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J Am Soc Nephrol 15: S64S70, 2004

ACE Inhibition versus Angiotensin Receptor Blockade: Which


Is Better for Renal and Cardiovascular Protection?
GOZEWIJN D. LAVERMAN,* GIUSEPPE REMUZZI, and PIERO RUGGENENTI
*Department of Medicine, Division of Nephrology, University of Groningen, the Netherlands; and Mario
Negri Institute for Pharmacological Research, Bergamo, Italy

Abstract. Chronic renal disease is characterized by a gradual


loss of renal function and an increased cardiovascular risk.
Renin-angiotensin system blockade by angiotensin-converting
enzyme inhibition or angiotensin receptor blockade has distinct
renoprotective and cardiovascular protective effects, but which
of the two drug classes confers more protection is still a matter
of debate. This review highlights and compares the effects of
the two drug-classes in nondiabetic renal disease and in overt
or incipient nephropathy of type 1 and type 2 diabetes. Both
renal and cardiovascular outcomes are considered. Regardless
of their relative efficacy, both drug classes have a dose-re-

sponse relationship for intermediate renal and cardiovascular


parameters. Moreover, combined treatment with angiotensinconverting enzyme inhibition and angiotensin receptor blockade seems to provide better long-term renoprotection than
monotherapy. Actually, in most patients, achieving maximal
renal and cardiovascular protection requires a multidrug regimen, usually including several antihypertensives. Within this
approach, full dose titration of either RAS blocker followed by
add-on with the second drug is more important than the choice
of the initial drug.

Chronic renal disease is characterized by a gradual loss of


renal function and an increased cardiovascular risk (1). A
disturbed renal function per se is a major predictor of cardiovascular complications (2). Particularly patients who have
reached ESRD experience dramatically reduced life expectancy as a result of cardiovascular mortality. Thus, renoprotection (aimed to prevent ongoing renal function loss toward
ESRD) and cardiovascular protection (to prevent cardiovascular events) are independent but related goals in patients with
chronic nephropathies.
During the past decades, a tremendous body of research,
both experimental and clinical, has unequivocally shown that
pharmacologic blockade of the renin-angiotensin system
(RAS) slows progressive renal function loss more effectively
than other antihypertensive treatments (reviewed in 3).
Two classes of antihypertensive drugs that block the RAS
are in clinical use: the angiotensin-converting enzyme (ACE)
inhibitors and the angiotensin receptor blockers (ARB). Both
types of drugs limit the effects of angiotensin II (AngII), the
former by inhibiting the AngIII conversion and the latter by
blocking the type 1 receptor of AngII. In addition to the
antihypertensive effect, AngII inhibition exerts specific effects
in the vasculature (4) and the kidney, i.e., decreased intraglo-

merular pressure, improved glomerular-barrier size selectivity,


and reduction of proteinuria (5,6).
Renoprotection trials with ACE inhibition and ARB have
invariably shown that the renoprotective benefit of these drugs
is mainly explained by their specific antiproteinuric effect
(79). This is consistent with the view that proteins, once
leaked through the glomerular barrier, act as mediators of
ongoing renal fibrosis (10).
Still, the mechanisms of action are not completely similar.
Inhibition of ACE results also in decreased breakdown of the
vasodilator bradykinin (11), whereas signaling through the
AT2 receptor may be increased during ARB treatment. Thus,
theoretically, there might be relevant differences between the
drug classes, but the clinical importance for renal disease of
these differences is not clear. In this review, we discuss the
renal and cardiovascular effects of ACE inhibition and ARB in
patients with chronic nephropathies, and we attempt to answer
the question of which treatment is to be preferred in renal
patients.

