Angiotensin converting enzyme inhibitors and angiotensin

Angiotensin-converting enzyme inhibitors and angiotensin

receptor blockers for adults with early (stage 1 to 3) non-

diabetic chronic kidney disease (Review)

Sharma P, Blackburn RC, Parke CL, McCullough K, Marks A, Black C

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 10

http://www.thecochranelibrary.com

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic

kidney disease (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

16ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .

18DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 ACEi versus placebo, Outcome 1 Mortality. . . . . . . . . . . . . . . . . 44

Analysis 1.2. Comparison 1 ACEi versus placebo, Outcome 2 Cardiovascular events. . . . . . . . . . . . 45

Analysis 1.3. Comparison 1 ACEi versus placebo, Outcome 3 Doubling of creatinine. . . . . . . . . . . . 46

Analysis 1.4. Comparison 1 ACEi versus placebo, Outcome 4 Doubling of creatinine by underlying renal pathologies. 47

Analysis 1.5. Comparison 1 ACEi versus placebo, Outcome 5 Adverse events. . . . . . . . . . . . . . . 48

48ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

55INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iAngiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic



[Intervention Review]

Angiotensin-converting enzyme inhibitors and angiotensinreceptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease

Pawana Sharma1, Rachel C Blackburn2 , Claire L Parke2, Keith McCullough2, Angharad Marks2, Corri Black2

1Health Services Research Unit, University of Aberdeen, Aberdeen, UK. 2Institute of Applied Health Sciences, University of Aberdeen,

Aberdeen, UK

Contact address: Corri Black, Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, Grampian, AB52

6NZ, UK. [email protected].

Editorial group: Cochrane Renal Group.

Publication status and date: New, published in Issue 10, 2011.

Review content assessed as up-to-date: 7 March 2010.

Citation: Sharma P, Blackburn RC, Parke CL, McCullough K, Marks A, Black C. Angiotensin-converting enzyme inhibitors and

angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database of SystematicReviews 2011, Issue 10. Art. No.: CD007751. DOI: 10.1002/14651858.CD007751.pub2.


A B S T R A C T

Background

Chronic kidney disease (CKD) is a long term condition that occurs as a result of damage to the kidneys. Early recognition of CKD

is becoming increasingly common due to widespread laboratory estimated glomerular filtration rate (eGFR) reporting, raised clinical

awareness, and international adoption of Kidney Disease Outcomes Quality Initiative (K/DOQI) classification. Early recognition and

management of CKD affords the opportunity not only to prepare for progressive kidney impairment and impending renal replacement

therapy, but also for intervening to reduce the risk of progression and cardiovascular disease. Angiotensin-converting enzyme inhibitors

(ACEi) and angiotensin receptor blockers (ARB) are two classes of antihypertensive drugs that act on the renin-angiotensin-aldosterone

system. Beneficial effects of ACEi and ARB on renal outcomes and survival in people with a wide range of severity of renal impairment

have been reported; however, their effectiveness in the subgroup of people with early CKD (stage 1 to 3) is less certain.

Objectives

This review aimed to evaluate the benefits and harms of ACEi and ARB or both in the management of people with early (stage 1 to 3)

CKD who do not have diabetes mellitus.

Search methods

In March 2010 we searched The Cochrane Library, including The Cochrane Renal Group’s specialised register and The Cochrane

Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. Reference lists of review articles and relevant studies

were also checked. The search was conducted using the optimally sensitive strategy developed by the Cochrane Collaboration for the

identification of randomised controlled trials (RCTs) with input from an expert in trial search strategy.

Selection criteria

All RCTs reporting the effect of ACEi or ARB in people with early (stage 1 to 3) CKD who did not have diabetes mellitus were selected

for inclusion. Only studies of at least four weeks duration were selected. Authors, working in teams of two, independently assessed the

retrieved titles and abstracts, and whenever necessary the full text of these studies were screened to determine which studies satisfied

the inclusion criteria.

1Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic



mailto:[email protected]

Data collection and analysis

Data extraction was carried out by two authors, independently, using a standard data extraction form and cross checked by two other

authors. Methodological quality of included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one

author and cross checked by another author. When more than one study reported similar outcomes, data were pooled using the random-

effects model, but a fixed-effect model was also analysed to ensure the robustness of the model chosen and to check susceptibility to

outliers. Heterogeneity was analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance

and with the I² test. Where data permitted, subgroup analysis was used to explore possible sources of heterogeneity. The quality of the

evidence was analysed.

Main results

Four RCTs enrolling 2177 participants met our inclusion criteria. Of these, three compared ACEi with placebo and one compared

ACEi with ARB. Two studies had an overall low risk of bias, and the other two were considered to be at moderate to high risk of bias.

Low to moderate quality of evidence (from two studies representing 1906 patients) suggested that ACEi had no impact on all-cause

mortality (RR 1.80, 95% CI 0.17 to 19.27, P = 0.63) or cardiovascular events (RR 0.87, 95% CI 0.66 to 1.14, P = 0.31) in people

with stage 3 CKD. For all-cause mortality, there was substantial heterogeneity in the results. One study (quality assessment: low risk

of bias) reported no difference in the risk of end-stage kidney disease in those with an eGFR > 45 mL/min/1.74 m² treated with ACEi

versus placebo (RR 1.00, 95% CI 0.09 to 1.11, P = 0.99). The (high risk of bias) study that compared ACEi with ARB reported little

difference in effect between the treatments when urinary protein, blood pressure or creatinine clearance were compared. No published

studies comparing ARB with placebo or ACEi and ARB with placebo were identified.

Authors’ conclusions

Our review demonstrated that there is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with

stage 1 to 3 CKD who do not have diabetes mellitus. We have identified an area of significant uncertainty for a group of patients who

account for most of those labelled as having CKD.

P L A I N L A N G U A G E S U M M A R Y

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early chronic kidney disease who

do not have diabetes

Chronic kidney disease (CKD) is a long-term condition that occurs as a result of the kidneys being damaged. Progressive deterioration

of kidney function can lead to end-stage kidney disease (ESKD). People with ESKD cannot maintain healthy kidney function and

need kidney dialysis or transplant. In the early stages of CKD, patients may not have any outward symptoms or signs of illness, and

may only be detected following investigations such as urine or blood testing. Two types of drugs - angiotensin-converting enzyme

inhibitors (ACEi) and angiotensin receptor blockers (ARB) - have been widely recommended in clinical guidelines for doctors to use

in the management of CKD. This review identified four studies (enrolling 2177 people). Three studies compared ACEi to placebo or

no treatment and one study compared ACEi to ARB. There is not enough evidence in the published literature at present to determine

how effective drugs in the ACEi or ARB families are for treating patients with early (stage 1 to 3) CKD who do not have diabetes.




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Patientorpopulation:patientswithearly(stage1to3)non-diabeticchronickidneydisease

Settings:hospital

Intervention:ACEi

Com

parison:placebo

Outcomes

Illustrative

comparativerisks*

(95%CI)

Relativeeffect

(95%CI)

NoofParticipants

(studies)

Qualityoftheevidence

(GRADE)

Com

ments

Assumed

risk

Correspondingrisk

placebo

ACEi

Mortality-CKDstage

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Follow-up:

36to

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months

Studypopulation

RR1.8

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1906

(2studies)

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low

1,2,3

103per1000

185per1000

(18to1000)

Mediumriskpopulation

76per1000

137per1000

(13to1000)

Cardiovascularevents-

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3

Follow-up:

36to

42

months

Studypopulation

RR0.87

(0.66to1.14)

1906

(2studies)

⊕⊕

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moderate

2,3

104per1000

90per1000

(69to119)

Mediumriskpopulation

82per1000

71per1000

(54to93)




http://www.thecochranelibrary.com/view/0/SummaryFindings.html

*The

basisfortheassumedrisk

(e.g.themediancontrolgroupriskacross

studies)isprovided

infootnotes.Thecorrespondingrisk(and

its95%confidence

interval)isbasedon

the

assumedriskinthecomparison

groupandtherelativeeffectoftheintervention(andits95%CI).

CI:Confidenceinterval;RR:Riskratio;

GRADEWorkingGroupgradesofevidence

Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.

Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate.

Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate.

Verylowquality:Weareveryuncertainabouttheestimate.

1Therewasasignificantheterogeneityof81%.OnestudyfavourscontrolwhileanotherfavoursACEi.

2Thequalityofevidenceisimprecisebecausethetotalnum

berofeventsislessthan

300(athresholdrule-of-thum

bvalue)(based

on:

Muelleretal.AnnInternMed.2007;146:878-881<http://www.annals.org/cgi/content/abstract/146/12/878>

)3Lessthan10

studies,socreatingafunnelplotwasnotapplicable.




B A C K G R O U N D

Description of the condition

Chronic kidney disease (CKD) is a long-term condition that oc-

curs as a result of damage to the kidneys. In 2002, the US Kidney

Disease Outcomes Quality Initiative (K/DOQI) proposed a clas-

sification for CKD that has been widely adopted internationally

(Levey 2003).

K/DOQI Stages for CKD

Stage Description

1 Normal GFR: GFR > 90 mL/min/1.73 m² with other evidence of chronic kidney damageª

2 Mild impairment: GFR 60 to 89 mL/min/1.73 m² with other evidence of chronic kidney damageª

3 Moderate impairment: GFR 30 to 59 mL/min/1.73 m²

4 Severe impairment: GFR 15 to 29 mL/min/1.73 m²

5 End stage kidney disease (ESKD): GFR < 15 mL/min/1.73 m²

a Other evidence of CKD may be one of the following: persistentproteinuria; persistent haematuria (after exclusion of other causes,such as urological disease); structural abnormalities of the kidneysdemonstrated on ultrasound scanning or other radiological tests (e.g.polycystic kidney disease, reflux nephropathy); or biopsy-proven chronicglomerulonephritis (most of these patients will have microalbuminuriaor proteinuria, and/or haematuria).Classification is based on two markers: evidence of kidney damage

(such as the presence of microalbuminuria, proteinuria or struc-

tural abnormality); and the sustained impairment of glomerular

filtration rate (GFR) for at least three months. Normal GFR in

young adults is around 100 to 120 mL/min/1.73 m².

Early CKD has been described as stages 1 to 3 of the K/DOQI

classification. At these stages, a patient may have no outward symp-

toms or signs of illness and only testing such as dipstick urine

measurement for proteinuria/haematuria or blood test may detect

the presence of a renal abnormality.

Prevalence

Prevalence estimates for CKD vary substantially. Several large,

high quality, population-based screening studies have reported the

prevalence of CKD stage 3 to 5 disease to be around 3.8% to

4.7%; more than 95% of people with an estimated GFR of less

than 60 mL/min/1.73 m² have stage 3 disease (Coresh 2005; Drey

2003; Hallan 2006). In most epidemiological studies, the GFR is

estimated (eGFR) from serum creatinine (SCr) measurements us-

ing an equation; several equations exist and this contributes to the

variation in prevalence reported in these studies. The prevalence

of stage 1 and 2 disease (based on microalbuminuria (albumin/

creatinine ratio (ACR) of 17 to 250 mg/g for men or 25 to 355

mg/g for women) or macroalbuminuria (ACR > 250 mg/g for men

or > 355 mg/g for women) has been reported to be as high as 11%

of the population (CDC 2007). The prevalence of CKD increases

with age (Coresh 2005; Hallan 2006; Imai 2007; John 2004).

An ageing population, escalating prevalence of diabetes mellitus

(one of the major risk factors for CKD), and increasing recogni-

tion are contributing to a reported increase in the prevalence of

early CKD and its growing recognition as a major public health

problem.

Consequences of early CKD

Early CKD, whilst often asymptomatic, is an important health

issue and has implications for individuals and health services. Pro-

gressive deterioration of kidney function can result in end-stage

kidney disease (ESKD) and the need for renal replacement ther-




apy (RRT) in the forms of dialysis or transplantation. The rate of

progression of CKD may be influenced by secondary factors such

as age, race, intraglomerular haemodynamic factors, hypertension

and proteinuria. ESKD has risen globally over the last two decades

at high cost to individuals, their carers and families, and health

services. However, the proportion of people with early CKD who

progress to ESKD is low (Daly 2007; Hallan 2006). A greater

risk for people with early CKD is cardiovascular disease (CVD).

One study that followed patients over a period of five years, re-

ported that 3.1% of people with CKD progressed to requiring

RRT, whereas 24.9% died before reaching dialysis, probably as a

result of CVD (Daly 2007).

Early recognition and management of CKD affords the opportu-

nity not only to prepare for progressive kidney impairment and im-

pending RRT (CHOICE Study 2001; Dogan 2005; Khan 2007;

Kinchen 2002), but also for intervening to reduce the risk of pro-

gression and CVD.

Description of the intervention

Angiotensin-converting enzyme inhibitors (ACEi) and an-

giotensin receptor blockers (ARB) are two classes of antihyper-

tensive drugs that act on the renin-angiotensin-aldosterone sys-

tem (RAAS). Both drug classes have been widely recommended

in guidelines for the management of CKD, particularly in pa-

tients with evidence of proteinuria, and have been reported to pro-

vide both cardioprotective and renoprotective effects. Beneficial

effects of ACEi and ARB on renal outcomes and survival in people

with diabetic kidney disease (DKD) have been reported (Strippoli

2006). For non-diabetic patients with moderate to severe CKD,

there was evidence of benefit in terms of renal outcomes whether

or not proteinuria was present (Jafar 2003a). The evidence for

cardioprotective effects, particularly in non-diabetic patients with

CKD, is less consistent (ASCOT-BPLA Study 2005; HOPE Study

2000; Strippoli 2006).

