systematic review and meta-analysis

The effect of combination treatment with aliskiren and ACEI/ARB on hyperkalaemia and acute kidney injury

Systematic review and meta-analysis

Ziv Harel et al. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis BMJ 2012;344:e42

R2 林瀚榮 /Attending Dr. 鄭昌錡

Outline

Introduction

Methods

Results

Outcomes

Discussion

Introduction

RAS

►Block RAS at multiple foci has compelling rationale

► But may be associated with significant toxicity

►First highlighted the danger of dual inhibition with increased risk of acute dialysis and hyperkalaemia

ONTARGET

Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-53.

Introduction

Aliskiren

Direct inhibit renin, the most proximal aspect of RAS

.

May be associated with similar adverse effects

Shown to be efficacious either as monotherapy or in

combination with ACEI/ARB Most trials focused on surrogate outcomes and underpowered to provide robust estimates of adverse events

Wood JM, et al. 2003

Aliskiren

• Molecular weight = 609.8• High solubility in water and biological fluids• Non-peptide drug suitable for oral

administration

O

NH

CONH2

OHH2N

CH3O

O

CH3O

Angiotensinogen

Aliskiren Binds to active site of renin

Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I

Renin

Aliskiren

Adapted from Wood JM, et al. 2003

Renin Angiotensin System Inhibition

Renin Angiotensin SystemPathophysiologic Effects

ACE

Renin

Na+/H2O retentionVasoconstrictionHypertension

AT1 Receptor

Aldosterone

Angiotensinogen

Ang I

Ang II

Gibbons GH. 1998; Adapted from: Müller DN & Luft FC. 2006

· Glomerularvasoconstriction

· Inflammation· Fibrosis

Kidney

· Hypertrophy· Fibrosis· Vasoconstriction

Heart

· Vasoconstriction

Brain

· Hyperplasia hypertrophy· Inflammation· Oxidation· Fibrosis

Vessels

Biological effects

ACEis

Non ACE pathways

ARBs

PRA

Direct renin inhibitor

PRA

(Pro)reninreceptor

Target cell

· Vasoconstriction· Remodelling

Vessels

Kidney

Heart

Direct renin inhibitor

Azizi M et al. 2006;

Feedback Loop

Carried out a systematic review and meta-analyses

To determine whether use in combination is associated with adverse events

Goal of study

Introduction

Introduction

Ovid Medline (1948 to 7 May 2011)

Embase (1980 to 7 May 2011)

Cochrane central register of controlled trials (1993 to 7 May 2011)

Clinical trials registry (www.clinicaltrials.gov)

Novartis clinical trial results database

Abstracts of past five years from conferences of the American Society of Nephrology and the European Renal Association for ongoing or completed trials

Databases

http://www.clinicaltrials.gov/

Outline

Introduction

Methods

Results

Outcomes

Discussion

Methods

Study Selection

Aliskiren + ACEI/ARB vs Aliskiren/ACEI/ARB

At Least 4 wks duration

Randomised controlled trials

All available drugs and all dosing regimen

Methods

Validity assessment

Two authors scanned titles and abstracts for initial selection

Selected articles were reviewed in full and independently assessed for eligibility by the same two reviewers

Used the most complete publication Where more than one publication of a trial existed

Diagram

Exclusion Criteria

Combinations with agents other than ACEI/ARB, e.x., telmisartan and hydrochlorothiazide

Enrolled patients receiving chronic dialysis

Abstracts only Risk of bias could not be determined

Observational studies, case series, letters, commentaries, reviews, and editorials

Methods

Outcome Mesures

Primary outcome Hyperkalaemia (>5.5 )

Secondary outcomes Moderate Hyperkalaemia (K: 5.5-5.9)

Acute kidney injury (Cr >2.0)

Severe Hyperkalaemia ( 6.0)≧

Assessment of risk of bias

Methods

Using the predefined checklist of the Cochrane Database of Systematic Reviews

The classification in each category was yes, no, or unclear carried out an overall assessment of the risk of bias based on the responses for the selected criteria

Assessed risk of bias in sequence generation, allocation concealment, blinding, attrition, selection bias, and other biases

Methods

Data extraction and

synthesis

For binary outcome variables

(hyperkalaemia and acute kidney injury)

Two reviewers independently

extracted data by using custom made

data extraction forms

►Risk ratios►Risk differences►Numbers needed to harm (NNH)►95% confidence intervals

Methods

Funnel plot

method

Random effects model

Statistical heterogeneity

• Cochrane Q test (significance set at 0.01)