Correspondence to Dr. Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research, Negri Bergamo Laboratories, Via Gavazzeni, 11-24125
Bergamo, Italy. Phone: 39-035-319-888; Fax: 39-035-319-331; E-mail:
gremuzzi@marionegri.it
1046-6673/1512-0064
Journal of the American Society of Nephrology
Copyright 2004 by the American Society of Nephrology
DOI: 10.1097/01.ASN.0000093368.27046.3C

RAS Blockade: Renoprotective Effects in


Chronic Nephropathies
Renoprotective Effects of ACE Inhibition
Nondiabetic Renal Disease. In nondiabetic renal disease,
there is a clear renoprotective advantage of ACE inhibitors as
compared with BP-lowering therapies not interfering with the
RAS. The Ramipril Efficacy In Nephropathy (REIN) study
included 352 patients with chronic nephropathies, primarily of
nondiabetic origin, and these were randomized to treatment
with the ACE inhibitor ramipril or placebo on top of other
antihypertensive agents. The main finding was that ramipril
treatment resulted in a slower decline in GFR compared with
placebo, despite equivalent BP control (12). A later analysis

J Am Soc Nephrol 15: S64S70, 2004

indicated that a subset of patients on prolonged treatment with


ramipril even had a rise in GFR (13). Recently, a large-scale
trial demonstrated that the renoprotective effect of ACE inhibition is superior to that of conventional antihypertensive regimens (including blockers and calcium channel blockers)
also in black patients (14), a population so far considered to be
poorly responsive to RAS blockade.
Type 1 Diabetes. The collaborative study found that in
patients with overt nephropathy of type 1 diabetes, ACE inhibition with captopril induced a clear reduction in proteinuria,
as compared with treatment not directly interfering in the RAS.
The antiproteinuric benefit of captopril was associated with a
slower decline in creatinine clearance and a reduction of the
primary end point doubling of serum-creatinine of approximately 50% (8).
The European Microalbuminuria Captopril Study showed
that in microalbuminuric patients with type 1 diabetes, ACE
inhibition decreases the risk to develop overt nephropathy by
approximately 75% (15), which proves that ACE inhibition has
beneficial renal effects also at the earlier stage of incipient
nephropathy. This is clinically important because microalbuminuria is a strong predictor of overt nephropathy and cardiovascular morbidity (16).
Type 2 Diabetes. Six small studies that included 352
patients altogether uniformly found that ACE inhibition reduces proteinuria more effectively than conventional therapy
also in overt nephropathy of type 2 diabetes (17). However, as
well as the post hoc analysis on the small subgroup of patients
with diabetes (n 27) enrolled in the REIN study (18), these
studies did not have sufficient statistical power to detect a
difference in renal function loss. Thus, a considerably larger
clinical trial of approximately 1000 to 2000 patients would be
required to test the hypothesis of a specific renoprotective
effect of ACE inhibition in type 2 diabetic nephropathy. Unfortunately, such a trial has not been conducted so far.
At the stage of incipient nephropathy, a decrease in microalbuminuria has been observed with ramipril compared with
placebo (19). The substudy in 3577 patients with diabetes
(primarily type 2) of the Heart Outcomes Prevention Evaluation (HOPE) trial showed that, compared with placebo, treatment with the ACE inhibitor ramipril resulted in a 24% reduction of the risk to develop overt nephropathy in patients who
were either normo- or microalbuminuric (20). In the same line,
ACE inhibition with enalapril reduced in normoalbuminuric
patients with type 2 diabetes the risk to develop microalbuminuria by 12.5% (21). The BErgamo NEphrology DIabetic
Complications Trial (BENEDICT) is now in progress to test
whether the ACE inhibitor trandolaprilalone or in combination with the calcium channel blocker verapamilreduces the
risk to develop microalbuminuria in hypertensive patients with
type 2 diabetes and normoalbuminuria (22).

Renoprotective effects of ARB


Nondiabetic Renal Disease and Type 1 Diabetes. Largescale trials on the long-term renoprotective effect of ARB in
nondiabetic and type 1 diabetic renal disease are missing so far.