To date, reviews have combined evidence from study participants

with a wide range of severity of renal impairment but the subgroup

of those with early CKD (stage 1 to 3) have not been presented

separately.

How the intervention might work

As kidneys become damaged and begin to lose nephrons, patients

experience systemic hypertension, proteinuria and a progressive

decline in GFR (Metcalfe 2007). Common pathological changes

are observed regardless of the underlying causes and include early

renal inflammation; tubulointerstitial injury, and glomeruloscle-

rosis (Ruster 2006). The pathophysiology of progressive kidney

function loss involves complex haemodynamic, endocrine, and in-

flammatory factors (Metcalfe 2007; Ruster 2006).

ACEi and ARB both act to inhibit the RAAS endocrine system.

ACEi mode of action includes blocking the conversion of inactive

angiotensin I to active angiotensin II at the level of the enzyme

needed for its conversion. ARB works at a later stage in the RAAS

system and selectively blocks the type I subtype which is a receptor

for angiotensin II (Kumar 2002). Once thought of as a systemic

endocrine system important in mediating vascular tone, RAAS is

now understood to be complex, operating both systemically and

locally within the kidney. Products of the RAAS are understood to

impact on a wide range of renal, as well as haemodynamic, factors

that contribute to the progression of CKD (Kshirsagar 2000a;

Kumar 2002; Ruster 2006).

The action of ACEi and ARB extends beyond simple blood pres-

sure (BP) control and may reflect effects on the complex RAAS

pathways. The ability of both of these drugs to inhibit the RAAS

at different points means that they have the potential to moderate

the functional and structural changes that occur in progressive re-

nal insufficiency (Giatras 1997a; Jafar 2003a; Kshirsagar 2000a).

Why it is important to do this review

Early recognition of CKD is becoming increasingly common due

to widespread laboratory reporting of eGFR, raised clinical aware-

ness, and international adoption of K/DOQI classification. The

high prevalence of early CKD means that many individuals and

clinicians are faced with choices about management. Another

Cochrane review (Strippoli 2006) has reviewed the evidence of

effectiveness in people with diabetic CKD and demonstrated that

ACEi and ARB play a core role in the management and preven-

tion of DKD where proteinuria is a key feature. For people with-

out diabetes, particularly those with normal or mild to moderate

kidney function impairment where proteinuria may or may not

be present, the role of ACEi and ARB is less certain. This review

seeks to summarise the evidence in relation to benefits and harms

of ACEi and ARB for non-diabetic patients with early (stage 1 to

3) CKD.

O B J E C T I V E S

This review aimed to evaluate the benefits and harms of ACEi and

ARB or both in the management of people with early (stage 1 to

3) non-diabetic CKD.

M E T H O D S

Criteria for considering studies for this review

Types of studies




All randomised controlled trials (RCTs) and quasi-RCTs (studies

in which allocation to treatment was obtained by alternation, use

of alternate medical records, date of birth or other predictable

methods) looking at the effect of ACEi or ARB were included.

The first period of randomised cross-over studies were considered

for inclusion. Only studies of at least four weeks duration were

included.

Types of participants

Inclusion criteria

All non-diabetic adults (18 years or over) with early CKD, with

no restriction to gender or race, were considered. Early CKD was

defined as K/DOQI stage 1 to 3. We included studies that mea-

sured eGFR by any method (excretion of iohexol, inulin or simi-

lar marker; estimated from 24 hour urine collection; or estimated

from SCr using a recognised equation).

Studies defining CKD based on SCr or other thresholds of GFR

were included in the review where the results had been presented

separately for those with K/DOQI stage 1 to 3. Studies in general

populations that included people with diabetes were kept in the re-

view where the results were presented separately for those with and

without diabetes. If the results were not presented separately, and

less than 30% of the study population had diabetes mellitus, then

the study was included and the effect on the outcomes assessed in

the sensitivity analysis. The same process was adopted for study

populations that included people with specific renal pathologies

(e.g. immunoglobulin A (IgA) nephropathy, lupus nephritis, poly-

cystic kidney disease).

Exclusion criteria

Any studies of patients with a diagnosis of diabetes mellitus (type I

or II) were excluded. Because the prognosis for people with specific

renal diagnoses cannot be generalised to the wider population with

CKD, studies restricted to patients with a single specific renal

diagnosis (e.g. IgA nephropathy, lupus nephropathy, polycystic

kidney disease) were excluded.

Types of interventions

All ACEi and ARB or combinations were included as outlined

below:

1. Treatment with ACEi versus placebo

2. Treatment with ARB versus placebo

3. Treatment with ACEi and ARB versus placebo

4. Treatment with ACEi versus ARB.

The ACEi class includes the drugs:

• Benazepril

• Captopril

• Cilazapril

• Delapril

• Enalapril maleate

• Fosinopril sodium

• Imidapril hydrochloride

• Lisinopril

• Moexipril hydrochloride

• Perindopril erbumine

• Quinapril

• Ramipril

• Spirapril

• Trandolapril

• Zofenopril.

The ARB class includes:

• Candesartan

• Eprosartan

• Irbesartan

• Losartan

• Olmesartan

• Telmisartan

• Valsartan.

Any dose and dosing regimen was included in the review. Com-

bination preparations with medicines other than ACEi and ARB

were not included. Only oral preparations were included.

As they are licensed, new drugs will be added to the review in

subsequent updates.

Types of outcome measures

Primary outcomes

1. All-cause mortality

2. CVD morbidity and mortality (including myocardial

infarction, cerebrovascular accident, congestive heart failure)

3. ESKD (including RRT)

Secondary outcomes

1. Quality of life (QoL) measured by the visual analogue scale,

such as SF-36 and KDQoL

2. Adverse events including but not limited to: allergic

reactions, cough, headache, hyperkalaemia, hypotension,

angioedema and acute kidney injury (AKI)

3. Kidney failure progression defined by: GFR rate of decline,

doubling of creatinine or progression of CKD stage

4. Proteinuria and albuminuria including: progression of

microalbuminuria to macroalbuminuria, regression of

macroalbuminuria to microalbuminuria, progression of

normoabluminuria to microalbuminuria, regression of

microalbuminuria to normoabluminuria measured by protein/

creatinine ratio (mg/mmol); urinary total protein excretion (g/24




hours); urinary ACR (mg/mmol); urinary albumin excretion

(µg/min)

5. BP: systolic and diastolic BP (mm Hg) reported as mean

change from baseline or percentage reaching study specific target

6. Costs: total health care costs

7. Hospital admission rates.

Search methods for identification of studies

We searched the following resources:

Electronic searches

1. The Cochrane Renal Group’s specialised register (searched

8 March 2010) and the Cochrane Central Register of Controlled

Trials (CENTRAL) in The Cochrane Library, Issue 1, 2010).

CENTRAL and the Renal Group’s specialised register contain

the handsearched results of conference proceedings from general

and speciality meetings. This is an ongoing activity of the

Cochrane Collaboration and is both retrospective and

prospective (Master List 2009). We did not therefore specifically

search conference proceedings. The Cochrane Renal Group’s

Module in The Cochrane Library provides an up-to-date list of

conference proceedings (Renal Group 2011).

2. MEDLINE (OvidSP 1950 - 8 March 2010) search was

conducted using the optimally sensitive strategy developed for

the Cochrane Collaboration for the identification of RCTs

(Lefebvre 2008) with a search strategy developed with input

from the Cochrane Renal Group’s Trial Search Co-ordinator.

3. EMBASE (OvidSP 1980 - 8 March 2010) search was

conducted using a search strategy adapted from that developed

for the Cochrane Collaboration for the identification of RCTs

(Lefebvre 2008) with a search strategy developed with input

from the Cochrane Renal Group’s Trial Search Co-ordinator.

See Appendix 1 for search terms used.

Searching other resources

1. Reference lists of review articles and relevant studies.

2. We planned to write letters seeking information about

unpublished or incomplete studies to investigators where only

abstracts were identified, but none of the included studies

presented this requirement.

Data collection and analysis

Selection of studies

The review was undertaken by six authors (CB, PS, RB, CP,

KMcC, AM). The search strategy described was used to obtain ti-

tles and abstracts of studies potentially relevant to the review. The

titles and abstracts were shared for screening by two teams of two

authors who worked independently (CB, RB, CP and PS). The

authors discarded the studies that were not applicable; however,

studies and reviews that might include relevant data or informa-

tion on trials were retained initially. Authors, working in teams of

two as before, independently assessed the retrieved abstracts, and

whenever necessary the full text of these studies were screened to

determine which studies satisfied the inclusion criteria.

Data extraction and management

Data extraction was carried out by at least two authors, indepen-

dently, using a standard data extraction form. Studies reported

in non-English language journals were to be translated before as-

sessment, but none of the included studies required translation.

Where more than one publication of one study existed, reports

were grouped together and only the publication with the most

complete data was included. Where relevant outcomes were only

published in earlier versions, these data were used. Any discrepancy

between published versions was highlighted. It was planned that

any further information required from the original investigator

was to be requested by written correspondence and any relevant

information obtained in this manner was to be included in the

review. Disagreements were resolved in consultation with KMcC.

Assessment of risk of bias in included studies

The following items were independently assessed by two authors

(CP, RB) using the risk of bias assessment tool (Higgins 2008) (seeAppendix 2). Discrepancies were resolved by discussion with CB.

• Was there adequate sequence generation?

• Was allocation adequately concealed?

• Was knowledge of the allocated interventions adequately

prevented during the study?

• Were incomplete outcome data adequately addressed?

• Are reports of the study free of suggestion of selective

outcome reporting?

• Was the study apparently free of other problems that could

put it at a risk of bias?

Measures of treatment effect

Data entry was carried out by CB and cross checked by PS. For

dichotomous outcomes (such as death, cardiovascular morbidity,

adverse events) results were expressed as risk ratios (RR) with 95%

confidence intervals (CI). Where continuous scales of measure-

ment were used to assess the effects of treatment (such as SCr),

the mean difference (MD) was used. According to the protocol,

the standardised mean difference (SMD) was to be used where

different scales had been applied. In instances where change from

baseline data (change scores) were reported, the difference in mean

change scores was to be used. It was planned that if standard devi-

ations for change scores were not available, missing data were not




to be imputed. Data were presented in tabular form and, where

appropriate, final score data and change from baseline were incor-

porated into meta-analyses. If adjustment had been undertaken to

account for baseline values, these data were to be reported. Time

to event data (such as survival, time to ESKD) were to be anal-

ysed as a dichotomous variable where data were presented for all

participants up to a specified time period. Alternatively, hazard

ratios (and 95% CI) were to be used, with application of the pro-

portional hazard assumption, for the purpose of comparison and

meta-analysis (Higgins 2008).

Unit of analysis issues

We did not anticipate that there would be any non-standard de-

signs, such as crossover studies and cluster-RCTs, but multiple arm

studies could be identified. Here, all intervention groups relevant

to the review were included. It was planned that if there were sev-

eral relevant comparisons, all independent comparisons were to

be included. It was also planned that if a comparator group over-

lapped (such as a single placebo arm), either comparison groups

would be combined (if appropriate), or only the most important

comparison would be selected for meta-analysis.

Dealing with missing data

Intention-to-treat was the primary analysis sought from studies.

Missing outcomes data, and the implications were discussed but

imputation of missing data was not undertaken.

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N-1 degrees of

freedom, with an alpha of 0.05 used for statistical significance and

with the I² test (Higgins 2003). I² values of 25%, 50% and 75%

correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

It was planned that funnel plots were to be assessed for evidence

of publication bias, and to plot effect estimates against study size

where data permit.

Data synthesis

Data were pooled using the random-effects model but the fixed-

effects model was also analysed to ensure the robustness of the

model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Where data were available subgroup analysis was undertaken to

explore possible sources of heterogeneity related to the following

characteristics:

• CKD stage

• Presence of microalbuminuria/proteinuria

• Age and gender

• Comorbidities (CVD, hypertension)

• Distribution of underlying renal pathologies

• Interventions (heterogeneity in treatments could be related

to prior agent(s) used and the agent, dose and duration of

therapy)

• Study quality.

Adverse effects were tabulated and assessed with descriptive tech-

niques because they were likely to be different for the various agents

used. Where possible, the risk difference (RD) with 95% CI was

to be calculated for each adverse effect, compared with either no

treatment or another agent.

It was planned that QoL measures would be tabulated and re-

ported descriptively, or if data permitted, meta-analysis would be

undertaken as described.

Sensitivity analysis

It was planned to undertake sensitivity analysis to explore the

robustness of findings to key decisions in the review process. These

were to be determined as the review process took place (Higgins

2008).

The authors aimed to determine the applicability of the results to

the individual with early CKD (stage 1 to 3).

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

See Characteristics of included studiestables.

Results of the search

Electronic searching retrieved a total of 2118 titles and abstracts,

from which 126 potentially eligible studies were considered fur-

ther. Analysis of the full text left us with four studies that met

the inclusion criteria (AIPRI Study 1996; Matsuda 2003; PEACE

Study 2006; REIN Stratum 1 1999). There was no disagreement

among the authors about the inclusion of studies. Further infor-

mation is presented in the study flow diagram (Figure 1).




Figure 1. Study flow diagram.

Included studies

Types of study

All four included studies were RCTs and were published in full.

Types of participants

Of the four studies, three recruited patients with CKD using a

range of definitions:

1. Matsuda 2003: stage 1 to 3 CKD (SCr < 265 µmol/L or

“creatinine clearance > 30 mL/min/1.73 m²” plus proteinuria >

0.3 g/24 hours).

2. AIPRI Study 1996: stage 3 CKD only (SCr 133 to 354

µmol/L and 24 hour creatinine clearance (CrCl) 30 to 60 mL/

min).

