therapy as compared with
monotherapy in high-risk cardiovascular and diabetic subjects.
Another factor to consider is the generalizability of the
ONTARGET trial to the diabetic population. Only 4% of the
diabetics enrolled in this trial had macroalbuminuria, and
evidence has suggested that this high-risk population is the
most likely to derive benefit from combination therapy.
Clinical trial evidence is lacking at this time to fully answer
how best to manage diabetics with overt nephropathy. There
is some evidence that suggests that in a small cohort of
patients with nephrotic range proteinuria, targeted treatment
of proteinuria is beneficial. Ruggenenti et al. published their
experience using ‘remission clinics’ in the treatment of CKD.
In this cohort, one-third of the subjects with nephrotic range
proteinuria were diabetic and were compared with matched
historical controls of therapy targeted at blood pressure.67
The remission clinics initiated therapy with ramipril, then
losartan, and finally verapamil titrated to maximal doses to
reduce proteinuria excretion to o0.3 g/day. When analyzing
diabetic subjects as compared with non-diabetics, active
remission clinic treatment reduced 24 h proteinuria excretion
by 50%, but only a small percentage of diabetics achieved
remission of o0.3 g/day. In addition, diabetics in remission
clinics did not demonstrate protection in decline in eGFR as
did non-diabetic subjects, and there was no benefit in
diabetic subjects in the projection of reaching ESKD.
Acceptable goal blood pressures were not achieved in diabetic
subjects, and thus may have influenced the study results with
this targeted proteinuria approach.
If one considers ONTARGET a failure for combination
therapy acknowledging the criticisms, then why did it fail?
Was the perception of benefit of combination therapy
brought on by our interpretation of previous small, under-
powered, clinical trials in which proteinuria reduction was
used as a surrogate marker for CKD outcomes? There have
been numerous occasions in which a surrogate marker of a
Kidney International (2011) 80, 245–255
MW Krause et al.: Combination inhibition of the renin–angiotensin system
Table 3 | Current clinical trials of combination therapy in diabetic nephropathy: NEPHRON-D study (Combination angiotensin
receptor blockers and angiotensin-converting enzyme inhibitor for the treatment of diabetic nephropathy), VALID trial
(Preventing ESRD in overt nephropathy of type 2 diabetes), and the ALTITUDE trial (Aliskiren in Type 2 Diabetes using
cardiorenal end points)
Clinical trial Study population
NEPHRON-D Type 2 diabetes mellitus with
macroalbuminuria
VALID Type 2 diabetes mellitus with
macroalbuminuria 42000 mg/g
ALTITUDE Type 2 diabetes mellitus and/or
AgeX35 years
Microalbuminuria and eGFR
30–60 ml/min per 1.73 m2
History of cardiovascular
disease with an eGFR
30–60 ml/min per 1.73 m2
Abbreviations: ACE, angiotensin-converting enzyme; CHF, congestive heart failure; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease. See references
Freid et al.74; Parving et al.75; and Dillon.76
disease does not correlate with clinical benefit especially in
cardiovascular disease trials.68,69 At present, the FDA will only
accept hard clinical end points for drug approval for the
treatment of CKD, which includes the need for dialysis
or kidney transplantation, doubling of serum creatinine,
cardiovascular disease events, or death. Proteinuria reduction
is not accepted at this time as a valid surrogate marker for
CKD progression. In addition, any clinical trial of CKD using
microalbuminuria as a surrogate marker of nephropathy is
now in question with evidence to suggest that microalbumi-
nuria may be considered as a marker of endothelial
dysfunction rather than nephropathy, there is a lack of
correlation for reduction in microalbuminuria and clinical
outcomes in progressive kidney failure, there is spontaneous
resolution of microalbuminuria in up to one-third of
patients, and finally, microalbuminuria is markedly variable
in patients on repeated measurements.70–72 In 2008, the
National Kidney Foundation and the FDA led a scientific
workshop entitled ‘Proteinuria as a Surrogate Outcome in
Chronic Kidney Disease’.73 The charge of the workshop was
to address three areas: ‘1. the importance of proteinuria in
CKD, 2. evaluation of surrogacy in clinical trials, and
3. evaluation of change in proteinuria as a surrogate outcome
in kidney disease progression in 3 broad clinical areas: early
diabetic kidney disease, nephrotic syndrome, and disease
with mild to moderate proteinuria’.73 The conclusions of the
scientific panel at this workshop was that there is insufficient
