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A cetylcysteine for the prevention of C ontrast-induced nephropa T hy (ACT) Trial:. A Pragmatic Multicenter Randomized Trial to Evaluate the Efficacy of Acetylcysteine for the Prevention of Renal Outcomes in Patients Undergoing Coronary and Vascular Angiography. The ACT Trial Investigators

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a cetylcysteine for the prevention of c ontrast induced nephropa t hy act trial

Acetylcysteine for the prevention of Contrast-induced nephropaThy (ACT) Trial:

A Pragmatic Multicenter Randomized Trial to Evaluate the Efficacy of Acetylcysteine for the Prevention of Renal Outcomes in Patients Undergoing Coronary and Vascular Angiography

The ACT Trial Investigators

Presenter: Otavio Berwanger (MD; PhD)

Chair - SteeringCommitte

Sponsor: Ministry of Health-Brazil

presenter disclosure information
Presenter Disclosure Information

Presenter: Otavio Berwanger

Acetylcysteine for the Prevention of Contrast-Induced nephropaThy (ACT) Trial: a Pragmatic Multicenter Randomized Trial to Evaluate the Efficacy of Acetylcysteine for the Prevention of Renal Outcomes in Patients Undergoing Coronary and Vascular Angiography

FINANCIAL DISCLOSURE:

None to declare

slide3

Why do WeNeed a

NewAcetylcysteine Trial ?

  • THE PROBLEM
  • CIN is associatedwithmortalityandprolongedhospitalization. The incidence in patientswithriskfactors (such as renal failure, diabetes, age > 70 y) varies between 9% and 38%.
  • ONE POTENTIAL SOLUTION
  • Acetylcysteinerepresents a safe, non-expensive , easy to administer, andwidelyavailabledrug
  • THE EVIDENCE
  • Lowquality (fewtrialswithallocation concealment, blinding, and ITT analysis)
  • Lowstatisticalpower (mediantrialsize = 80 patients)
  • Uncertaineffectsonclinicalendpoints
  • Lackofstandardizationofacetylcysteine dose/schemeandco-interventions
slide4

The ACT Trial

  • Design: Academic,PragmaticRandomizedMulticenter Trial ofAcetylcysteine versus Placebo for thePreventionof Renal Outcomes
  • Preventionof Bias:
    • Concealedallocation (central web-basedrandomization) andIntention-to-treatanalysis
    • Blindingofpatients, investigators, caregivers, andoutcomeassessors
  • Quality control: on-site monitoring + central statistical checking + e-CRF
  • Trial Size: 2,308* patients from 46 hospitals in Brazil recruited between September 2008 and July 2010

* Original Target Sample Size: 2300, considering incidence of CIN =15%, 30% relative risk reduction (RRR), with 90% statistical power, and two-tailed alpha of 5%

trial organization
Trial Organization

Trial Steering Committe

Otavio Berwanger Alexandre Biasi Cavalcanti

Amanda Sousa Celso Amodeo

J. Eduardo Sousa Leda D. Lotaif

Project Office Data Management/e-CRF

Research Institute HCorCarlos Cardoso

Alexandre Biasi Cavalcanti Andre L.A. Firmino

Anna Maria Buehler Dalmo Silva

Mariana Carballo Paulo J. Soares

Alessandra Kodama Adailton Mendes

Eliana Santucci Jose Lobato

Centres Top Recruiting Sites:

46 Institutions in BrazilHospital Bandeirantes (Sao Paulo)

Beneficiencia Portuguesa (Sao Paulo)

Hospital P.S. Mat. Santa Lucia (Minas Gerais)

Instituto de Cardiologia (StaCatarina)

slide6

2,308 Patients undergoing an angiographic procedure with at least one of the following risk factors:

Age > 70 years;

Chronic Renal Failure;

Diabetes Mellitus;

Heart Failure or LVEF <0.45;

Shock

Concealed

Randomization

Acetylcysteine 1200mg

Orally Twice Daily for 2 Doses Before and 2 Doses After Procedure

Matching Placebo

ITT

ITT

Primary Endpoint: Contrast-induced nephropathy (CIN)

(≥ 25% elevation of serum creatinine above baseline 48h-96h after angiography)

Secondary Endpoints: Total mortality, CV mortality, Need for dialysis, Doubling of serum creatinine, Side effects

slide7

(1172)

Placebo (1136)

Acetylcysteine

Age – yr

68.0  10.4

68.1  10.4

Female sex

38.0%

39.3%

Patients fulfilling inclusion criteria

15.4%

16.0%

Chronic Renal Failure*

Diabetes mellitus

61.2%

59.7%

Heart failure

9.9%

9.2%

Shock

0.3%

0.2%

History of hypertension

13.5%

13.9%

61.4 (45.2 to 83.3)

60.2 (45.4 to 84.5)

Estimated creatinine clearance

Baseline Characteristics

Coronary diagnostic angiography

67.1%

68.7%

28.5%

30.1%

Percutaneous coronary intervention

* Serum creatinine >1.5mg/dL (stable measurements)

slide8

Compliance and Co-interventions

(1172)

Placebo (1136)

Acetylcysteine

Adherence to study drug

  • 1st dose

99.0%

99.4%

2nd dose

97.6%

97.3%

3rddose

96.4%

96.1%

4th dose

95.6%

94.9%

Hydration before procedure

47.1%

47.5%

NaCl 0.9% - 1ml/Kg/h ≥ 6 h

NaCl 0.9% - any scheme

94.3%

94.3%

5.1%

Bicarbonate

4.6%

Hydration after procedure

NaCl 0.9% - 1ml/Kg/h ≥ 6 h

52.3%

54.8%

NaCl 0.9% - any scheme

71.2%

74.1%

28.8%

28.5%

Bicarbonate

Contrast

High/low/iso-osmolar (%)

22.0/ 75.0 / 3.0

22.9 / 74.3 / 2.9

Volume (mL)

100 (70 to 130)

100 (70 to 130)

slide9

Results

PrimaryEndpoint

slide11

Side Effects

Placebo

n (%)

Acetylcysteine

P

value

n (%)

Adverse events

89 (7.6)

0.61

80 (7.0)

8 (0.7)

15 (1.2)

Nausea

0.12

4 (0.3)

Vomiting

14 (1.2)

0.01

25 (2.1)

Angina

14 (1.2)

0.09

Fatigue

13 (1.1)

19 (1.6)

0.33

Diarrhea

10 (0.9)

7 (0.6)

0.43

Serious adverse events *

25 (2.2)

15 (1.3)

0.09

Includes: stroke, pneumonia, sepsis, acute pulmonary edema - (Less then 10 events per endpoint)

subgroup analysis
SubgroupAnalysis

Also no difference for subgroups:

Creatinine ≥ 2mg/dl

Time of measurement of post-procedure creatinine

slide13

Updated Meta-Analysis

All criteria adequate * =

Allocation concealment, double-blind and ITT

main conclusions
MainConclusions

Largest acetylcysteine randomized trial conducted to date.

Acetylcysteine does not reduce the short-term risk of CIN nor other clinically relevant outcomes (30 days) even among the higher risk subgroups.

These results are consistent with meta-analysis of previous smaller high quality trials (zero heterogeneity).

These results may help to inform clinical practice and to update current guidelines.