3. REIN Stratum 1 1999: included those with eGFR 20 to 70

mL/min/1.73 m² plus proteinuria ≥ 1 to 2.9 g/24 hours at

baseline but reported a relevant CKD group - eGFR > 45 mL/

min/1.73 m²separately (stage 1 to 3a).

4. PEACE Study 2006: included patients with stable coronary

artery diseases and those with reduced left ventricular function at

baseline. The study reported relevant CKD group with eGFR 45

to 59.9 mL/min/1.73 m² (stage 3a) and eGFR < 45 mL/min/

1.73 m² (minimum 27 mL/min/1.73 m²) (stage 3b).

Therefore, in two studies the included participants were a sub-

group of the originally randomised patients (PEACE Study 2006;

REIN Stratum 1 1999).

The proportion of participants in CKD stage 3a and 3b varied;

39% (AIPRI Study 1996) to 88% (PEACE Study 2006) were in

stage 3a CKD, and 12% (PEACE Study 2006) to 61% (AIPRI

Study 1996) were in stage 3b CKD. Different definitions and

measures of GFR were reported in each study.

One study had fewer than 100 participants (Matsuda 2003); two

had between 100 and 1000 (AIPRI Study 1996; REIN Stratum 1

1999); and one had more than 1000 participants (PEACE Study

2006).

All studies included both male and female adult participants, al-

though a higher proportion of males was common among all stud-

ies. Two studies had an age range of 18 to 70 years (AIPRI Study

1996; REIN Stratum 1 1999); one study included participants

aged over 50 years (PEACE Study 2006), and another indicated

that at baseline, all participants were adults without specifying an

age range (Matsuda 2003).

There were two studies that included patients with diabetes mel-

litus (AIPRI Study 1996; PEACE Study 2006), but these patients

represented less than 30% of the total participants at baseline. One

study included only people with stable coronary artery disease or

left ventricular failure (PEACE Study 2006).

Hypertension was common among study participants: one study

included only patients with hypertension (Matsuda 2003); and in

the other three studies, more than 50% of participants were hyper-




tensive. Each study included multiple underlying kidney diseases:

glomerular diseases accounted for 33% (AIPRI Study 1996) to

98% (Matsuda 2003) of study participants; interstitial nephritis

or polycystic disease was present in 7% (REIN Stratum 1 1999) to

29% (AIPRI Study 1996); nephrosclerosis occurred 2% (Matsuda

2003) to 16% (AIPRI Study 1996); and 18% (AIPRI Study 1996)

to 47% (REIN Stratum 1 1999) of patients had unknown or other

renal diagnosis. The results were not presented separately for dif-

ferent disease subgroups.

Two studies defined CKD based on CrCl level from 24 hour urine

collection at baseline (AIPRI Study 1996; Matsuda 2003); one

estimated GFR using iohexol clearance (REIN Stratum 1 1999);

and another used eGFR (four-variable Modification of Diet in

Renal Disease [MDRD] formula) to define relevant CKD groups

(PEACE Study 2006). One study used SCr (133 to 354 µmol/L)

in addition to CrCl level, thus excluding patients with the most

mild stage 3 CKD (AIPRI Study 1996).

Two studies included patients with proteinuria at baseline (REIN

Stratum 1 1999: ≥ 1 to 2.9 g/24 hours; Matsuda 2003: > 0.3

g/24 hours); the remaining two studies did not report presence

or absence of proteinuria among participants at baseline (AIPRI

Study 1996; PEACE Study 2006).

Types of interventions

Three of the four included studies compared three different ACEi

drugs with placebo:

• Ramipril (REIN Stratum 1 1999)

• Benazepril (AIPRI Study 1996)

• Trandolapril (PEACE Study 2006).

None of the included studies compared ARB with placebo or ACEi

and ARB with placebo.

Only one study compared ACEi (perindopril or trandolapril) with

ARB (losartan or candesartan) (Matsuda 2003).

Type of outcomes

Three studies presented data on our listed primary outcomes:

• All-cause mortality (AIPRI Study 1996; PEACE Study

2006)

• Cardiovascular morbidity/mortality (AIPRI Study 1996;

PEACE Study 2006)

• ESKD (REIN Stratum 1 1999).

Of our listed secondary outcomes, no study reported findings for

QoL, hospital admission rates or costs.

Two studies reported their findings for stage 3a and 3b CKD

separately (AIPRI Study 1996; PEACE Study 2006) and one study

reported by low and high proteinuria level (Matsuda 2003).

Excluded studies

A total of 93 studies were excluded. The main reason for exclusion

was that studies did not present outcomes separately for stage

1 to 3 CKD. See Characteristics of excluded studies for further

information.

The COOPERATE Study 2003 was excluded after a letter of

retraction was published by the editors of The Lancet in October

2009.

The REIN study was split into two stratum based on baseline

proteinuria. The low proteinuria study has been reported here.

The high proteinuria study (> 3 g/24 hours) did not report find-

ings separately by eGFR or CKD stage and was excluded (REIN

Stratum 2 1997).

Risk of bias in included studies

Details of the risk of bias are given in the Risk of Bias Table. Two

studies had an overall low risk of bias (PEACE Study 2006; REIN

Stratum 1 1999). One small study was characterised by particularly

high risk of bias: there was little information reported about the

randomisation method and no indication of blinding (Matsuda

2003). Two studies reported longer term follow-up beyond the end

of the treatment phase and were subject to substantial switching

between treatment groups (AIPRI Study 1996; PEACE Study

2006). See Figure 2 and Figure 3 for the summary results for risk

of bias.




Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality

item for each included study.




Figure 3. Methodological quality graph: review authors’ judgements about each methodological quality

item presented as percentages across all included studies.

Two studies reported data for relevant subgroups but the full

study population is not included here (PEACE Study 2006; REIN

Stratum 1 1999).

Using funnel plots to detect publication bias was not feasible be-

cause of the small number of studies included in this review.

Allocation

The method of sequence generation and allocation concealment

was adequately reported in two studies (PEACE Study 2006;

REIN Stratum 1 1999), unclear in one (AIPRI Study 1996), and

the method of randomisation was not described in the fourth study

(Matsuda 2003).

Blinding

Two studies were double blinded (AIPRI Study 1996; REIN

Stratum 1 1999) and one study was blinded to treatment only

(PEACE Study 2006). The study that compared two active

treatment groups did not report on blinding (Matsuda 2003).

The PEACE Study 2006, which started randomisation in 1996,

blinded study treatment until 2002, when the study’s steering com-

mittee recommended open label treatment with ACEi of those pa-

tients with diabetes, hypertension and microalbuminuria, or pro-

teinuria. The REIN Stratum 1 1999 continued its treatment as

open label after 27 months of blinding.

Incomplete outcome data

Two studies reported no missing data (AIPRI Study 1996;

Matsuda 2003) and the other two addressed missing data (PEACE

Study 2006; REIN Stratum 1 1999). Analysis was performed based

on intention-to-treat analysis in all but one study (Matsuda 2003).

Selective reporting

There was no evidence of the selective reporting of outcomes in

the included studies.

Other potential sources of bias

Studies presenting long term outcomes were based on open label

follow-up (AIPRI Study 1996; PEACE Study 2006). The protein-

uria subgroup of the REIN Stratum 1 1999 was stopped ahead of

schedule by the advisory panel because of significant benefits to

the treatment group. Matsuda 2003 provided insufficient infor-

mation to determine if there were any other potential sources of

bias.

Effects of interventions

See: Summary of findings for the main comparison ACEi

compared to placebo for early (stage 1 to 3) non-diabetic chronic

kidney disease; Summary of findings 2 ACEi compared to

placebo (single study outcomes)

See Summary of findings for the main comparison; Summary of

findings 2.

ACEi versus placebo

Three studies compared ACEi with placebo. Duration of treat-

ment ranged from 36 (AIPRI Study 1996) to 63 months (REIN

Stratum 1 1999). Follow-up extended to 6.6 years (AIPRI Study

1996). None of the studies reported information for subgroups

based on age, gender, proteinuria or comorbidities. Where sub-

group data were available by disease stage and underlying kidney




disease, these are reported. Each of the studies used a different

ACEi; therefore, it was not possible to explore differences in effect

by agent, dose or duration of therapy. There were too few studies

to explore the effect of study quality on effect size. The summary

effect was estimated in a meta-analysis of two studies (AIPRI Study

1996; PEACE Study 2006). REIN Stratum 1 1999 did not report

the number of participants with early stages of CKD who received

ACEi or placebo. A total of 1001 patients who were treated with

ACEi (benazepril and trandolapril) and 905 treated with placebo

were included for analysis.

Primary outcomes

All-cause mortality

Two studies reported all-cause mortality for stage 3 CKD only.

A total of 170 deaths occurred in 1906 patients (77/1001 in the

treated group versus 93/905 in the placebo group). In the AIPRI

Study 1996, a total of nine deaths occurred (8/300 in the treat-

ment group versus 1/283 in the placebo group) during a treat-

ment period of three years. In the PEACE Study 2006, 161 deaths

were reported (69/701 in the treatment group versus 92/622 in

the placebo group) during a median follow-up period of 4.8 years.

There was no statistically significant difference in the risk of death

among those treated with ACEi compared with placebo. (Analysis

1.1.1 (2 studies, 1906 participants): RR 1.80, 95% CI 0.17 to

19.27). There was statistically significant heterogeneity (I² = 81%,

P = 0.02); PEACE Study 2006 reported a statistically significant

reduction in deaths in the treated group (RR 0.67, 95% CI 0.50

to 0.89); AIPRI Study 1996 observed fewer deaths in the placebo

group.

Long-term follow-up

AIPRI Study 1996 reported an extended period of follow-up at the

end of the treatment phase of the study to give a total median dura-

tion of 6.6 years. During the extended follow-up, 64% of those pa-

tients randomised to benazepril continued on an ACEi, and 61%

in the placebo arm started treatment with an ACEi. At the end of

this time no statistically significant differences were observed in

the number of deaths between the groups (based on their original

treatment allocation); 25/300 patients who were originally treated

with benazepril and 23/283 who received placebo had died (RR

1.55; 95% CI 0.95 to 59.96).

Cardiovascular mortality and morbidity

Two studies reported cardiovascular events (AIPRI Study 1996;

PEACE Study 2006) for stage 3 CKD only. A total of 186 cardio-

vascular events occurred in 1906 patients (92/1001 in the treat-

ment group and 94/905 in the placebo group).

There was no statistically significant difference in the risk of car-

diovascular events in the ACEi group compared with the placebo

group (Analysis 1.2.1 (2 studies, 1906 participants): RR 0.87, 95%

CI 0.66 to 1.14). None of the included studies had statistically

significant point estimates. The estimate was dominated by one

study (PEACE Study 2006) that contributed to 92% weight to

the summary estimate. There was no statistical evidence of het-

erogeneity (I² = 0%, P = 0.49).

Definition of cardiovascular events varied in two studies. PEACE

Study 2006 included cardiovascular death plus myocardial infarc-

tion, and AIPRI Study 1996 included all cardiovascular events and

stroke.

ESKD

Only REIN Stratum 1 1999 reported kidney survival in a sub-

group of patients whose baseline GFR was > 45 mL/min/1.73 m²

(maximum GFR 70 mL/min/1.73 m²) . At 63 months, only 3%

of patients in this subgroup progressed to RRT. No statistically sig-

nificant difference in RR was reported between ACEi and placebo

(RR 1.00, 95% CI 0.09 to 1.11, P = 0.99).

Kidney impairment and progression

Doubling of creatinine

AIPRI Study 1996 reported 88/583 participants experienced dou-

bling of creatinine or the need for dialysis during a follow-up of 3

years. (Of the 583 patients only two needed dialysis, one each in

the treatment group and the placebo group). There was a statis-

tically significant reduction in the doubling of creatinine among

the ACEi group versus placebo (Analysis 1.3.1: RR 0.51, 95% CI

0.34 to 0.77).

Change in GFR

REIN Stratum 1 1999 reported the mean rate of change in GFR/

month for patients whose baseline GFR was > 45 mL/min/1.73

m² as 0.19 mL/min/1.73 m² (standard error (SE) 0.07) in the

ACEi group compared with 0.34 mL/min/1.73 m² (SE 0.09) in

the placebo group (P = 0.25).

Adverse events and withdrawals

Only AIPRI Study 1996 reported adverse events or withdrawals

for relevant patient groups (See Table 1). A total of 71 adverse

events were reported in 583 patients (38/300 in the ACEi group

and 33/283 in the placebo group) (Analysis 1.5: RR 1.09, 95% CI

0.70 to 1.68). Fewer than 1% of patients reported dry cough in

both the ACEi and the placebo groups. Few patients experienced




hyperkalaemia (2% ACEi versus 1% placebo). Hypertensive crisis

was not reported by any patient in the treatment group compared

with 1.4% of patients in the placebo group.

Adverse events caused withdrawal from the study by 12% of pa-

tients in the ACEi group and 9% in the placebo group. With-

drawals due to other events, such as loss to follow-up, protocol vi-

olation or lack of cooperation, was 6% in the ACEi group and 8%

in the placebo group. Further details on withdrawals and adverse

events are presented in Table 1.

Two studies (PEACE Study 2006; REIN Stratum 1 1999) reported

adverse events and withdrawals for those who were randomised at

study level, but not for the relevant subgroups that were of interest

for this review.

Secondary outcomes

Proteinuria

AIPRI Study 1996 reported on proteinuria observing a decrease

in urinary protein of 29% in the ACEi group and an increase by

9% in the placebo group at 36 months (statistical significance not

reported).

