Transcript ESTUDO ACT

Acetylcysteine for the prevention of Contrastinduced 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 - Steering Committe
Sponsor: Ministry of Health-Brazil
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
Why do We Need a
New Acetylcysteine Trial ?
THE PROBLEM
CIN is associated with mortality and prolonged hospitalization. The
incidence in patients with risk factors (such as renal failure, diabetes,
age > 70 y) varies between 9% and 38%.
ONE POTENTIAL SOLUTION
Acetylcysteine represents a safe, non-expensive , easy to administer,
and widely available drug
THE EVIDENCE
Low quality (few trials with allocation concealment, blinding, and ITT analysis)
Low statistical power (median trial size = 80 patients)
Uncertain effects on clinical endpoints
Lack of standardization of acetylcysteine dose/scheme and co-interventions
The ACT Trial
Design: Academic, Pragmatic Randomized Multicenter Trial of
Acetylcysteine versus Placebo for the Prevention of Renal
Outcomes
Prevention of Bias:

Concealed allocation (central web-based randomization) and
Intention-to-treat analysis

Blinding of patients, investigators, caregivers, and outcome
assessors
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 Steering Committe
Otavio Berwanger
Amanda Sousa
J. Eduardo Sousa
Alexandre Biasi Cavalcanti
Celso Amodeo
Leda D. Lotaif
Project Office
Research Institute HCor
Alexandre Biasi Cavalcanti
Anna Maria Buehler
Mariana Carballo
Alessandra Kodama
Eliana Santucci
Data Management/e-CRF
Carlos Cardoso
Andre L.A. Firmino
Dalmo Silva
Paulo J. Soares
Adailton Mendes
Jose Lobato
Centres
46 Institutions in Brazil
Top Recruiting Sites:
Hospital Bandeirantes (Sao Paulo)
Beneficiencia Portuguesa (Sao Paulo)
Hospital P.S. Mat. Santa Lucia (Minas Gerais)
Instituto de Cardiologia (Sta Catarina)
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
Baseline Characteristics
Acetylcysteine (1172)
Age – yr
Female sex
68.0  10.4
38.0%
Patients fulfilling inclusion criteria
Chronic Renal Failure*
Diabetes mellitus
Heart failure
Placebo (1136)
68.1  10.4
39.3%
15.4%
16.0%
61.2%
59.7%
9.9%
9.2%
0.3%
0.2%
History of hypertension
13.5%
13.9%
Coronary diagnostic angiography
67.1%
68.7%
Percutaneous coronary intervention
30.1%
28.5%
Shock
Estimated creatinine clearance
60.2 (45.4 to 84.5) 61.4 (45.2 to 83.3)
* Serum creatinine >1.5mg/dL (stable measurements)
Compliance and Co-interventions
Acetylcysteine (1172) Placebo (1136)
Adherence to study drug
1st dose
2nd dose
3rd dose
4th dose
Hydration before procedure
NaCl 0.9% - 1ml/Kg/h ≥ 6 h
NaCl 0.9% - any scheme
Bicarbonate
Hydration after procedure
NaCl 0.9% - 1ml/Kg/h ≥ 6 h
NaCl 0.9% - any scheme
Bicarbonate
Contrast
High/low/iso-osmolar (%)
Volume (mL)
99.0%
97.6%
96.4%
95.6%
99.4%
97.3%
96.1%
94.9%
47.1%
94.3%
5.1%
47.5%
94.3%
4.6%
52.3%
71.2%
28.8%
54.8%
74.1%
28.5%
22.0/ 75.0 / 3.0 22.9 / 74.3 / 2.9
100 (70 to 130) 100 (70 to 130)
Results
Primary Endpoint
Clinical Endpoints at 30 days
Side Effects
Acetylcysteine
n (%)
Placebo
n (%)
P
value
89 (7.6)
80 (7.0)
0.61
Nausea
8 (0.7)
15 (1.2)
0.12
Vomiting
4 (0.3)
14 (1.2)
0.01
Angina
25 (2.1)
14 (1.2)
0.09
Fatigue
19 (1.6)
13 (1.1)
0.33
7 (0.6)
10 (0.9)
0.43
15 (1.3)
25 (2.2)
0.09
Adverse events
Diarrhea
Serious adverse events *
Includes: stroke, pneumonia, sepsis, acute pulmonary edema - (Less then 10 events per endpoint)
Subgroup Analysis
Also no difference for subgroups:
Creatinine ≥ 2mg/dl
Time of measurement of post-procedure
creatinine
Updated Meta-Analysis
All criteria adequate * =
Allocation concealment, double-blind and ITT
Main Conclusions
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.