1 / 56

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. R2 林瀚榮 /Attending Dr. 鄭昌錡.

meara
Download Presentation

Systematic review and meta-analysis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. The effect of combination treatment with aliskirenand ACEI/ARB onhyperkalaemiaand acute kidney injury Systematic review and meta-analysis R2 林瀚榮 /Attending Dr.鄭昌錡 ZivHarel 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

  2. Outline Introduction Methods Results Outcomes Discussion

  3. Introduction RAS ONTARGET • Block RAS at multiple foci has compelling rationale • First highlighted the danger of dual inhibition with increased risk of acute dialysis and hyperkalaemia • But may be associated with significant toxicity Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renaloutcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGETstudy): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-53.

  4. Introduction • Direct inhibit renin, the most proximal aspect of RAS • . • May be associated with similar adverse effects Aliskiren • 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

  5. Aliskiren Molecular weight = 609.8 High solubility in water and biological fluids Non-peptide drug suitable for oral administration CH3O OH H N H2N CONH2 O O CH3O Wood JM, et al. 2003

  6. AliskirenBinds to active site of renin Renin Aliskiren Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I Angiotensinogen Adapted from Wood JM, et al. 2003

  7. ReninAngiotensin SystemPathophysiologic Effects ReninAngiotensin System Inhibition Direct renin inhibitor Kidney • Glomerularvasoconstriction • Inflammation • Fibrosis Angiotensinogen Renin Ang I Heart PRA Non ACE pathways • Hypertrophy • Fibrosis • Vasoconstriction PRA ACE ACEis Feedback Loop Vessels Ang II Aldosterone • Hyperplasia hypertrophy • Inflammation • Oxidation • Fibrosis ARBs Direct renin inhibitor AT1 Receptor Target cell Brain Biological effects Vasoconstriction Hypertension (Pro)reninreceptor • Vasoconstriction Na+/H2O retention Azizi M et al. 2006; Gibbons GH. 1998; Adapted from: Müller DN & Luft FC. 2006 Heart Kidney Vessels • Vasoconstriction • Remodelling

  8. Introduction • Carried out a systematic review and meta-analyses • To determine whether use in combination is associated with adverse events Goal of study

  9. 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) Databases • 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

  10. Outline Introduction Methods Results Outcomes Discussion

  11. Methods Study Selection • Randomised controlled trials • All available drugs and all dosing regimen • At Least4 wks duration • Aliskiren + ACEI/ARB vsAliskiren/ACEI/ARB

  12. Methods Validity assessment • Used the most complete publication Where more than one publication of a trialexisted • Selected articles were reviewed in full and independently assessed for eligibility by the same two reviewers • Two authors scanned titles and abstracts for initialselection

  13. Diagram • Combinations with agents other than ACEI/ARB, e.x., telmisartan and hydrochlorothiazide Exclusion Criteria • Observationalstudies, case series, letters, commentaries, reviews, and editorials • Enrolled patients receiving chronic dialysis • Abstracts only • Riskof bias could not be determined

  14. Methods • Hyperkalaemia (>5.5 ) • Primary outcome Outcome Mesures Acute kidney injury (Cr >2.0) Moderate Hyperkalaemia (K: 5.5-5.9) • Secondary outcomes Severe Hyperkalaemia (≧ 6.0)

  15. 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 Assessment of risk of bias

  16. Methods • For binary outcome variables (hyperkalaemia and acute kidney injury) Data extraction and synthesis • Two reviewers independently extracted data by using custom made data extraction forms • Risk ratios • Risk differences • Numbers needed to harm (NNH) • 95% confidence intervals

  17. Methods • Accounts to an extent for variability within and between studies • Random effects model To evaluate publication bias • Funnel plot method Statistical heterogeneity Data extraction and synthesis • Cochrane Q test (significance set at 0.01) • I2 values