Blood pressure

AIPRI Study 1996 reported change in mean BP from baseline

values at 36 months. Mean systolic BP decreased by 4.5 to 8.0

mm Hg in the ACEi group versus an increase of 1.0 to 3.7 mm

Hg in the placebo group at 6, 12, 24 and 36 months.

Mean diastolic BP decreased by 3.5 to 5.0 mm Hg in the ACEi

group versus increases of 0.2 to 1.5 mm Hg in the placebo group

at 6, 12, 24 and 36 months. The study also reported that uncon-

trolled hypertension decreased from 28% to 18% in the ACEi

group and there was an increase from 27% to 32% in the placebo

group.

Subgroup analyses

There was insufficient data to pool estimates for subgroup analysis

for any of the outcomes. The analysis is based on single study data.

CKD stage

PEACE Study 2006, which reported results for all-cause mortality

and CVD events, stratified by stage 3a and 3b, found no statistical

significant effect of ACEi over placebo in either mortality (Analysis

1.1.2, stage 3a: RR 0.73, 95% CI 0.52 to 1.01; Analysis 1.1.3,

stage 3b: RR 0.64, 95% CI 0.34 to 1.20) or CVD events (Analysis

1.2.2, stage 3a: RR 0.92, 95% CI 0.67 to 1.26; Analysis 1.2.3,

stage 3b: RR 0.83, 95% CI 0.46 to 1.50).

AIPRI Study 1996 reported results for doubling of creatinine by

CKD stage. The effect of ACEi to reduce the number with dou-

bling of creatinine varied according to stage of CKD. A 70% re-

duction in the risk of doubling creatinine was observed in the ACEi

group versus placebo for CKD stage 3a (Analysis 1.3.2: RR 0.30,

95% CI 0.11 to 0.79) and 39% reduction for stage 3b (Analysis

1.3.3: RR 0.61, 95% CI 0.39 to 0.94).

Presence of proteinuria

REIN Stratum 1 1999 included only participants with proteinuria.

AIPRI Study 1996 reported reduction in risk of the doubling of

creatinine level (or ESKD) in people with stage 3 CKD stratified

by baseline 24 hour urinary protein. For those with ≤ 1 g/L and

> 1 g/L to < 3 g/L there was no statistically significant difference

compared with placebo (≤ 1 g: 31%, 95% CI -67 to 71; > 1 g

to < 3 g: 53%, 95% CI -14 to 81) but a statistically significant

reduction was observed for those with ≥ 3 g/L (66%, 95% CI 34

to 82). A similar pattern was observed when adjusted for change

in diastolic BP and change in urinary protein excretion. PEACE

Study 2006 did not report on proteinuria.

Age and comorbidities

PEACE Study 2006, which included older patients who had es-

tablished CVD at baseline, reported a significant beneficial effect

of ACEi on all-cause mortality, but not on cardiovascular or renal

outcomes.

Most of the included study participants were hypertensive (

PEACE Study 2006: 54%; AIPRI Study 1996: 81% (ACEi group),

83% (placebo group); REIN Stratum 1 1999: 79% (ACEi group),

85% (placebo group)). AIPRI Study 1996 reported the effect of

ACEi on doubling of creatinine stratified by baseline diastolic BP.

For those with a treated diastolic BP ≤ 90 mm Hg there was a

statistically significant reduction in doubling of creatinine in those

treated with ACEi compared with placebo (51%, 95% CI 13 to

73). After adjusting for changes in diastolic BP and proteinuria,

the difference was lost. For those with normal, untreated BP or a

treated diastolic BP > 90 mm Hg at baseline, there was no statis-

tically significant difference (58%, 95% CI -72 to 89; 50%, 95%

CI -8 to 76 respectively).

Distribution of underlying renal pathologies

AIPRI Study 1996 reported data for doubling of creatinine or

ESKD at 36 months by underlying renal pathology (Analysis 1.4)).

The effect of ACEi in reducing doubling of creatinine varied ac-

cording to the underlying renal pathologies. Among those with

underlying glomerular diseases, a statistically significant reduction

in the doubling of creatinine was observed in the ACEi group

compared with placebo (Analysis 1.4.1: RR 0.42, 95% CI 0.22

to 0.81). In the patients with other renal diagnoses (diabetic kid-

ney disease, polycystic kidney disease, nephrosclerosis, interstitial

nephritis and unknown renal disorders), there was no statistically

significant difference observed.




None of the included studies reported ESKD events and change

in GFR by subgroup.

ARB versus placebo

There were no published studies identified that compared ARB

with placebo.

ACEi plus ARB versus placebo

There were no published studies identified that compared ACEi

plus ARB with placebo.

ACEi versus ARB

Matsuda 2003 compared ACEi with ARB. The study reported BP,

CrCl and proteinuria stratified by baseline proteinuria level; those

with mild (< 1 g/day), and moderate (> 1 g/day) proteinuria levels.

The authors reported that no significant difference was observed

between ACEi and ARB in terms of change of BP from baseline

and at 48 weeks (no values reported). Twenty seven patients were

treated with ACEi (perindopril or trandolapril) and 25 patients

were treated with ARB (losartan or candesartan).

Subgroup analysis

Presence of proteinuria

No significant change in urinary protein excretion was observed for

patients with mild proteinuria who received either ACEi or ARB

(data were reported graphically only). A statistically significant

benefit was observed among patients with moderate proteinuria at

48 weeks: ACEi significantly reduced urinary protein excretion by

54% (standard error of mean (SEM) 7%) (from 2.7 (SEM 0.5) g/

day to 1.2 (0.2) g/day, P < 0.05). Similarly, a statistically significant

reduction of 41% (SEM 6%) (from 2.7 (0.4) g/day to 1.6 (0.3)

g/day, P < 0.05) was observed in the ARB group. For ARB versus

ACEi, there was a statistically significant reduction in the ARB

group at 48 weeks (P < 0.05) but not at 12 weeks (P > 0.2).

Among patients with mild proteinuria, a statistically significant

reduction in systolic/diastolic BP was reported from baseline to

48 weeks for both ACEi and ARB.

• ACEi: difference of mean* 17/12 mm Hg; from 148/86

(SEM 3/5) mm Hg to 131/74 (SEM 4/4) mm Hg, (P < 0.05)

• ARB: difference of mean* 17/15 mm Hg; from 154/86

(SEM 4/3) mm Hg to 137/71 (SEM 3/2) mmHg, P < 0.05).

For those with moderate proteinuria, marked reductions in BP

(systolic/diastolic) were observed at 48 weeks in the ACEi group

(difference of mean* 28/12 mm Hg; from 152/90 (SEM 4/3) mm

Hg to 124 (SEM 3)(diastolic BP only reported in graph) mm Hg,

P < 0.01) while only a modest reduction was observed in the ARB

group (difference of mean* 13/10; from 150/89 (SEM 3/3) mm

Hg to 137/79 (SEM 4/3) mm Hg, P < 0.05).

(*difference of mean baseline values and the values at 48 weeks).CrCl was stable (data were reported graphically only) in both

ACEi and ARB treatment groups and for both mild and moderate

proteinuria.




A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Outcomes Illustrative comparative risks* (95% CI) for study

population

Relative effect

(95% CI)

No. of Participants

Assumed risk Corresponding risk

Placebo ACEi

Mortality - CKD stage 3a

Follow-up: median 4.8

years

Study population

124 per 1000 91 per 1000

(64 to 125)

RR 0.73

(0.52 to 1.01)

1203

Mortality - CKD stage 3b


years

Study population

256 per 1000 164 per 1000

(87 to 307)

RR 0.64

(0.34 to 1.2)

157

Cardiovascular events -

CKD Stage 3a


years

Study population

117 per 1000 108 per 1000

(78 to 147)

RR 0.92

(0.67 to 1.26)

1203

Cardiovascular events -

CKD Stage 3b

Study population

244 per 1000 203 per 1000

(112 to 366)

RR 0.83

(0.46 to 1.5)

157

Doubling of creatinine -

CKD stage 3

Follow-up: 36 months

Study population

201 per 1000 103 per 1000

(68 to 155)

RR 0.51

(0.34 to 0.77)

583

Doubling of creatinine -

CKD Stage 3b


Study population

239 per 1000 146 per 1000

(93 to 225)

RR 0.61

(0.39 to 0.94)

356

Adverse events


Study population

117 per 1000 128 per 1000

(82 to 197)

RR 1.09

(0.7 to 1.68)

583

*The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect

of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio




http://www.thecochranelibrary.com/view/0/SummaryFindings.html

D I S C U S S I O N

Summary of main results

Despite growing international emphasis on the early detection

and management of CKD, and that stage 1 to 3 CKD accounts

for most people with evidence of kidney impairment, we found

very few studies that reported the effectiveness of ACEi or ARB

in this population. Only three studies that compared ACEi with

placebo in people with stage 1 to 3 CKD were identified (AIPRI

Study 1996; PEACE Study 2006; REIN Stratum 1 1999), and

one study that compared ACEi with ARB was found (Matsuda

2003). Two studies were considered to be at moderate to high

risk of bias (Matsuda 2003; REIN Stratum 1 1999). The patient

groups included in the studies varied considerably, particularly in

terms of comorbidities and severity of proteinuria. This made it

difficult to draw any overall conclusions. Each of the four included

studies differed in their definitions of CKD in terms of GFR cut-

off levels and measures of GFR. These differences are particularly

important when identifying a cohort of people with stage 3 CKD.

Invariably, participants in each study differed in regard to their

reported degrees of kidney impairment.

The low to moderate quality evidence from two studies (AIPRI

Study 1996; PEACE Study 2006) suggested that ACEi had no

impact on all-cause mortality or cardiovascular events in people

with stage 1 to 3 CKD. There was substantial heterogeneity in the

results relating to all-cause mortality: one study reported a mod-

est benefit and the other reported potential harm. The study that

showed a small potential benefit included older patients (aged > 50

years) with coronary artery disease (PEACE Study 2006). Approx-

imately 20% of patients who participated in this study had diag-

noses of diabetes at baseline. The study that reported potentially

harmful outcomes (AIPRI Study 1996) included comparatively

younger patients with no underlying CVD, but including small

numbers of participants with hypertension and with diabetes mel-

litus (4%). There was insufficient evidence to assess whether these

are true subgroups of the study population who had different re-

sponses to ACEi treatment, or if these outcomes reflect chance or

other variations in the studies, including the specific ACEi study

drug (Trandolapril was used in the PEACE Study 2006 and be-

nazepril in the AIPRI Study 1996).

In terms of renal outcomes, one study assessed as having a low risk

of bias reported no difference in the risk of ESKD among those

with an eGFR > 45 mL/min/1.73 m² treated with ACEi versus

placebo (REIN Stratum 1 1999). One study that featured a mod-

erate risk of bias reported a 50% reduction in the risk of creatinine

doubling in those with stage 3 CKD who were treated with ACEi

(AIPRI Study 1996). This study also reported a reduction in pro-

teinuria among people in the ACEi group. The greatest benefit

was observed in those people with stage 3a CKD.

Only one study reported adverse events for the relevant study par-

ticipants, and no statistically significant difference between pa-

tients in the ACEi and placebo groups (AIPRI Study 1996). Very

few people reported cough or hyperkalaemia.

The one study with a high risk of bias that compared ACEi with

ARB (Matsuda 2003), reported little difference in effect between

treatments when urinary protein, BP or CrCl were measured. This

study did not report all-cause mortality, cardiovascular events,

ESKD or adverse events.

Overall completeness and applicability ofevidence

This review highlights the striking lack of studies in people with

stage 1 to 3 CKD, which is the population group that accounts

for most people identified as having CKD. Identification of CKD

stages 1 and 2 requires evidence of kidney damage such as confir-

mation of proteinuria, haematuria or structural abnormality. This

requirement may make identifying people to participate in studies

more challenging, and even more so for investigators looking into

single, specific renal diagnoses.

The two major issues around applicability of the evidence to clin-

ical practice and patients were:

• definition of CKD and

• the underlying pathologies that caused the kidney damage.

Two of the four included studies that reported data for all-cause

mortality and cardiovascular morbidity and mortality defined their

CKD groups based on single eGFR assays (AIPRI Study 1996;

PEACE Study 2006), and therefore were prone to classification

bias because of the chance of including people with AKI. Only one

study based the definition of CKD on an eGFR using standard

equations (PEACE Study 2006), which is the method most widely

adopted in clinical practice, but likely to underestimate GFR in

those with true GFR level of around 60 mL/min/1.73 m².

The included patient population comprised mainly hypertensive

patients with varying renal pathologies, and 4% (AIPRI Study

1996) to 19% (PEACE Study 2006) had diabetes mellitus at base-

line. The high proportion of people with diabetes, and the in-

clusion of only people with existing CVD in the PEACE Study

2006, make it difficult to draw conclusions for the wider popula-

tion with early CKD. The PEACE Study 2006 reported a reduc-

tion in all-cause mortality consistent with other studies of ACEi in

populations with CVD; however the investigators did not report

the statistically significant benefits in kidney outcomes that were

observed in other studies conducted among diabetic study partici-

pants only. The proportions of patients with CVD and specifically

reported renal diagnoses varied from study to study.

We identified a number of significant gaps in the evidence. No

studies were identified that compared ARB with placebo or ACEi

combined with ARB. Only some of the many preparations of

ACEi and ARB drugs available were investigated in the studies

and none compared one preparation with another. Intervention

features such as compliance, timing, dosing or intensity could not




be elicited because of poor reporting in studies. Although most of

the included studies reported on some measure of kidney function

over time, mortality and ESKD, none reported on quality of life,

admissions to hospital or costs.