evidence that proteinuria reduction correlates with outcomes
in CKD and should not be used as a primary end point in
clinical treatment trials for early diabetic nephropathy. There
was support for the use of proteinuria reduction as a
surrogate outcome in nephrotic syndromes especially if
remission is achieved as this has been reliably associated with
improved CKD outcomes in past studies. Targeted protei-
nuria reduction in kidney diseases with mild-to-moderate
Kidney International (2011) 80, 245–255
review
Intervention Primary outcome
Losartan and lisinopril versus losartan Reduction of 30 ml/min per 1.73 m2 for those
alone with a eGFRX60 ml/min per 1.73m2
Reduction in 50% of eGFR for those with a
eGFR of o60 ml/min per 1.73 m2 at study initiation
Progression to ESKD
Death
Benazepril and valsartan versus Progression to ESKD
benazepril or valsartan alone
Aliskiren versus ACE inhibitors or Cardiovascular death
angiotensin receptor blockers Resuscitated death
Myocardial infarction
Stroke
Hospitalization for CHF
ESKD
Doubling of serum creatinine
proteinuria may be a viable option for surrogacy for CKD
outcomes, but the evidence for this approach is not as strong
as in nephrotic syndromes. There are currently three ongoing
large randomized controlled treatment trials and include the
NEPHRON-D study (Combination ARBs and ACE inhibitor
for the treatment of diabetic nephropathy: NCT00555217),74
the VALID trial (Preventing ESRD in Overt Nephropathy of
Type 2 Diabetes: NCT00494715) (http://clinicaltrials.gov/ct2/
show/study/NCT00494715), and the ALTITUDE (Aliskiren
in Type 2 Diabetes using cardio-renal end points:
NCT00549757) trial75 (Table 3). Results of these trials will
likely provide further insights into the role of combination
therapy in diabetic nephropathy.
Non-diabetic kidney disease
Non-diabetic kidney disease is believed to be a different
entity as compared with diabetic kidney disease and may
correspond with diseases that are more apt to respond to
combination therapy. Several small clinical trials have
demonstrated the benefit of proteinuria reduction and blood
pressure lowering with combination therapy in IgA nephro-
pathy76,77 and in primary glomerular diseases.78,79 Further
clinical evidence for the benefit of combination therapy in
non-diabetic kidney disease occurred in 2003 with the
publication of the COOPERATE (Combination treatment
of angiotensin receptor blocker and angiotensin converting
enzyme inhibitor in non-diabetic renal disease) study.80 The
COOPERATE study was designed to evaluate the efficacy of
combination therapy with trandolapril and losartan as
compared with monotherapy alone, and the authors
concluded that combination therapy was superior to
monotherapy by reducing CKD progression measured by
doubling of the serum creatinine or ESKD. However, in 2006,
the COOPERATE trial study results came into question by a
letter to the Editor in the American Journal of Nephrology by
251
review
Anil Bidani with regard to blood pressure reporting,81 and
additionally in preparation for a meta-analysis of combina-
tion therapy in CKD, Kunz et al.82 submitted a letter of
warning to The Lancet that suggested that further investiga-
tion should be performed to validate the previously
published COOPERATE trial results. The Lancet responded
to the letter of warning and in 2008 retracted the
COOPERATE trial after investigation concluded that the
scientific merits of the study followed gross misconduct.
After retraction of the COOPERATE trial, two subsequent
meta-analysis studies were published examining the effects of
combination therapy in CKD.83,84 Both meta-analyses
demonstrated benefit in proteinuria reduction with combi-
nation therapy; however, the inclusion of the trials was
limited by small sample sizes, short-term follow-up, lack of
demonstrable benefit for meaningful clinical end points such
as mortality, progression of CKD, or ESKD, and the authors
concluded that clinical evidence is lacking to support the use
of combination therapy in the treatment of CKD.
In contrast to the results published in the meta-analyses for
CKD, Ruggenenti et al.67 have demonstrated dramatic results
with a targeted proteinuria reduction approach with combi-
nation therapy in their remission clinics for non-diabetic
kidney disease. Approximately 30% of the non-diabetic
subjects achieved remission proteinuria of p0.3 g/day. There
was a significant reduction in the projection to ESKD in the
subject’s lifetime from 72 to 28%, and the projected time to
reach ESKD increased from 8 years to 29 years. Perhaps
targeting proteinuria rather than blood pressure is an optimal
approach in the management of high-risk CKD.