ACEi versus ARB in Chronic Nephropathies

S65

Type 2 Diabetes. Two rigorously powered trials that included 1500 patients, the Irbesartan in Diabetic Nephropathy
Trial (IDNT) (23) and the Reduction of Endpoints in Type 2
Diabetes Mellitus with the Angiotensin II Antagonist Losartan
(RENAAL) trial (24), compared ARB with conventional therapy in patients with type 2 diabetes and overt nephropathy. In
these two studies, ARB treatment reduced the relative risk of
reaching the primary composite end point (doubling of serum
creatinine, ESRD, or death) by 20% and 16%, respectively. In
addition, the IDNT showed a reduction of the risk to reach the
primary end point by 23% also as compared with calcium
channel blockade by amlodipine, the third treatment arm in this
study.
Recently, the Microalbuminuria Reduction with Valsartan
study (25) and the Irbesartan in Patients with Type 2 Diabetes
and Microalbuminuria study (26) showed the beneficial effect
of ARB also at the stage of incipient nephropathy. In the
Microalbuminuria Reduction with Valsartan study, valsartan
reduced albuminuria by 44%, compared with an 8% reduction
in the control arm with amlodipine. Moreover, normoalbuminuria was restored in 30% of the patients who were treated with
valsartan (versus 15% with amlodipine). The Irbesartan in
Patients with Type 2 Diabetes and Microalbuminuria study
showed, in addition to a clear-cut reduction of the primary end
point overt nephropathy (i.e., progression to macroalbuminuria), a 24% and 38% decrease in albuminuria with irbesartan
150 mg and 300 mg, respectively, whereas albuminuria remained almost unchanged (2%) in the placebo arm.

Renoprotective Effects of ACE Inhibition versus ARB


In summary, there is ample evidence that blocking the RAS
is advantageous for renoprotection over other antihypertensive
drugs. At first sight, however, the trials with ACE inhibitors
and ARB show some striking differences (Figure 1). If one
considers only the renal end points in the trials in type 2
diabetic nephropathy, then ARB reduced the risk of ESRD by
28% in the RENAAL and by 23% in the IDNT. Although
statistically significant and clinically important, these reductions look remarkably less impressive as compared with those
observed with ACE inhibitor therapy in nondiabetic renal
disease and type 1 diabetic nephropathy, which are close to
50% (Figure 1). Because the characteristics of the different
study populations may of course contribute to the differences
in outcomes with ACE inhibition and ARB treatment, these
data clearly call for trials aimed to compare formally the
renoprotective effects of the two classes in similar clinical
settings.
In this respect, however, data from trials primarily designed
to compare the effects of combined ACE inhibitor and ARB
treatment to single therapy with each agent alone provide some
useful information, albeit indirect. The recent Combination
Treatment of Angiotensin Receptor Blocker and Angiotensin
Converting Enzyme Inhibitor in Non-diabetic Renal Disease
(COOPERATE) trial studied in 263 Japanese patients with
nondiabetic nephropathies whether dual RAS blockade with
trandolapril and losartan provided better renoprotection than
either drug alone (9). Although not designed or powered to test

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Journal of the American Society of Nephrology

J Am Soc Nephrol 15: S64S70, 2004

Figure 1. Risk reduction of ESRD achieved by angiotensin-converting enzyme inhibition or angiotensin receptor blockade versus placebo plus
conventional treatment in large, prospective trials in patients with and without diabetes and overt nephropathy.

this, during 3 yr of follow-up, the investigators found that the


effects of trandolapril and losartan seemed remarkably similar,
with respect to both reduction of proteinuria and reaching the
end point. On the same line, the Candesartan and Lisinopril
Microalbuminuria study found that the ACE inhibitor lisinopril
and the ARB candesartan, at comparable BP control, achieved
a similar reduction in albuminuria in 197 patients with type 2
diabetes and incipient nephropathy (27).
Altogether, these data suggest that in nondiabetic renal disease and in type 2 diabetes with incipient nephropathy, ACE
inhibition and ARB share a similar renoprotective effect. That
this may apply also to type 1 diabetes and to overt nephropathy
of type 2 diabetes is reasonable but still unproved.