Quality of the evidence

Figure 2 and Figure 3 summarise the quality of the included stud-

ies. Although it was found that two studies were of low risk of

bias, the small number of studies, their relatively small size, and

low event rates for some of the primary outcomes meant that the

evidence was of low to moderate quality or based on a single study.

Findings should therefore be viewed with caution.

Potential biases in the review process

Strengths and limitations

This review was conducted as per the protocol following pre-

specified inclusion criteria and included comprehensive literature

searches to find all relevant studies. Two authors screened all ti-

tles, abstracts and full papers to avoid selection bias. There was no

arbitration required during the selection process, data extraction

or quality assessment that needed a third author.

We found very few studies reporting outcomes for the group of

patients of interest in this review (stage 1 to 3 CKD). We excluded

studies of single specific renal diagnoses, and it is acknowledged

that some of these may include patients with evidence of isolated

proteinuria (stage 1 CKD). A large number of studies conducted

in people with CKD were excluded because the authors did not

report their findings in subgroups that were relevant to this study.

In addition, studies of the use of ACEi and ARB drugs in hyper-

tensive patients may also include people with stage 1 to 3 CKD.

Before asking authors to consider re-analysing data into specified

subgroups, we considered it appropriate to establish what data

were available in the published literature.

Agreements and disagreements with otherstudies or reviews

We did not find any other published reviews that matched our

inclusion criteria. Two systematic reviews reported that ACEi was

found to have little benefit over placebo or other antihypertensive

drugs in reducing all-cause mortality among patients with CKD

or hypertension (P = 0.12) (Jafar 2001) or those with diabetes

mellitus (Strippoli 2006). In the meta-analysis (21 studies, 7295

patients) of patients with diabetes and CKD, no survival benefit

was observed compared with placebo (RR 0.91, 95% CI 0.71 to

1.17) except when treated with maximum tolerable doses (RR

0.78, 95% CI 0.61 to 0.098) (Strippoli 2006).

Jafar 2001 reported ACEi to be effective in reducing mean BP

(mean decrease - systolic: 4.5 mm Hg; 95% CI 3.0 to 6.1 mm Hg

and diastolic: 2.3 mm Hg; 95% CI 1.4 to 3.2 mm Hg); protein

excretion (mean decrease: 0.46 g/d; 95% CI 0.33 to 0.59 g/d);

and in reducing the risk of renal progression (doubling of SCr or

onset of ESKD: RR 0.70 95% CI 0.55 to 0.88) compared with

placebo or other antihypertensive drugs. The 11 included studies

used different measures of CKD. Baseline mean creatinine was

>155 µmol/L in all but two studies (where it was 124 µmol/L

and 88 µmol/L). In general, these studies included participants

with greater kidney impairment than we have included here. The

findings reported by Jafar 2001 were not stratified by CKD stage,

and therefore, they could not be compared directly. The authors

did note that the benefit of ACEi on reducing progression to ESKD

was modified by the presence of proteinuria at baseline (RR 0.09,

95% CI 0.07 to 0.11) and was lower for those with proteinuria

levels of 2.0 g/24 hours compared with 1.0 g/24 hours). Baseline

creatinine was not found to modify the effect of ACEi on ESKD.

Similarly, in people with diabetes and CKD, ACEi produced a

31% risk reduction of ESKD compared with placebo (RR 0.60,

95% CI 0.39 to 0.93). These outcomes were found to be similar for

ARB (RR 0.78, 95% CI 0.67 to 0.91) (Strippoli 2006). However,

the findings were not reported separately by stage.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

With increased recognition of the importance and impact of CKD,

the diagnosis and labelling of people with early (stage 1 to 3) CKD

is now common. Drugs in the ACEi and ARB families are the

cornerstone for management of CKD. This review highlights that

there have been very few studies that report on the effectiveness of

ACEi and ARB drugs for patients with early CKD, without those

studies investigating single, specific renal diagnoses. Despite that

people with early CKD are at greater risk of all-cause mortality

and cardiovascular events than progression to ESKD (Daly 2007;

Hallan 2006; Sharma 2010), we found very few studies that con-

sidered the early management of CKD to reduce cardiovascular

risk, all-cause mortality or kidney disease progression.

Our review demonstrated that there is currently insufficient evi-

dence to determine the effectiveness of ACEi or ARB treatment for

patients with stage 1 to 3 CKD who do not have diabetes mellitus.

Studies have been conducted among patients with single, specific

renal diagnoses but we have not included these here. Based on

evidence from studies of specific renal conditions, current clinical

guidelines (Levey 2003; NICE Guideline 2008; SIGN Guideline

2008) and practice support the use of ACEi and ARB drugs for




patients with proteinuric kidney disease. We have not found suf-

ficient evidence to support any change in current practice.

Implications for research

We have identified an area of significant uncertainty for a group of

patients who account for most of those labelled as having CKD.

We identified more than 50 studies where relevant data may ex-

ist, but the subgroups of patients that are necessary to derive sup-

ported evidence were not presented in the original publications

(see Characteristics of excluded studies). These studies may pro-

vide relevant subgroup or individual patient data for analysis of

patients with stage 1 to 3 CKD. In addition, studies of ACEi (such

as HOPE Study 2000; PART 2 (MacMahon 2000); PROGRESS

Collaborative Group 2001; SCAT Study 2000) and ARB (such

as LIFE (Lindholm 2002); SCOPE (Lithell 2003)) conducted in

people with hypertension or CVD may also include people who

meet the criteria of CKD stage 1 to 3 that would potentially enable

subgroup or individual patient data analysis.

There is potential need for further RCTs to be conducted that focus

on patients with stage 1 to 3 CKD. These studies should feature

designs that are adequate in size and duration, include quality of

life outcomes and establish recruitment criteria to ensure that the

study population can be generalised to the wider community.

A C K N O W L E D G E M E N T S

We wish to thank the referees for their comments and feedback

during the preparation of this review.

R E F E R E N C E S

References to studies included in this review

AIPRI Study 1996 {published data only}

Locatelli F, Carbarns IR, Maschio G, Mann JF, Ponticelli

C, Ritz E, et al.Long-term progression of chronic

renal insufficiency in the AIPRI Extension Study. The

Angiotensin-Converting-Enzyme Inhibition in Progressive

Renal Insufficiency Study Group. Kidney International

- Supplement 1997;52(Suppl 63):S63–6. [MEDLINE:

9407424]

Maschio G, Alberti D, Janin G, Locatelli F, Mann J,

Motolese M, et al.The use of benazepril in the treatment

of progressive renal disease [abstract]. 13th International

Congress of Nephrology; 1995 Jul 2-6; Madrid, Spain.

1995:65.∗ Maschio G, Alberti D, Janin G, Locatelli F, Mann JF,

Motolese M, et al.Effect of the angiotensin-converting-

enzyme inhibitor benazepril on the progression of chronic

renal insufficiency. The Angiotensin-Converting-Enzyme

Inhibition in Progressive Renal Insufficiency Study Group.

New England Journal of Medicine 1996;334(15):939–45.

[MEDLINE: 8596594]

Maschio G, Alberti D, Locatelli F, Mann JF, Motolese

M, Ponticelli C, et al.Angiotensin-converting enzyme

inhibitors and kidney protection: the AIPRI trial. The ACE

Inhibition in Progressive Renal Insufficiency (AIPRI) Study

Group. Journal of Cardiovascular Pharmacology 1999;33

(Suppl 1):S16–20. [MEDLINE: 10028949]

Matsuda 2003 {published data only}

Matsuda H, Hayashi K, Homma K, Yoshioka K, Kanda

T, Takamatsu I, et al.Differing anti-proteinuric action

of candesartan and losartan in chronic renal disease.

Hypertension Research: Official Journal of the Japanese

Society of Hypertension 2003;26(11):875–80. [MEDLINE:

14714578]∗ Matsuda H, Hayashi K, Saruta T. Distinct time courses of

renal protective action of angiotensin receptor antagonists

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12692572]

PEACE Study 2006 {published data only}

Solomon SD, Rice MM, Jablonski A, Jose P, Domanski

M, Sabatine M, et al.Renal function and effectiveness of

angiotensin-converting enzyme inhibitor therapy in patients

with chronic stable coronary disease in the Prevention of

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2006;114(1):26–31. [MEDLINE: 16801465]

REIN Stratum 1 1999 {published data only}

Remuzzi G, Tognoni G, Ruggenenti P, Perna A, Maggiorre

Q, Pizzarelli F, et al.A long term, randomized clinical trial

to evaluate the effects of ramipril on the evolution of renal

function in chronic nephropathies. Journal of Nephrology

1991;4(3):193–202. [EMBASE: 1992157069]∗ Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali

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[MEDLINE: 10437863]

Ruggenenti P, Perna A, Mosconi L, Matalone M, Gaspari

F, Garini G, et al.The angiotensin-converting-enzyme

(ACE) inhibitor ramipril slows the rate of GFR decline

(GFR) and the progression to end stage renal failure

(ESRF) in proteinuric, non-diabetic chronic renal diseases

[abstract]. Journal of the American Society of Nephrology

1997;8(Program & Abstracts):147A.

Ruggenenti P, Perna A, Remuzzi G, Gruppo Italiano di

Studi Epidemiologici in Nefrologia. ACE inhibitors to

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the American Society of Nephrology 2001;12(12):2832–7.




[MEDLINE: 11729254]

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combined therapy with ace-inhibitor and angiotensin

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Appel LJ, Wright JT, Greene T, Kusek JW, Lewis JB,

Wang X, et al.Long-term effects of renin-angiotensin

system-blocking therapy and a low blood pressure goal

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Lopez V, et al.Long-term renoprotective effects of standard

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nephropathies. American Journal of Kidney Diseases 2005;46

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Bakris GL, Siomos M, Bolton WK, Hebert l, Agerwall

R, Catanzaro D, et al.Differential effects of valsartan

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hypertensive patients with nephropathy [abstract]. Journal

of the American Society of Nephrology 1999;10(Program &

Abstracts):68A.∗ Bakris GL, Siomos M, Richardson D, Janssen I, Bolton

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Campbell R, Sangalli F, Perticucci E, Aros C, Viscarra

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COOPERATE Study 2003 {published data only}

Nakao N, Baba M, Seno H, Kasuga H, Toriyama T,

Kawahara H, et al.Baseline b-adrenergic blockade-based

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for the treatment of non-diabetic hypertensive patients

with chronic kidney failure: a COOPERATE-Carvedilol

substudy. [abstract no: F-PO621]. Journal of the American

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design prospective study [abstract]. Nephrology Dialysis

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T, Ideura T. Combination treatment of angiotensin-

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Coratelli P, Buongiorno E, Giannattasio M, Passavanti G.

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Crowe 2001 {published data only}

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de Jong 1999 {published data only}

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De Rosa 2001 {published data only}

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Kamper AL, Thomsen HS, Nielsen SL, Strandgaard S.

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Kamper A, Strandgaard S, Leyssac PP. Late outcome of a

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Kamper A, Strandgaard S, Leyssac PP. Randomised

controlled trial of enalapril in progressive chronic renal

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Kamper AL, Holstein-Rathlou NH, Leyssac PP, Strandgaard

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Kanno Y, Takenaka T, Nakamura T, Suzuki H. Add-on

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Kanno Y, Takenaka T, Nakamura T, Suzuki H. Add-

on angiotensin receptor blocker in patients who have

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Keane 1989 {published data only}

Keane WF, Anderson S, Aurell M, de Zeeuw D, Narins

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Keilani 1993 {published data only}∗ Keilani T, Schlueter WA, Levin ML, Batlle DC.

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the combined therapy of angiotensin II receptor antagonist

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controlled crossover study of the effect on proteinuria

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Maione A, Nicolucci A, Craig JC, Tognoni G, Moschetta

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MacGregor MS, Deighan CJ, Rodger RSC, Boulton-Jones

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MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey

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Maki DD, Ma JZ, Louis TA, Kasiske BL. Long-term

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Mann JFE, Maschio G, Alberti D, AIPRI investigators.

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McFate Smith W, Davies RO, Gabriel MA, Kramsch DM,

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Mimura T, Takenaka T, Kanno Y, Moriwaki K, Okada H,

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Minetti EE, Cozzi MG, Guidi E. Long- versus short-

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Pedersen EB. [Reduced progression, increased mortality in

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REIN Stratum 2 1997 {published data only}∗ Anonymous. Randomised placebo-controlled trial of

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Renke M, Tylicki L, Ruthkowski P, Wonjnarowski K,

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PROGRESS Collaborative Group. Randomised trial of a

perindopril-based blood-pressure-lowering regimen among

6,105 individuals with previous stroke or transient ischaemic

attack. Lancet 2001;9287:1033–41. [MEDLINE:

11589932]

Renal Group 2011

Willis NS, Mitchell R, Higgins GY, Webster AC, Craig

JC. Cochrane Renal Group. About The Cochrane

Collaboration (Cochrane Review Groups (CRGs) 2011,

Issue 6. Art. No: RENAL (accessed July 2011).

Ruster 2006

Ruster C, Wolf G. Renin-angiotensin-aldosterone system

and progression of renal disease. Journal of the American

Society of Nephrology 2006;17(11):2985–91. [MEDLINE:

17035613]

SCAT Study 2000

Teo KK, Burton JR, Buller CE, Plante S, Catellier D,

Tymchak W, et al.Long-term effects of cholesterol lowering

and angiotensin-converting enzyme inhibition on coronary

atherosclerosis: the Simvastatin/Enalapril Coronary

Atherosclerosis Trial (SCAT). Circulation 2000;102(15):

1748–54. [MEDLINE: 11023927]

Sharma 2010

Sharma P, McCullough K, Scotland G, McNamee P, Prescott

G, MacLeod A, et al.Does stage-3 chronic kidney disease

matter? A systematic literature review. British Journal

of General Practice 2010;60(575):e266–76. [EMBASE:

2010704927]

SIGN Guideline 2008

Scottish Intercollegiate Guidelines Network. Diagnosis and

management of chronic kidney disease. www.sign.ac.uk/

guidelines/fulltext/103/index.html (accessed August 2010)

2008.