• I2 values

Accounts to an extent for variability within and between studies To evaluate

publication bias

Data extraction and synthesis

Methods

• Subgroup analyses – For clinical heterogeneity from the characteristics

of study populations and interventions• Age• Sex• Comorbidities

– Chronic kidney disease– Proteinuria– Congestive heart failure– Diabetes

• Aliskiren dosage

Methods

• Retrospective sensitivity analyses– Based on outcome of severe hyperkalaemia, stratified by

patient risk for hyperkalaemia into low and high risk groups– High risk group

• Chronic kidney disease• Diabetes• Decompensated heart failure• Intravascular volume depletion• β blockers• Potassium sparing diuretics• Aldosterone antagonists

– Sensitivity analyses were planned to assess effects after removal of outlier studies identified in funnel plots

Outline

Introduction

Methods

Results

Outcomes

Discussion

Results

• • Inclusion studies

– 841 screened citations met the search criteria– Excluding 38 duplicate citations, 803 citations

were evaluated– 77 were reviewed in detail– 10 eligible randomised controlled studies

were identified and included

Inclusion studies

Results

• Study characteristics– 7/10 studies

• Compare Aliskiren + ARB vs ARB

– valsartan, losartan, or irbesartan

• 5/7 compare Aliskiren + ARB vs Aliskiren

– 2/10 studies• Compare Aliskiren +

unspecified ARB/ACEI vs ARB/ACEI

– 1/10 study• Compare aliskiren + ACEI

vs ACEI/ aliskiren

(7/10) Aliskiren + ARB vs ARB(2/10) Aliskiren + unspecified ARB/ACEI vs ARB/ACEI

(1/10) Aliskiren + ACEI vs ACEI/ aliskiren

Results

• Dosage– Varied among studies– Nearly all reach the maximum recommended

doses for aliskiren and ACEI/ARB• Duration

– 8~36 wks• Study participants

– Mostly male and relatively young– Exclude severe renal impairment

Results

• Concurrent antihypertensive therapy– 6/10 studies

• 4 studies with β blocker• 2 studies with spironolactone

Results

• Risk of bias– The risk of bias was low – 7 studies described the methods used for generation

of the randomisation sequence, whereas six adequately reported details about allocation concealment

– All studies reported blinding of participants and investigators

– Although safety events were monitored and recorded for all included studies, only two studies provided definitions of such outcomes

Results

• Risk of bias– Complete data for hyperkalaemia and acute

kidney injury were available for 10 and 8 studies, respectively

– Withdrawal rates for all studies were less than 20%

– All included studies were sponsored by Novartis

Outline

Introduction

Methods

Results

Outcomes

Discussion

Outcomes - Hyperkalaemia

• Aliskiren + ACEI/ARB vs ACEI/ARB – All 10 studies– n=4814– Significantly higher– Relative risk

• 1.58 (95% CI: 1.24 to 2.02)– Risk difference

• 0.02 (95% CI: 0.01 to 0.04)– Number needed to harm

• 43 (95% CI: 28 to 90)– I2=0%

– Aliskiren + ACEI/ARB vs Aliskiren – 6 studies– n=2974– Significantly higher– Relative risk

• 1.67 (95% CI: 1.01 to 2.79)– Risk difference

• 0.02 (95% CI: 0.03 to 0.01)– Number needed to harm

• 50 (95% CI: 30 to 125)– I2=19%


Favor combination therapy

Favor monotherapy

Aliskiren + ACEI/ARB vs ACEI/ARB


Aliskiren + ACEI/ARB vs Aliskiren

Outcomes

Moderated Hyperkalaemia (K: 5.5-5.9)

• Aliskiren + ACEI/ARB vs ACEI/ARB – Significantly increased

risk– Relative risk

• 1.85 (95% CI: 1.18 to 2.91)

– Risk difference • 0.02 (95% CI: , 0.01 to

0.03)– Number needed to harm

• 50 (95% CI: 33 to 100)

• Aliskiren + ACEI/ARB vs Aliskiren – Significantly increased

risk– Relative risk

• 4.04 (95% CI: 2.12 to 7.71)

– Risk difference • 0.03 (95% CI: , , 0.02 to

0.04 )– Number needed to harm

• 33 (95% CI: 25 to 50)

Outcomes

Moderated Hyperkalaemia (K: 5.5-5.9)


Outcomes

Severe Hyperkalaemia (K: 6.0)≧

• Aliskiren + ACEI/ARB vs ACEI/ARB – No significantly

increased risk– Relative risk

• 1.12 (95% CI: 0.55 to 2.29)

• Aliskiren + ACEI/ARB vs Aliskiren – No significantly

increased risk– Relative risk

• 0.45 (95% CI: 0.53 to 1.53 )

Outcomes

Severe Hyperkalaemia (K: 6.0)≧


Outcomes - Acute kidney injury

• Aliskiren + ACEI/ARB vs Aliskiren – 6 studies– n=3063– No significantly

increased – Relative risk

• 0.80(CI:0.31 to 2.04)– I2=0%

• Aliskiren + ACEI/ARB vs ACEI/ARB – 8 studies– n=4345– No significantly

increased– Relative risk

• 1.14 (95% confidence interval 0.68 to 1.89)