  18. Methods • Subgroup analyses • For clinicalheterogeneity from the characteristics of studypopulations and interventions • Age • Sex • Comorbidities • Chronic kidney disease • Proteinuria • Congestive heart failure • Diabetes • Aliskiren dosage

  19. Methods • Retrospective sensitivity analyses • Based on outcome ofsevere hyperkalaemia, stratified by patient risk for hyperkalaemia into low and high risk groups • High risk group • Chronic kidneydisease • Diabetes • Decompensated heart failure • Intravascularvolume depletion • β blockers • Potassium sparing diuretics • Aldosterone antagonists • Sensitivity analyses were planned to assess effects after removal of outlierstudies identified in funnel plots

  20. Outline Introduction Methods Results Outcomes Discussion

  21. 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

  22. Inclusion studies

  23. Results • Study characteristics • 7/10 studies • CompareAliskiren + ARB vs ARB • valsartan, losartan, or irbesartan • 5/7 compare Aliskiren + ARB vsAliskiren • 2/10 studies • Compare Aliskiren + unspecified ARB/ACEI vs ARB/ACEI • 1/10 study • Compare aliskiren + ACEI vs ACEI/ aliskiren

  24. Results • Dosage • Varied among studies • Nearly all reach the maximum recommendeddoses for aliskiren and ACEI/ARB • Duration • 8~36 wks • Study participants • Mostly male and relatively young • Exclude severerenal impairment

  25. Results • Concurrent antihypertensive therapy • 6/10 studies • 4 studies with β blocker • 2 studies with spironolactone

  26. Results • Risk of bias • The risk of bias was low • 7 studies described the methods used for generation of therandomisation 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 includedstudies, only two studies provided definitions of such outcomes

  27. 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

  28. Outline Introduction Methods Results Outcomes Discussion

  29. 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 vsAliskiren • 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%

  30. Outcomes- Hyperkalaemia Favor combination therapy Favor monotherapy Aliskiren + ACEI/ARB vs ACEI/ARB

  31. Outcomes - Hyperkalaemia Aliskiren + ACEI/ARB vsAliskiren

  32. 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 vsAliskiren • 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)

  33. OutcomesModerated Hyperkalaemia (K: 5.5-5.9) Aliskiren + ACEI/ARB vs ACEI/ARB

  34. OutcomesSevere 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 vsAliskiren • No significantly increased risk • Relative risk • 0.45 (95%CI: 0.53 to 1.53 )

  35. OutcomesSevere Hyperkalaemia (K: ≧ 6.0) Aliskiren + ACEI/ARB vs ACEI/ARB

  36. Outcomes - Acute kidney injury • Aliskiren + ACEI/ARB vsAliskiren • 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%

  37. Outcomes - Acute kidney injury Aliskiren + ACEI/ARB vsAliskiren

  38. Outcomes - Acute kidney injury Aliskiren + ACEI/ARB vs ACEI/ARB

  39. Outcomes • Subgroup analysis • Not possible from available data • Retrospective sensitivity analysis • Carried out on the outcome ofsevere hyperkalaemia • Stratifying patients with combination therapy by risk of hyperkalaemia into low and high risk groups

  40. 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

  41. Outcomes - Retropective sensitivity analysis High risk groups

  42. Outcomes-Retropective sensitivity analysis Low risk groups

  43. 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

  44. Outline Introduction Methods Results Outcomes Discussion

  45. Discussion • Significance of this study • Hyperkalaemia • 50% greater in Aliskiren + ACEI/ARB vs ACEI/ARB • 70% greater in Aliskiren + ACEI/ARB vsAliskiren • Acute kidney injury • No evidence of a significant difference

  46. 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

  47. 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 al2010 2 • Hyperkalaemia was higher in aliskiren + ARB compared with ARB alone • 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. • 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 ClinHypertens (Greenwich) 2010;12:765-75.

  48. 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

  49. 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 hyperkalaemiapersisted 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

  50. 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

More Related