Post on 24-Feb-2016
description
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
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%
Outcomes - Hyperkalaemia
Favor combination therapy
Favor monotherapy
Aliskiren + ACEI/ARB vs ACEI/ARB
Outcomes - Hyperkalaemia
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)
Aliskiren + ACEI/ARB vs ACEI/ARB
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)≧
Aliskiren + ACEI/ARB vs ACEI/ARB
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%
Outcomes - Acute kidney injury
Aliskiren + ACEI/ARB vs Aliskiren
Outcomes - Acute kidney injury
Aliskiren + ACEI/ARB vs ACEI/ARB
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
Outcomes - Retropective sensitivity analysis
High risk groups
Outcomes - Retropective sensitivity analysis
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!