RAS Blockade: Cardiovascular Protective


Effects in Chronic Nephropathies
Cardiovascular Protective Effects of ACE Inhibition
ACE inhibitors decrease mortality and cardiovascular morbidity in a wide array of conditions, including type 2 diabetes
(20), post-myocardial infarction (with/without left ventricular
dysfunction) (28 33) and heart failure, and New York Heart
Association (NYHA) II-IV (34 36). Recent studies found that
this specific cardioprotective effect may apply also to patients
with renal disease.
Nondiabetic Renal Disease. The HOPE study included
9541 high-risk patients, and the main finding was that
ramipril on top of other agentswas associated with a reduction of the cardiovascular risk (37). The outcomes of the
980 patients with impaired renal function at baseline (serum
creatinine 1.4 mg/dl) were evaluated in a separate analysis
and, first of all, this substudy highlighted the strikingly increased risk of cardiovascular mortality and morbidity associated with chronic renal failure (38). Of note, treatment with
ramipril resulted in a clear-cut reduction of the cardiovascular
risk in the patients with impaired renal failure, and this benefit

seemed even larger than in patients with normal renal function


(especially with respect to cardiovascular and total mortality
and heart-failure related hospitalization).
The precise mechanisms of this specific cardioprotective
effect are unclear. In addition to direct vascular effects of
limiting AngII, the specific reduction in proteinuria by ACE
inhibitors and the secondary amelioration of the lipid profile
may contribute to exemplify the direct beneficial effects of
RAS blockade on heart and vessels (39).
Type 1 Diabetes. In the Collaborative Study, captopril
treatment reduced the combined end point, which included
mortality, by 50% (8). Although the relatively small number of
events did not allow the analysis to detect the effect on mortality as statistically significant, these findings suggest that
ACE inhibitor therapy may be cardioprotective in overt nephropathy of type 1 diabetes.
Type 2 Diabetes. No data from large clinical trials are
available showing the effects on cardiovascular outcomes of
ACE inhibition in type 2 diabetic nephropathy. Nevertheless,
the subgroup analysis of the HOPE study that focused on
diabetic patients (micro-HOPE) showed a clear reduction in
cardiovascular end points with ramipril also in this clinical
setting (20). In addition, among the patients with impaired
renal function included in HOPE, ramipril had the same benefits in diabetic as in nondiabetic patients (38). In summary,
these HOPE findings support the use of ACE inhibition to
prevent cardiovascular complications in patients with type 2
diabetes with or without concomitant renal disease.

Cardiovascular Protective Effects of ARB


ARB, on top of other antihypertensives, reduces mortality
and morbidity in heart failure (40). Moreover, the Losartan
Intervention for Endpoint Reduction in Hypertension study
showed in 9222 patients with hypertension and left ventricular
hypertrophy (based on ECG) that ARB by losartan resulted in

J Am Soc Nephrol 15: S64S70, 2004

a clear reduction of the primary composite end point of death,


myocardial infarction, and stroke as compared with the
blocker atenolol, and this difference was found despite equivalent BP control (41). A substudy of the Losartan Intervention
for Endpoint Reduction in Hypertension study showed that the
reduction of the primary composite end point with losartan also
applied to 1195 patients with diabetes and hypertension (42).
Whether this beneficial effect applies also to patients with renal
disease has not been proved so far.
Nondiabetic Renal Disease and Type 1 Diabetes. Data
on cardiovascular outcomes with ARB in nondiabetic and type
1 diabetic renal disease are lacking so far.
Type 2 diabetes. The RENAAL and IDNT were designed
to test the effects of ARB in patients with type 2 diabetic
nephropathy, and both studies had formulated a secondary
composite outcome of cardiovascular mortality and morbidity.
Both studies showed a reduction in the rate of heart failure with
ARB. Disappointingly, however, despite the large sample size,
these trials failed to demonstrate any beneficial effect on cardiovascular events.

ACEi versus ARB in Chronic Nephropathies

S67

bined treatment with the ARB candesartan and the ACE inhibitor lisinopril resulted in stronger BP reduction than monotherapy (27).
In summary, these data show the added renoprotective benefit of combined RAS blockade, at least in nondiabetic renal
disease and incipient nephropathy of type 2 diabetes. Nevertheless, the cardiovascular effects of such a regimen remain to
be established.

How Should RAS Blockade Be Applied in


Renal Patients for Optimal Renal and
Cardiovascular Protection?