Strippoli 2006

Strippoli GF, Bonifati C, Craig M, Navaneethan SD,

Craig JC. Angiotensin converting enzyme inhibitors and

angiotensin II receptor antagonists for preventing the

progression of diabetic kidney disease. Cochrane Database

of Systematic Reviews 2006, Issue 4. [DOI: 10.1002/

14651858.CD006257]∗ Indicates the major publication for the study




C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

AIPRI Study 1996

Methods • Study design: randomised, double-blind, placebo-controlled RCT

• Study period: January 1989 to December 1990

• Duration of follow-up: median 3.6 year additional extended follow-up

Participants Inclusion criteria

• Setting: Hospitals (49 centres)

• Countries: Germany, Italy, France

• Relevant health status

◦ Renal diagnosis (n): glomerular disease (192, 33%); interstitial nephritis

(105, 18%); nephrosclerosis (97, 16%); polycystic kidney disease (64, 11%); DKD

(21, 4%); chronic renal insufficiency of unknown cause (104, 18%)

◦ SCr: 1.5 to 4.0 mg/dL (133 to 354 µmol/L)

◦ 24 hour estimated CrCl: 30 to 60 mL/min

◦ 21 (4%) of participants with type 2 diabetes mellitus included and not

presented separately

• Number: Treatment group (300); control group (283)

• Age (mean ± SD years): Treatment group (51 ± 13); control group (51 ± 12)

• Age range: 18 to 70 years

• Sex (M/F): Treatment group (220/80); control group (201/82)

• Hypertension: Treatment group (244, 81%); control group (234, 83%)

Exclusion criteria

• Therapy-resistant oedema; treated with corticosteroids, NSAIDs, or

immunosuppressive drugs; exhibited urinary protein excretion > 10 g/24 hours or

serum albumin < 25 g/L; insulin-dependent diabetes mellitus, hypertension

(renovascular, malignant); experienced myocardial infarction, cerebrovascular accident

or congestive heart failure; elevated aminotransferase concentration; collagen disease;

obstructive uropathy; cancer; chronic cough; allergy to ACEi, history of drug or

alcohol abuse; pregnancy

Interventions Treatment group (ACEi)

• Benazepril

• 10 mg once daily

Control group (placebo)

• Placebo

• 1 tablet per day

Co-interventions

• All patients were advised to reduce their salt intake to approximately 3 g/day and

to consume 0.8 g protein/kg ideal body weight/day

• Antihypertensive therapy was adjusted as necessary to maintain the target value

for the diastolic pressure

Outcomes Reported outcomes (at 36 months)

• All-cause mortality

• Cardiovascular morbidity/mortality




AIPRI Study 1996 (Continued)

• Adverse events

• Kidney failure progression: time to sustained doubling of SCr or RRT

• Proteinuria: urinary protein excretion

• BP: systolic/diastolic

Open label follow-up at median of 6.6 years for all-cause mortality and kidney failure

progression (ESKD reported only as part of composite renal progression endpoint)

Not studied

• QoL; costs; admissions to hospital

Definition of CKD • 24 hour urine collection was used to calculate CrCl

• Relevant CKD group reported: all participants were required to have CrCl of 30

to 60 mL/min (Stage 3 CKD). Participants were also required to have SCr levels of 1.5

to 4.0 mg/dL (133 to 354 µmol/L), thus, some patients with the most mild stage 3

CKD may have been excluded.

• 39% (227) of participants had mild CKD (CrCl: 46 to 60 mL/min).

• 61% (356) of participants had moderate CKD (CrCl: 30 to 45 mL/min).

Notes • Funded by grant from Ciba-Geigy and Novartis Pharma

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Quote: “double blind, randomised study”

“randomly assigned”. Comment: method

not described

Allocation concealment (selection bias) Unclear risk Quote: “randomisation balanced for dis-

ease severity at each centre”

Comment: method not described

Blinding (performance bias and detection

bias)

All outcomes

Low risk Placebo given. “Each patient was exam-

ined by physician, who was unaware of the

group assignment”

Comment: probably done

Incomplete outcome data (attrition bias)

All outcomes

Low risk No missing outcome data reported

Selective reporting (reporting bias) Low risk Data for all stated outcomes reported

Other bias High risk Long term outcomes based on open label

follow up (for 504 patients - various reasons

for withdrawals given. “there was consider-

able usage of ACE i during the follow up

period in both the randomised treatment

groups: 64% of those randomised to be-

nazepril and 61% of those randomised to

placebo.”




AIPRI Study 1996 (Continued)

Intention-to-treat analysis.

Matsuda 2003

Methods • Study design: RCT

• Study period: 1998 to 1999

• Study duration: 48 weeks


• Setting: Hospital (one centre)

• Country: Japan

• Relevant health status

◦ Renal diagnosis: IgAN (8, 15%); membranous nephropathy (5, 10%); FSGS

(1, 2%); proliferative glomerulonephritis (38, 73%).

◦ SCr < 265 µmol/L or CrCl > 30 mL/min/1.73m² (reported to be measured

by 24 hour CrCl - method not specified)

◦ Hypertension: systolic > 140 mm Hg and/or diastolic 90 mm Hg

◦ Proteinuria: > 0.3 g/24 hours

◦ Diagnosis of CKD

• Number: Treatment group 1 (27; mild proteinuria 13, moderate proteinuria 14);

treatment group 2 (25; mild proteinuria 13, moderate proteinuria 12)

• Age: Participants described only as “adult”

• Sex (M/F): treatment group 1 (14/13); treatment group 2 (15/10)

• Mean systolic/diastolic BP mm Hg (SEM)

◦ Treatment group 1: mild proteinuria group (148/86 (3/5)); moderate

proteinuria group (152/90 (4/3))

◦ Treatment group 2: mild proteinuria group (154/86 (4/3)); moderate

proteinuria group (150/89 (3/3))

• Comorbidities: All patients were hypertensive

Exclusion criteria

• DKD; polycystic kidney disease and chronic pyelonephritis

Interventions Treatment group 1 (ACEi)

• Intervention: Perindopril or trandolapril

• Perindopril 2 mg/day; trandolapril 1 mg/day orally

• Doses titrated to achieve systemic BP to < 135/85 mm Hg

Treatment group 2 (ARB)

• Intervention: Losartan or candesartan

• Losartan 25 mg; candesartan 4 mg orally

• Doses adjusted according to the level of the blood pressure or renal

haemodynamics

Co-interventions

• All patients underwent education on low protein and sodium diet

Outcomes Reported outcomes (12, 24 and 48 weeks)

• Kidney failure progression: CrCl (24 hour urine collection)

• Proteinuria: urinary protein excretion

• BP: systolic/diastolic

Not studied




Matsuda 2003 (Continued)

• All-cause mortality; CVD morbidity/mortality; adverse events; QoL; costs;

admissions to hospital

Definition of CKD • 24 hour urine collection at baseline to calculate CrCl

• Relevant CKD group reported: all participants had proteinuria (>0.3 g/24 hour)

and CrCl > 30 mL/min/.73m ² (stage 1 to 3)

Notes • Funding: NS

Risk of bias



bias)

High risk Quote: “patients were randomly assigned”

Comment: method not described, Study

not described as randomised trial in title or

methods. Probably not done

Allocation concealment (selection bias) High risk Quote: “patients were randomly assigned”

Comment: method not described, Study

not described as randomised trial in title or

methods. Probably not done


bias)

All outcomes

High risk Not described as “blinded study”. Com-

parison of two active treatment groups. No

placebo mentioned


All outcomes

Low risk Not clear if all patients had complete follow

up data.

Probably complete


Other bias Unclear risk There is insufficient information to assess

whether an important risk of bias exists

PEACE Study 2006

Methods • Study design: Placebo controlled RCT. Design was changed to open label (ACEi)

in 2002 for patients with diabetes or proteinuria or hypertension plus

microalbuminuria - analysis as per randomisation allocation

• Study duration: November 1996 to June 2000

• Duration of follow-up: Planned for at least 3.5 years (median 4.8 years)


• Setting: Hospitals (187 centres)

• Countries: Canada, Italy, Puerto Rico, USA

• Relevant health status: > 50 years with stable coronary artery disease and normal




PEACE Study 2006 (Continued)

or mildly reduced left ventricular function (left ventricular ejection fraction > 40%)

• Renal diagnosis: not reported

• Number: Treatment group (4153); control group (4127); CKD stage 3a (1198);

CKD stage 3b (157)

• Age (mean ± SD years): Treatment group (64 ± 8); control group (64 ± 8); CKD

stage 3a (68.0 ± 7.7); CKD stage 3b (70.2 ± 7.9)

• Sex (F, %): Treatment group (NS, 19); control group (NS, 17); CKD stage 3a

(338, 28.2); CKD stage 3b (71, 45.2)

• Systolic BP (mean ± SD mm Hg): Treatment group (134 ± 17); control group

(133 ± 17); CKD stage 3a (135 ± 17.2); CKD stage 3b (138 ± 19.5)

• Diastolic BP (mean ± SD mm Hg): Treatment group (78 ± 10); control group (78

± 10); CKD stage 3a (76.9 ± 9.9); CKD stage 3b (75.9 ± 10.9)

Comorbidities

• Hypertension (733, 54%); diabetes (262, 19%); myocardial infarction (711,

52%); angina pectoris (974, 72%), percutaneous transluminal coronary angioplasty

(521, 38%); coronary artery bypass surgery (565, 42%); stroke (81, 6%)

Exclusion criteria

• Hospitalised for unstable angina in preceding 2 months, coronary

revascularisation within prior 3 months, had a planned elective coronary

revascularisation or had SCr > 2.0 mg/dL (177 µmol/L), patients contraindicated to

ACEi and ARB

Interventions Treatment group (ACEi)

• Intervention: Trandolapril

• Dose, duration, frequency, administration: oral (target 4 mg/d)

• 4158 randomised; 1 not treated; 3 did not attend after randomisation

Control group

• Intervention: Oral placebo oral

• 4132 randomised; 1 not treated; 8 did not attend after randomisation

Discrepancy not accounted for between publications

• Other treatments: none reported

Outcomes Outcomes at minimum 3.5 years after recruitment (median 4.8 years)

• All-cause mortality

• CVD morbidity/mortality

Not presented for relevant subgroups

• Adverse events; kidney failure progression; proteinuria; BP

Not studied

• costs; QoL; admissions to hospital

Definition of CKD • Single eGFR (4-variable Modification of Diet in Renal Disease) at baseline.

• Relevant CKD group reported:

◦ eGFR 45 to 59.9 mL/min/1.73 m² (n=1198)

◦ eGFR < 45 mL/min/1.73 m² (minimum eGFR 27 mL/min/1.73 m² so

included as stage 3b) (n=157)

• eGFR estimated from the SCr concentration and the 4-variable Modification of

Diet in Renal Disease equation




PEACE Study 2006 (Continued)

Notes • Baseline characteristics similar for two treatment groups

• Funding: National Heart, Lung and Blood Institute and Knoll Pharmaceuticals

and Abbott Laboratories.

Risk of bias



bias)

Low risk Quote: “randomised by a call to the data

coordination centre”

Comment: probably adequate generation -

not described further

Allocation concealment (selection bias) Low risk Quote: “randomised by a call to the data

coordination centre”


bias)

All outcomes

Low risk blinded to treatment until 2002 when

study steering committee recommended

open label treatment with ACEi of those

with diabetes, hypertension and microal-

buminuria, or proteinuria


All outcomes

Low risk 10/8290 with missing baseline creatinine

excluded.

Intention to treat analysis. “The percent-

age of patients assigned to trandolapril or

placebo who withdrew from therapy and

were not taking an open label ACE in-

hibitor was 25.5% and 8.3% respectively”


Other bias High risk Long term outcomes based on open label

follow up for some of the participants

“The percentage of patients assigned to

trandolapril or placebo who withdrew from

therapy and were not taking an open la-

bel ACE inhibitor was 25.5% and 8.3% re-

spectively”

Intention to treat analysis.