Future trials may be able to further provide us with
recommendations for combination therapy in non-diabetic
CKD. The HALT PKD (HALT Progression of Polycystic Kidney
Disease: NCT00283686) trial is evaluating the effect of the
combination of lisinopril and telmisartan compared with
lisinopril alone in polycystic kidney disease, with outcomes
measured by change in total kidney volume by abdominal
magnetic resonance imaging for those with eGFR 460 ml/min
per 1.73 m2, or time to reach 50% reduction in baseline eGFR,
ESKD, or death for those with eGFR 25–60 ml/min per 1.73 m2
(ref. 85). The LIRICO (Long-term Impact of RAS Inhibition on
Cardiorenal Outcomes) trial is designed to evaluate the effects
of combination therapy on high-risk subjects with micro-
albuminuria with a primary composite outcome of cardiovas-
cular death, coronary hearty disease, nonfatal stroke,
hospitalization for a cardiovascular event.86
Summary of the evidence for dual blockade of the
renin–angiotensin system and CKD
Large-scale randomized controlled outcome trials thus far
have failed to demonstrate superiority for combination
therapy for halting progression of CKD. An argument should
be made that targeting proteinuria rather than blood pressure
and using supra-therapeutic dosing regimens may have an
advantage over our current practice patterns for combination
therapy in CKD.67,87–89
252
MW Krause et al.: Combination inhibition of the renin–angiotensin system
DIRECT RENIN INHIBITION COMBINED WITH ACE INHIBITORS
OR ARBs
As stated earlier, combination therapy does not result in
complete inhibition of the renin–angiotensin system. Renin
is a significant risk factor for cardiovascular disease and
kidney injury,20,90 and plasma renin activity increases with
ACE inhibitor and ARB use. It may be that this ‘incomplete’
blockade of the renin–angiotensin system with combination
therapy has led to the lack of benefit seen thus far in
cardiovascular disease and CKD trials. After approval in
2007, clinical trials were developed to study the effects of
aliskiren in combination with either ACE inhibitors or ARBs
in cardiovascular disease and CKD. Recently, the results of
the ASPIRE (Aliskiren Study in Post-MI patients to Reduce
rEmodeling) trial were presented at the American College of
Cardiology in 2010. In this trial, aliskiren was added to either
ACE inhibitors or ARBs in subjects with acute myocardial
infarction and left ventricular dysfunction. The investigators
cited that there was no benefit of aliskiren on cardiovascular
death, recurrent myocardial infarction, stroke, and resusci-
tated sudden death.91 Little evidence is available for direct
renin inhibition with CHF; however, an ongoing trial, the
ATMOSPHERE trial (Efficacy and Safety of Aliskiren and
Aliskiren/Enalapril Combination on Morbi-mortality in
Patients With Chronic Heart Failure: NCT00853658), is
evaluating the efficacy and safety of aliskiren and aliskiren/
enalapril combination in patients with chronic heart
failure with a primary outcome of cardiovascular death or
CHF hospitalization (http://clinicaltrials.gov/ct2/show/
NCT00853658). Similar to previous CKD trials, the AVOID
(Aliskiren in the Evaluation of Proteinuria in Diabetes) trial
has demonstrated efficacy for aliskiren on proteinuria
reduction in combination with losartan for diabetic nephro-
pathy over a short time period but lacked clinical end
points.92 The ongoing ALTITUDE trial75 will be provide
further insights into the role of aliskiren in the treatment of
diabetic nephropathy.
CURRENT RECOMMENDATIONS AND FUTURE DIRECTIONS
FOR THE USE OF COMBINATION THERAPY
On the basis of evidence to date, we have summarized
current recommendations in Table 4 (http://www.
uspreventiveservicestaskforce.org/3rduspstf/ratings.htm). We
believe that proteinuria remission is a reasonable target for
those with CKD and those with macroalbuminuria should be
considered a high-risk population that may benefit from
such an approach until further randomized clinical trial
evidence with meaningful clinical outcomes is available to
guide our practice. Importantly, it should be emphasized
that there have been no adequately powered completed
clinical trials or ongoing clinical trials that will fully
address cardiovascular outcomes with combination therapy
with ACE inhibitors and angiotensin II receptor blockers
in CKD.