– I2=30%


Aliskiren + ACEI/ARB vs Aliskiren

Outcomes

• Subgroup analysis– Not possible from available data

• Retrospective sensitivity analysis– Carried out on the outcome of severe

hyperkalaemia– Stratifying patients with combination therapy

by risk of hyperkalaemia into low and high risk groups

Outcomes - Retropective sensitivity analysis

• High risk groups– 7 studies– n=3141– No significantly higher– Relative risk

• 1.32 (95% CI: 0.64 to 2.74)

– Low risk groups– 3 studies– n=1673– No significantly higher– Relative risk

• 0.42 (95% CI: 0.08 to 2.14)

Severe hyperkalemia with combination therapy


High risk groups


Low risk groups

Outcomes

• Publication bias– No evidence of publication bias for the primary

outcome was suggested by visual inspection of the funnel plots

– The effect of two outlying studies on the hyperkalaemia outcome were assessed using a sensitivity analysis

– Removal of each of these studies decreased the magnitude of the effect for the risk of hyperkalaemia

Outline

Introduction

Methods

Results

Outcomes

Discussion

Discussion

• Significance of this study– Hyperkalaemia

• 50% greater in Aliskiren + ACEI/ARB vs ACEI/ARB• 70% greater in Aliskiren + ACEI/ARB vs Aliskiren

– Acute kidney injury• No evidence of a significant difference

Discussion

• Literature review– To date, no published systematic reviews or

meta-analyses have evaluated the safety of combination therapy

– Previously published pooled analyses provided discordant conclusions

Discussion

• Literature review– Weir MR et al 2007 1

• No difference in hyperkalaemia with combined aliskiren + valsartan

• However, only three of the trials we analysed were also analysed by this study

– White WB et al 2010 2

• Hyperkalaemia was higher in aliskiren + ARB compared with ARB alone

1. Weir MR, Bush C, Anderson DR, Zhang J, Keefe D, Satlin A. Antihypertensive efficacy, safety, and tolerability of the oral direct renin inhibitor aliskiren in patients with hypertension: a pooled analysis. J Am Soc Hypertens 2007;1:264-77.

2. White WB, Bresalier R, Kaplan AP, Palmer BF, Riddell RH, Lesogor A, et al. Safety and tolerability of the direct renin inhibitor aliskiren: a pooled analysis of clinical experience in more than 12,000 patients with hypertension. J Clin Hypertens (Greenwich) 2010;12:765-75.

Discussion

• Unique of this study– Included studies evaluated by these two

reviews and incorporated six recently completed randomized trials

– The populations studied varied widely, inlcuding HTN, DM, CHF, and recent ACS

– Such a heterogeneous group may increase generalisability, but may also bias the results because these populations possess differential risks for hyperkalaemia and acute kidney injury

Discussion

• Severity of Hyperkalaemia– Significantly increased risk of moderate but not

severe hyperkalaemia– Assessed high and low risk populations of severe

hyperkalaemia in a retrospective sensitivity analysis– The lack of an increased risk of severe hyperkalaemia

persisted in both populations– May also be explained by the close follow-up, which

may mitigate any differences in baseline risk through adjustments in the management of participants with moderate hyperkalaemia

Discussion

• Acute kidney injury– No significantly increased risk– Why?

• May result from close follow-up• Extremely conservative Cr threshold used to define AKI

in the included studies• May missed milder AKI cases• Short duration of follow-up• Hyperkalaemia often ensues shortly • AKI usually occurs later after a superimposed renal

insult

Discussion

• Quality of the evidence– Most of the trials included were of good

quality– Lack of standardisation of Cr assays among

the included studies may affect results

Discussion

• Strengths of this review– First review describing safety associated with

aliskiren– Broad and included published as well as

unpublished sources

Discussion

• Limitations of this review– Pooled the results of studies that were not originally

intended to explore safety outcomes– Many included studies were small, resulting in few

adverse safety events– Confidence intervals were wide– Did not access to original data – Included heterogeneous participants– Most patients had preserved baseline kidney function,

which may limit the likelihood of hyperkalaemia and acute kidney injury

Discussion

• Future research– ALTITUDE Study

• The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints

– ATMOSPHERE study• Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination

on Morbi-mortality in Patients With Chronic Heart Failure• Implications for practice

– Populations are selected with relatively preserved kidney function

– The generalisability of our findings to routine clinical practice is unknown

Conclusion

• The use of aliskiren in combination is associated with a significantly increased risk of hyperkalaemia

• No effect of on the risk of acute kidney injury

Thank You!

systematic review and meta-analysis

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