REIN Stratum 1 1999

Methods • Study design: Placebo controlled RCT

• Study duration: treatment planned for minimum 27 months

• Duration of follow-up: 3 years additional extended follow-up (open label basis);

median follow up: treatment group 32.2 months (IQR 29.4 to 54.5); placebo group

31.4 months (IQR 27.6 to 49.4)

• Run-in period: 1 month (single blind, placebo run-in phase)


• Setting: Hospital (14 centres)

• Country: Italy

• Relevant health status: glomerular disease (85, 46%), interstitial or polycystic

disease (14, 7%), other or unknown (87, 47%); urinary protein excretion ≥1 g/24

hours over at least 3 months; eGFR of 20 to 70 mL/min/1.73 m² (measured by plasma

clearance measurement of unlabelled iohexol); serum potassium 3.5 to 5.0 mmol/L

and capsule compliance exceeding 80%; non-diabetic patients

• Number: Treatment group (99); control group (87)

• Age (mean ± SD years): ACEi (49.1 ± 1.3); placebo (50.3 ± 1.5); range (18 to 70)

• Sex(M/F): Treatment group (75/24); control group (64/23)

Comorbidities

• Hypertension: Treatment group (78, 79%); control group (74, 85%)

• systolic/diastolic BP, mean (SE) mm Hg

◦ Treatment group: 142.0 (1.9)/88.6 (1.2)

◦ Control group: 144.9 (2.0)/89.8 (1.3)

Exclusion criteria

• ACEi therapy within 2 months prior to study start; treatment with

corticosteroids, NSAIDs, or immunosuppressive drugs; acute myocardial infarction or

cerebrovascular accident in the previous 6 months, severe uncontrolled hypertension

(diastolic BP 115 and/or systolic BP 220 mm Hg); evidence or suspicion of

renovascular disease; obstructive uropathy; insulin-dependent diabetes mellitus;

collagen disease; cancer; higher serum aminotransferase concentrations; chronic cough;

drug or alcohol abuse; pregnancy; breastfeeding; ineffective contraception

Interventions Treatment (ACEi) group (ACEi)

• Intervention: Ramipril

• Dose, duration, frequency, administration: 1.25 mg, 2.5 mg or 5.0 mg capsules

Control group

• Intervention: Placebo or conventional treatment

• Dose, duration, frequency, administration: NS

The dose (ACEi or placebo) was titrated every 2 weeks to achieve diastolic BP < 90 mm

Hg

Other treatment

• Other antihypertensive agents (excluding ACEi or ARB) introduced as required.

• Patients were recommended to limit sodium intake and to consume 0.6 to 0.8 g

protein/kg body weight/day

Outcomes Outcomes reported at 63 months

• ESKD at 48 months and 63 months (survival analysis)

• Kidney failure progression (mean change in eGFR)

Not presented for relevant subgroup

• all-cause mortality; cardiovascular morbidity and mortality; adverse events;




REIN Stratum 1 1999 (Continued)

proteinuria; BP

Not studied

• QoL; hospital admissions; costs

Definition of CKD • 24 hour urine collection to calculate CrCl

• All participants had proteinuria (1 to 2.9 g/24 hours) and eGFR 20 to 70 mL/

min/1.73 m² (stage 1 to 3 plus some patients in high stage 4 CKD not presented

separately)

• Relevant CKD subgroup reported: CrCl > 45 mL/min/1.73 m² (number of

patients not reported)

Notes • Funded by Hoechst Mario Roussel Clinical Research Institute, Frankfurt,

Germany

• Study divided into two subgroups at baseline:

• Low proteinuria (1 to 2.9 g/24 hours) (REIN Stratum 1 1999)

• High proteinuria (> 3 g/24 hours) (REIN Stratum 2 1997)

• The “high proteinuria” subgroup was stopped early at second interim analysis

(year 2) by independent adjudication panel because of evidence of significant benefit

Risk of bias



bias)

Low risk Quote: “Randomisation code prepared by

Hoechst Clinical Research Institute”

Allocation concealment (selection bias) Low risk Quote: “Randomisation code prepared by

Hoechst Clinical Research Institute”. “A se-

quence of patient numbers were randomly

assigned to each study centre, and the study

medication randomly assigned to patient

numbers in advance”


bias)

All outcomes

Low risk Double blind: placebo treatment given;

doctors enrolling patients and responsible

for follow up did not have access to the ran-

domisation codes


All outcomes

Low risk Low proteinuria subgroup: 175/186 had at

least 3 eGFR estimates but all 186 included

in main analysis


Other bias High risk Trial in High proteinuria group stopped

early due to apparent benefit

Long term outcomes based on open label

follow up




ACEi - angiotensin-converting enzyme inhibitor, ARB - angiotensin receptor blocker; BP - blood pressure; CKD - chronic kidney

disease; CrCl - creatinine clearance; DKD - diabetic kidney disease; eGFR - estimated glomerular filtration rate; FSGS - focal

segmental glomerulosclerosis; IgAN - Ig A nephropathy; NS - not stated; QoL - quality of life; RRT - renal replacement therapy

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

AASK Pilot Study 1996 Results not presented for stages 1 to 3

Acone 2003 Results not presented for stages 1 to 3

Appel 2008 Results not presented for stages 1 to 3

Aranda 2005 Results not presented for stages 1 to 3

Bakris 2000 Results not presented for stages 1 to 3

Bakris 2000a Results not presented for stages 1 to 3

Balamuthusamy 2008 Results not presented for stages 1 to 3

Bianchi 1992 Presents results for a subgroup with CrCl < 25 mL/min

Bonner 1993 Results not presented for stages 1 to 3

Campbell 2003 Results not presented for stages 1 to 3

Carlsen 1989 Results not presented for stages 1 to 3

Casas 2005 Not RCT

Cinotti 2001 Results not presented for stages 1 to 3. Wrong comparator - ACEi compared to another antihypertensive

and not placebo

COOPERATE Study 2003 Withdrawn from publication 2009

Coratelli 1988 Not RCT

Crowe 2001 Wrong comparator - comparison of dose with no placebo group

de Jong 1999 Not RCT

De Rosa 2001 Results not presented for stages 1 to 3

de Vinuesa 2006 Not RCT




(Continued)

Deuber 2003 Results not presented for stages 1 to 3

Dyadyk 1997 Results not presented for stages 1 to 3

Elung-Jensen 2003 Includes only people with severe CKD

ESPRIT Study 2005 Not RCT

Faulhaber 1997 Results not presented for stages 1 to 3

Fleischmann 2003 Wrong comparator - compares doses of ACEi, no placebo group

Fliser 1995 Includes people only with primary renal pathology

Garg 2005 Includes 64% with diabetes, results not presented separately for non diabetics

Giatras 1997b Results not presented for stages 1 to 3

Greenbaum 2000 Does not meet inclusion criteria, includes only people with CrCl < 30

Hannedouche 2001 Results not presented for stages 1 to 3

Haufe 1994 Results not presented for stages 1 to 3

Henriksen 1985 Results not presented for stages 1 to 3

Hogan 2002 Economic modelling not RCT

Hollenberg 2003 Not RCT

HOPE Study 2001 Results not presented for stages 1 to 3 for non-diabetes participants separately and includes > 30%

with diabetes

Hou 2006 Results not presented for stages 1 to 3

Ihle 1992 Results not presented for stages 1 to 3

Ihle 1996 Results not presented for stages 1 to 3

Ishimitsu 2005 Not RCT

Jafar 2001 Results not presented for stages 1 to 3

Jafar 2003b Results not presented for stages 1 to 3

Kamper 1990 Not RCT




(Continued)

Kamper 1992 Includes > 30% of patients with diabetics - data not presented separately for non-diabetics. Results not

presented for stages 1 to 3

Kanno 2005 Results not presented for stages 1 to 3

Kanno 2006 Results not presented for stages 1 to 3

Keane 1989 Not RCT

Keilani 1993 Results not presented for stages 1 to 3

Kim 2000 Results not presented for stages 1 to 3

Kincaid-Smith 2002 Results not presented for stages 1 to 3

Kindler 1989 Not RCT

Klein 2003 Results not presented for stages 1 to 3

Kshirsagar 2000b Includes diabetic patients - results for non-diabetic patients not reported separately and make up >30%

patients at baseline. Results not presented for stages 1 to 3

Kunz 2008 Results not presented for stages 1 to 3

Larczynski 2007 Wrong comparator

LIRICO Study 2007 Protocol only

MacGregor 2003 Wrong comparator

MacKinnon 2006 Results not presented for stages 1 to 3

Maki 1995 Does not include people with stages 1 to 3

Mann 1997 Results not presented for stages 1 to 3

Marcantoni 1997 Not RCT

McFate 1984 Not RCT

Mimura 2008 Prognostic study

Minetti 1995 Results not presented for stages 1 to 3

Mitchell 1997 Wrong comparator




(Continued)

Muirhead 2004 Results not presented for stages 1 to 3 for non-diabetic participants separately and includes > 30%

with diabetes

Nephros Study 2001 Results not presented for stages 1 to 3

Palmer 2008 Not RCT

Pedersen 1996 Letter, Results not presented for stages 1 to 3

Phillips 2007 Study population not early CKD

Plum 1998 Results not presented for stages 1 to 3

Praga 2002 Wrong comparator

PROGRESS Study 2007 Post hoc analysis of PROGRESS trial (stroke patients). Study population not early CKD

REIN Stratum 2 1997 Results not presented for stages 1 to 3

Renke 2004 Results not presented for stages 1 to 3

ROAD Study 2007 Results not presented for stages 1 to 3

Ruilope 2000 Results not presented for stages 1 to 3

Rump 1999 Results not presented for stages 1 to 3

Sanchez 1991 Results not presented for stages 1 to 3

Santoni 1989 Not RCT

SAVE Study 2004 Results not presented for stages 1 to 3

Scaglione 2005 Wrong comparator

Schmieder 2004 Wrong comparator - ACEi dose comparison, no placebo

Schulz 1999 Results not presented for stages 1 to 3

Shiigai 1998 Not RCT

Shoda 2006 Results not presented for stages 1 to 3

Takagi 1990 Results not presented for stages 1 to 3

Toto 1996 Results not presented for stages 1 to 3




(Continued)

Toto 1998 Results not presented for stage 1-3

VALERIA Study 2008 Results not presented for stages 1 to 3 for non-diabetic participants separately and includes > 30%

with diabetes

van Hout 1997 Economics model

Yildiz 1999 Results not presented for stages 1 to 3

Yilmaz 2007 Results not presented for stages 1 to 3

Zwettler 1994 Not RCT




D A T A A N D A N A L Y S E S

Comparison 1. ACEi versus placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Mortality 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 CKD Stage 3 2 1906 Risk Ratio (M-H, Random, 95% CI) 1.80 [0.17, 19.27]

1.2 CKD Stage 3a 1 1203 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.52, 1.01]

1.3 CKD stage 3b 1 157 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.34, 1.20]

2 Cardiovascular events 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only

2.1 CKD Stage 3 2 1906 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.66, 1.14]


2.3 CKD Stage 3 b 1 157 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.46, 1.50]

3 Doubling of creatinine 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only

3.1 CKD stage 3 1 583 Risk Ratio (M-H, Random, 95% CI) 0.51 [0.34, 0.77]


3.3 CKD Stage 3b 1 356 Risk Ratio (M-H, Random, 95% CI) 0.61 [0.39, 0.94]

4 Doubling of creatinine by

underlying renal pathologies

1 Risk Ratio (M-H, Random, 95% CI) Totals not selected

4.1 Glomerular disease 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]

4.2 Diabetic kidney disease 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]

4.3 Miscellaneous or

unknown renal disorders

1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]

4.4 Polycystic kidney disease 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]

4.5 Nephrosclerosis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]

4.6 Interstitial nephritis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]

5 Adverse events 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected

5.1 CKD stage 3 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]




Analysis 1.1. Comparison 1 ACEi versus placebo, Outcome 1 Mortality.

Review: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease

Comparison: 1 ACEi versus placebo

Outcome: 1 Mortality

Study or subgroup ACEi Placebo Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 CKD Stage 3

AIPRI Study 1996 8/300 1/283 41.0 % 7.55 [ 0.95, 59.96 ]

PEACE Study 2006 69/701 92/622 59.0 % 0.67 [ 0.50, 0.89 ]

Subtotal (95% CI) 1001 905 100.0 % 1.80 [ 0.17, 19.27 ]

Total events: 77 (ACEi), 93 (Placebo)

Heterogeneity: Tau2 = 2.46; Chi2 = 5.31, df = 1 (P = 0.02); I2 =81%

Test for overall effect: Z = 0.49 (P = 0.63)

2 CKD Stage 3a

PEACE Study 2006 56/622 72/581 100.0 % 0.73 [ 0.52, 1.01 ]

Subtotal (95% CI) 622 581 100.0 % 0.73 [ 0.52, 1.01 ]


Heterogeneity: not applicable


3 CKD stage 3b

PEACE Study 2006 13/79 20/78 100.0 % 0.64 [ 0.34, 1.20 ]

Subtotal (95% CI) 79 78 100.0 % 0.64 [ 0.34, 1.20 ]




0.01 0.1 1 10 100

Favours ACEi Favours placebo




Analysis 1.2. Comparison 1 ACEi versus placebo, Outcome 2 Cardiovascular events.



Outcome: 2 Cardiovascular events


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 CKD Stage 3

AIPRI Study 1996 9/300 7/283 7.7 % 1.21 [ 0.46, 3.21 ]

PEACE Study 2006 83/701 87/622 92.3 % 0.85 [ 0.64, 1.12 ]

Subtotal (95% CI) 1001 905 100.0 % 0.87 [ 0.66, 1.14 ]


Heterogeneity: Tau2 = 0.0; Chi2 = 0.48, df = 1 (P = 0.49); I2 =0.0%


2 CKD Stage 3a

PEACE Study 2006 67/622 68/581 100.0 % 0.92 [ 0.67, 1.26 ]

Subtotal (95% CI) 622 581 100.0 % 0.92 [ 0.67, 1.26 ]




3 CKD Stage 3 b

PEACE Study 2006 16/79 19/78 100.0 % 0.83 [ 0.46, 1.50 ]

Subtotal (95% CI) 79 78 100.0 % 0.83 [ 0.46, 1.50 ]




0.2 0.5 1 2 5





Analysis 1.3. Comparison 1 ACEi versus placebo, Outcome 3 Doubling of creatinine.