At present, development of novel therapies for halting
progression in CKD requires extensive resources and
Kidney International (2011) 80, 245–255
MW Krause et al.: Combination inhibition of the renin–angiotensin system review

Table 4 | Summary of recommendations based on clinical evidence for the use of dual blockade of the renin–angiotensin
system with ace inhibitors and angiotensin receptor blockers for cardiovascular and chronic kidney disease
Cardiovascular disease
Hypertension
Level of evidence D: No clinical evidence that supports recommendation for combination therapy in hypertension
Congestive heart failure
Preserved ejection fraction
Level of evidence D: No clinical evidence that supports recommendation for combination therapy
Reduced ejection fraction
Level of evidence B: No clinical evidence that supports recommendation for combination therapy for all-cause mortality, consideration for
combination therapy to reduce hospitalization for congestive heart failure or reduce cardiovascular death
Ischemic heart disease
Preserved ejection fraction
Level of evidence D: No clinical evidence that supports recommendation for combination therapy
Reduced ejection fraction
Level of evidence D: No clinical evidence that supports recommendation for combination therapy

Chronic kidney disease

Diabetic kidney disease
Microalbuminuria
Level of evidence I: Limited clinical evidence that supports recommendation for combination therapy
Macroalbuminuria
Level of evidence I: Limited clinical evidence that supports recommendation for combination therapy and awaiting further clinical trial evidence
for guidance
Non-diabetic kidney disease
Proteinuria o500 mg/day
Level of evidence I: Limited clinical evidence that supports recommendation for combination therapy and awaiting further clinical trial evidence
Proteinuria X500 mg/day
Level of evidence C: Limited clinical evidence that supports recommendation for combination therapy but favors use while awaiting further
clinical trial evidence
Level of evidence based on the US Preventive Services Task Force. Level A: good scientific evidence suggests that the benefits of the clinical service substantially outweigh the
potential risks. Clinicians should discuss the service with eligible patients. Level B: at least fair scientific evidence suggests that the benefits of the clinical service outweigh the
potential risks. Clinicians should discuss the service with eligible patients. Level C: at least fair scientific evidence suggests that there are benefits provided by the clinical
service, but the balance between benefits and risks are too close for making general recommendations. Clinicians need not offer it unless there are individual considerations.
Level D: at least fair scientific evidence suggests that the risks of the clinical service outweigh potential benefits. Clinicians should not routinely offer the service to
asymptomatic patients. Level I: Scientific evidence is lacking, of poor quality, or conflicting, such that the risk versus benefit balance cannot be assessed. Clinicians should help
patients understand the uncertainty surrounding the clinical service.

large-scale randomized clinical trials lasting several years. As DISCLOSURE

a result, proteinuria has often been used as a surrogate
marker to indicate potentially beneficial effects in halting
CKD progression. However, several examples exist that have
demonstrated that reduction in proteinuria does not always
lead to long-term benefit in halting progression of kidney
disease. In contrast, there are other examples wherein
therapies had no effect on proteinuria but were effective in
halting progression in CKD.93–95 Thus, we are in need of
other biomarkers for CKD progression that are easy to
measure and serve as acceptable surrogates for clinical
efficacy both to the regulatory agencies and to the nephrology
community. Recent studies have indicated that the urinary
biomarkers for acute kidney injury, namely neutrophil
gelatinase-associated lipocalin, kidney injury molecule, and
liver fatty acid-binding protein may also be useful to predict
progression in CKD.96–101 There is a need to urgently obtain
robust data, which would evaluate the utility of the known
and yet undiscovered biomarkers for predicting CKD
progression that would serve as acceptable surrogates for
drug development rather than awaiting the results of large-
scale randomized clinical trials that in the recent past have
not provided us with solid evidence to change our current
practice in the treatment of progressive CKD.
VAF: conflicts to report: Research support (to Tulane): Grants
from Novo-Nordisk, Sanofi-Aventis, Eli Lilly, Pan American
Laboratories, Halozyme, Daiichi-Sankyo, NIH; Honoraria for
Consulting and Lectures: Glaxo Smith Kline, Novartis, Takeda, Novo
Nordisk, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, Pan American
Laboratories, Xoma, NuMe Health. MWK and SVS declared no
competing interests.
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