In the COOPERATE trial, dual RAS blockade with trandolapril and losartan reduced the risk to reach the primary
composite end point of doubling of serum creatinine or ESRD
by almost 50% as compared with the single agents. The advantage was explained by the superior 75% reduction of proteinuria in the combined group compared with 40 to 45%
reduction with monotherapy (9).

Comparative data on the long-term renal and cardiovascular


protective effects of ACE inhibition and ARB are so scarce that
it is not possible to conclude which of the two drugs is better.
All renoprotection trials have invariably shown that the strongest predictor of long-term renoprotective efficacy is the antiproteinuric effect. It is becoming increasingly clear that the
ACE inhibitors (39,44,45) and ARB (46,47) have a dose
effect relationship for proteinuria, and substudies of HOPE
also show a dose-response for the effect of ACE inhibition on
the progression of atherosclerosis (48) and improvement of
myocardial remodeling (49). With respect to the renal effects,
it is also becoming clear that the dose effect relationship is
different between individual patients, and, as a general rule,
patients with a poor response to ACE inhibition also respond
poorly to ARB (reviewed in 50). Moreover, the differences
between individual patients exceed those observed between
classes of drugs (50). Therefore, these considerations implicate
that it is important to titrate individually for the optimal antiproteinuric effect, the choice of the initial drug being less
important.
A recent study found an additional antiproteinuric effect
when the combination of halved doses of ACE inhibitor and
ARB were used to reduce the BP to a level similar to that
achieved by full dose of monotherapy (51), and this extends
previous findings showing the additional antiproteinuric benefit of combination therapy (52,53). It also has been shown
now that there is additional antiproteinuric benefit of combined
ACE inhibition and RAS blockade, even if the combination is
applied at the top of the dose-response for proteinuria of the
individual agents (45). The COOPERATE trial has now provided evidence that also long-term renoprotection with dual
RAS blockade is better than monotherapy, at least when fixed
doses are used (9). It is tempting to speculate that even more
end points could have been prevented if a strategy of individual
dose titration had been applied (54). It would also be important
to know whether such an approach affects the cardiovascular
outcomes.

Types 1 and 2 Diabetes

Conclusions

In patients with diabetes and overt nephropathy, no data are


available so far on the long-term renoprotective effects of
combined RAS blockade. The Candesartan and Lisinopril Microalbuminuria study demonstrated in patients with type 2
diabetes and microalbuminuria and hypertension that com-

Notwithstanding differences in the mechanism of action


between ACE inhibitors and ARB, no formal comparisons are
available so far to conclude for a superiority of one drug class
over the other one as for renal and cardiovascular protection.
However, available data show impressive differences in re-

Cardiovascular Protective Effects of ACE Inhibition


versus ARB
No direct comparative data are available on cardiovascular
outcomes in chronic renal patients. Subgroup data from patients with diabetes and renal impairment in the HOPE study
seem to suggest better cardiovascular protection with ACE
inhibition than with ARB in RENAAL and IDNT. This comparison is hazardous, however, because the specific category of
high-risk patients with dipstick-positive proteinuria were excluded from the HOPE study. The possibility of a superior
cardioprotective effect of ACE inhibition as compared with
ARB is suggested by the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan study. This randomized, controlled trial in patients at increased cardiovascular
risk found less cardiovascular mortality in the captopril arm
than in the losartan arm (43). However, whether this may apply
also to patients with renal involvement is not established so far.

Effect of Combination Therapy on Renal and


Cardiovascular Outcomes
Nondiabetic Renal Disease

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Journal of the American Society of Nephrology

sponse to RAS blockade between subsets of patients, with


outspoken high risks in patients with type 2 diabetes and
nephropathy, even during treatment with RAS blockade.
For renoprotection, the first step is full titration of the ACE
inhibitor or ARB aimed at optimal reduction of proteinuria,
and this is probably much more important than the choice of
the initial drug. To achieve maximal cardiovascular and renal
protection in terms of BP control, dyslipidemia, and proteinuria
will usually require a multidrug regimen (55), based on dual
RAS blockade and combined therapy with diuretics and lipidlowering agents.

Acknowledgments
G.D.L. is awarded a Marie-Curie fellowship of the European
Union. G.J. Navis provided valuable comments on the manuscript.

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