Outcome: 3 Doubling of creatinine


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 CKD stage 3

AIPRI Study 1996 31/300 57/283 100.0 % 0.51 [ 0.34, 0.77 ]

Subtotal (95% CI) 300 283 100.0 % 0.51 [ 0.34, 0.77 ]




2 CKD Stage 3a

AIPRI Study 1996 5/120 15/107 100.0 % 0.30 [ 0.11, 0.79 ]

Subtotal (95% CI) 120 107 100.0 % 0.30 [ 0.11, 0.79 ]




3 CKD Stage 3b

AIPRI Study 1996 26/180 42/176 100.0 % 0.61 [ 0.39, 0.94 ]

Subtotal (95% CI) 180 176 100.0 % 0.61 [ 0.39, 0.94 ]




0.1 0.2 0.5 1 2 5 10





Analysis 1.4. Comparison 1 ACEi versus placebo, Outcome 4 Doubling of creatinine by underlying renal

pathologies.



Outcome: 4 Doubling of creatinine by underlying renal pathologies

Study or subgroup ACEi Placebo Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Glomerular disease

AIPRI Study 1996 11/94 27/98 0.42 [ 0.22, 0.81 ]

2 Diabetic kidney disease

AIPRI Study 1996 1/6 7/15 0.36 [ 0.06, 2.32 ]

3 Miscellaneous or unknown renal disorders

AIPRI Study 1996 6/61 9/43 0.47 [ 0.18, 1.22 ]

4 Polycystic kidney disease

AIPRI Study 1996 8/30 9/34 1.01 [ 0.45, 2.28 ]

5 Nephrosclerosis

AIPRI Study 1996 2/52 1/45 1.73 [ 0.16, 18.46 ]

6 Interstitial nephritis

AIPRI Study 1996 3/57 4/48 0.63 [ 0.15, 2.68 ]

0.01 0.1 1 10 100





Analysis 1.5. Comparison 1 ACEi versus placebo, Outcome 5 Adverse events.



Outcome: 5 Adverse events

Study or subgroup ACEi Placebo Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 CKD stage 3

AIPRI Study 1996 38/300 33/283 1.09 [ 0.70, 1.68 ]

0.5 0.7 1 1.5 2


A D D I T I O N A L T A B L E S

Table 1. Withdrawals and adverse events for ACEi versus placebo

Study ID: AIPRI Study 1996 Treatment (N = 300) Placebo (N = 283)

Withdrawals due to adverse events

Total adverse events 35 23

Cancer 8 5

Dry cough 1 2

Hyperkalaemia 5 3

Hypertensive crisis 0 4

Hypotension 3 3

Local or systemic allergic reaction 3 3

Other 15 7

Withdrawals due to other events

Total 18 22

Lack of cooperation 13 15




Table 1. Withdrawals and adverse events for ACEi versus placebo (Continued)

Violation of protocol 5 7

A P P E N D I C E S

Appendix 1. Electronic search strategies

Databases Search terms

CENTRAL 1. (ace near/2 inhibitor*):ti,ab,kw

2. (angiotensin next converting next enzyme next inhibitor*):ti,ab,kw

3. (“ACE” or “ACE1” or “ACEI” or “ACEs”):ti,ab

4. (angiotensin near/3 receptor next block*):ti,ab,kw

5. (angiotensin near/3 receptor next antagonist*):ti,ab,kw

6. (AT next 2 next receptor next block*):ti,ab,kw

7. (AT next 2 next receptor next antagon*):ti,ab,kw

8. (“ARB” or “ARBs”):ti,ab

9. captopril:ti,ab,kw

10. enalapril:ti,ab,kw

11. fosinopril:ti,ab,kw

12. lisinopril:ti,ab,kw

13. perindopril:ti,ab,kw

14. ramipril:ti,ab,kw

15. quinapril:ti,ab,kw

16. benazepril:ti,ab,kw

17. cilazapril:ti,ab,kw

18. trandolapril:ti,ab,kw

19. spirapril:ti,ab,kw

20. delapril:ti,ab,kw

21. moexipril:ti,ab,kw

22. zofenopril or imidapril:ti,ab,kw

23. candesartan:ti,ab,kw

24. eprosartan:ti,ab,kw

25. irbesartan:ti,ab,kw

26. losartan:ti,ab,kw

27. olmesartan:ti,ab,kw

28. telmisartan:ti,ab,kw

29. valsartan:ti,ab,kw

30. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14

OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27

OR #28 OR #29)

31. (kidney next disease*):ti,ab,kw




(Continued)

32. (kidney next failure):ti,ab,kw

33. (renal next insufficiency):ti,ab,kw

34. ur*emi*:ti,ab,kw

35. ((chronic next kidney) or (chronic next renal)):ti,ab,kw

36. (CKF or CKD or CRF or CRD):ti,ab,kw

37. glomerulo*:ti,ab,kw

38. glomerular:ti,ab,kw

39. nephritis:ti,ab,kw

40. nephropath*:ti,ab,kw

41. (#31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40)

42. (#30 AND #41)

MEDLINE 1. exp Angiotensin-Converting Enzyme Inhibitors/

2. angiotensin converting enzyme inhibit$.tw.

3. (ace adj2 inhibit$).tw.

4. (ACE or ACE1 or ACEI or ACE-I or ACEs).tw.

5. captopril.tw.

6. enalapril.tw.

7. fosinopril.tw.

8. lisinopril.tw.

9. perindopril.tw.

10. ramipril.tw.

11. quinapril.tw.

12. benazepril.tw.

13. cilazapril.tw.

14. trandolapril.tw.

15. spirapril.tw.

16. delapril.tw.

17. moexipril.tw.

18. zofenopril.tw.

19. imidapril.tw.

20. or/1-19

21. exp Angiotensin II Type 1 Receptor Blockers/

22. Receptors, Angiotensin/ai [Antagonists & Inhibitors]

23. (angiotensin adj3 receptor block$).tw.

24. (angiotensin adj3 receptor antagonist$).tw.

25. AT 2 receptor block$.tw.

26. AT 2 receptor antagon$.tw.

27. (ARB or ARBs).tw.

28. candesartan.tw.

29. eprosartan.tw.

30. irbesartan.tw.

31. losartan.tw.

32. olmesartan.tw.

33. telmisartan.tw.

34. valsartan.tw.

35. or/21-34

36. or/20,35

37. Renal Insufficiency/




(Continued)

38. Kidney Failure/

39. exp Renal Insufficiency, Chronic/ (includes Kidney Disease, Chronic/)40. Kidney Diseases/

41. Uremia/

42. (chronic kidney or chronic renal).tw.

43. (CKF or CKD or CRF or CRD).tw.

44. ur?emi$.tw.

45. or/37-44

46. and/36,45

EMBASE 1. exp Dipeptidyl Carboxypeptidase Inhibitor/

2. angiotensin converting enzyme inhibit$.tw.

3. (ace adj2 inhibit$).tw.

4. (ACE or ACE1 or ACEI or ACE-I or ACEs).tw.

5. captopril.tw.

6. enalapril.tw.

7. fosinopril.tw.

8. lisinopril.tw.

9. perindopril.tw.

10. ramipril.tw.

11. quinapril.tw.

12. benazepril.tw.

13. cilazapril.tw.

14. trandolapril.tw.

15. spirapril.tw.

16. delapril.tw.

17. moexipril.tw.

18. zofenopril.tw.

19. imidapril.tw.

20. or/1-19

21. exp Angiotensin Receptor Antagonist/

22. (angiotensin adj3 receptor blocker$).tw.

23. (angiotensin adj3 receptor antagonist$).tw.

24. AT 2 receptor block$.tw.

25. AT 2 receptor antagon$.tw.

26. (ARB or ARBs).tw.

27. candesartan.tw.

28. eprosartan.tw.

29. irbesartan.tw.

30. losartan.tw.

31. olmesartan.tw.

32. telmisartan.tw.

33. valsartan.tw.

34. or/21-33

35. or/20,34

36. Kidney Disease/

37. Chronic Kidney Disease/

38. Kidney Failure/

39. Chronic Kidney Failure/




(Continued)

40. Uremia/

41. (chronic kidney or chronic renal).tw.

42. (CKF or CKD or CRF or CRD).tw.

43. ur?emi$.tw.

44. or/36-43

45. and/35,44

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Was there adequate sequence generation? Yes (low risk of bias): Random number table; computer random

number generator; coin tossing; shuffling cards or envelopes;

throwing dice; drawing of lots; minimisation (minimisation may

be implemented without a random element, and this is considered

to be equivalent to being random)

No (high risk of bias): Sequence generated by odd or even date of

birth; date (or day) of admission; sequence generated by hospital

or clinic record number; allocation by judgement of the clinician;

by preference of the participant; based on the results of a laboratory

test or a series of tests; by availability of the intervention

Unclear: Insufficient information about the sequence generation

process to permit judgement

Was allocation adequately concealed? Yes (low risk of bias): Randomisation method described that would

not allow investigator/participant to know or influence interven-

tion group before eligible participant entered in the study (e.g. cen-

tral allocation, including telephone, web-based, and pharmacy-

controlled, randomisation; sequentially numbered drug contain-

ers of identical appearance; sequentially numbered, opaque, sealed

envelopes)

No (high risk of bias): Using an open random allocation schedule

(e.g. a list of random numbers); assignment envelopes were used

without appropriate safeguards (e.g. if envelopes were unsealed or

non-opaque or not sequentially numbered); alternation or rota-

tion; date of birth; case record number; any other explicitly un-

concealed procedure

Unclear: Randomisation stated but no information on method

used is available




(Continued)

Was knowledge of the allocated interventions adequately pre-

vented during the study?

Yes (low risk of bias): No blinding, but the review authors judge

that the outcome and the outcome measurement are not likely

to be influenced by lack of blinding; blinding of participants and

key study personnel ensured, and unlikely that the blinding could

have been broken; either participants or some key study personnel

were not blinded, but outcome assessment was blinded and the

non-blinding of others unlikely to introduce bias

No (high risk of bias): No blinding or incomplete blinding, and the

outcome or outcome measurement is likely to be influenced by

lack of blinding; blinding of key study participants and personnel

attempted, but likely that the blinding could have been broken;

either participants or some key study personnel were not blinded,

and the non-blinding of others likely to introduce bias

Unclear: Insufficient information to permit judgement of ‘Yes’ or

‘No’

Were incomplete outcome data adequately addressed? Yes (low risk of bias): No missing outcome data; reasons for missing

outcome data unlikely to be related to true outcome (for survival

data, censoring unlikely to be introducing bias); missing outcome

data balanced in numbers across intervention groups, with similar

reasons for missing data across groups; for dichotomous outcome

data, the proportion of missing outcomes compared with observed

event risk not enough to have a clinically relevant impact on the

intervention effect estimate; for continuous outcome data, plau-

sible effect size (difference in means or standardized difference in

means) among missing outcomes not enough to have a clinically

relevant impact on observed effect size; missing data have been

imputed using appropriate methods

No, high risk of bias: Reason for missing outcome data likely to

be related to true outcome, with either imbalance in numbers or

reasons for missing data across intervention groups; for dichoto-

mous outcome data, the proportion of missing outcomes com-

pared with observed event risk enough to induce clinically relevant

bias in intervention effect estimate; for continuous outcome data,

plausible effect size (difference in means or standardized differ-

ence in means) among missing outcomes enough to induce clini-

cally relevant bias in observed effect size; ‘as-treated’ analysis done

with substantial departure of the intervention received from that

assigned at randomisation; potentially inappropriate application

of simple imputation


‘No’




(Continued)

Are reports of the study free of suggestion of selective outcome

reporting?

Yes (low risk of bias): The study protocol is available and all of the

study’s pre-specified (primary and secondary) outcomes that are of

interest in the review have been reported in the pre-specified way;

the study protocol is not available but it is clear that the published

reports include all expected outcomes, including those that were

pre-specified (convincing text of this nature may be uncommon)

No (high risk of bias): Not all of the study’s pre-specified primary

outcomes have been reported; one or more primary outcomes

is reported using measurements, analysis methods or subsets of

the data (e.g. subscales) that were not pre-specified; one or more

reported primary outcomes were not pre-specified (unless clear

justification for their reporting is provided, such as an unexpected

adverse effect); one or more outcomes of interest in the review are

reported incompletely so that they cannot be entered in a meta-

analysis; the study report fails to include results for a key outcome

that would be expected to have been reported for such a study


‘No’

Was the study apparently free of other problems that could

put it at a risk of bias?

Yes (low risk of bias): The study appears to be free of other sources

of bias.

No (high risk of bias): Had a potential source of bias related to

the specific study design used; stopped early due to some data-de-

pendent process (including a formal-stopping rule); had extreme

baseline imbalance; has been claimed to have been fraudulent; had

some other problem


‘No’

C O N T R I B U T I O N S O F A U T H O R S

1. Draft the protocol: CB, RB, CP, PS, KMcC

2. Study selection: CB, RB, CP, PS

3. Extract data from studies: CB, RB, CP, PS

4. Enter data into RevMan: CB

5. Carry out the analysis: CB, PS, RB, CP, KMcC

6. Interpret the analysis: CB, PS, RB, CP, KMcC, AM

7. Draft the final review: CB, PS, RB, CP, KMcC, AM




D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

• University of Aberdeen, UK.

Funding of core staff salaries and support facilities

External sources

• No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

Modifications were made to the background to clarify terminology around GFR and to provide context with what is known with regard

to diabetic kidney disease.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Angiotensin Receptor Antagonists [∗therapeutic use]; Angiotensin-Converting Enzyme Inhibitors [∗therapeutic use]; Chronic Disease;

Glomerular Filtration Rate [physiology]; Kidney Diseases [∗drug therapy]; Kidney Failure, Chronic [prevention & control]; Randomized

Controlled Trials as Topic

MeSH check words

Adult; Female; Humans; Male




Angiotensin converting enzyme inhibitors and angiotensin

Health & Medicine

Transcript of Angiotensin converting enzyme inhibitors and angiotensin