Transcript Acetylcysteine

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
Contrast-induced nephropathy 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 (an antioxidant) 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 Preventon 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
Flow of patients
2,308 Underwent randomization
1,172 Allocated to N-acetylcysteine
1,136 Allocated to placebo
12 (1.0%) did not receive study
drug before angiography
7 (0.6%) did not receive study
drug before angiography
19 (1.6%) lost to 48-96 hour
serum creatinine follow-up
4 (0.3%) died before 48-96
hours
15 (1.3%) did not return
1 (0.1%) lost 30th day follow-up
17 (1.5%) lost to 48-96 hour
serum creatinine follow-up
3 (0.3%) died before 48-96
hours
14 (1.2%) did not return to
1 (0.1%) Was lost to 30th day
FU
1,153 (98.4%) Had data included
in the primary outcome
analysis
1,171 (99.9%) Had data included
in secondary outcome
analyses
1,119 (98.5%) Had data included
in the primary outcome
analysis
1,135 (99.9%) Had data included
in secondary outcome
analyses
Baseline Characteristics
Acetylcysteine (1172) Placebo (1136)
Age – yr
Female sex
68.0  10.4
38.0%
68.1  10.4
39.3%
Patients fulfilling inclusion criteria
Serum creatinine >1.5mg/dL
15.4%
16.0%
Diabetes mellitus
Known heart failure
61.2%
9.9%
59.7%
0.3%
0.2%
51.3%
52.9%
History of hypertension
86.5%
86.1%
Acute coronary syndrome
35.8%
35.1%
Shock
Age > 70 years
Weight - Kg
72 (63 to 81)
9.2%
72 (63 to 82)
Baseline Characteristics
Acetylcysteine (1172) Placebo (1136)
Previous Medication
Use of NSAIDS > 7 days
5.4%
5.2%
Use of diuretics
37.7%
35.4%
Use of metformin
30.9%
29.6%
Use of ACE inhibitor
59.6%
58.3%
Serum creatinine – mg/dL
Glomerular filtration rate
1.1 (0.9 to 1.4)
1.1 (0.9 to 1.4)
60.2 (45.4 to 84.5) 61.4 (45.2 to 83.3)
Compliance with study
protocol
Acetylcysteine (1172) Placebo (1136)
Adherence to study drug
1st dose
99.0%
99.4%
2nd dose
97.6%
97.3%
3rd dose
96.4%
96.1%
4th dose
95.6%
94.9%
Compliance with study
protocol
Acetylcysteine (1172) Placebo (1136)
Hydration before procedure
NaCl or bicarbonate
97.9%
NaCl 0.9% - 1ml/Kg/h for 6 h
47.1%
98.5%
47.5%
NaCl 0.9% - any scheme
NaCl 0.45%
Bicarbonate 0.9%
94.3%
94.3%
0.3%
0%
5.1%
4.6%
72.7%
52.3%
71.2%
0.1%
28.8%
75.6%
54.8%
74.1%
0%
28.5%
Hydration after procedure
NaCl or bicarbonate
NaCl 0.9% - 1ml/Kg/h for 6 h
NaCl 0.9% - any scheme
NaCl 0.45%
Bicarbonate 0.9%
Characteristics of the
angiography
Acetylcysteine (1172)
Placebo (1136)
Procedure
Peripheral vascular angiography
2.8%
2.9%
Coronary diagnostic angiography
67.1%
68.7%
Percutaneous coronary intervention
30.1%
28.5%
High osmolarity
22.0%
22.9%
Low osmolarity
75.0%
74.3%
3.0%
2.9%
Contrast type
Iso- osmolar
Contrast volume*
*Median (interquartile range)
100 (70 to 130)
100 (70 to 130)
Results
Acetylcysteine (N=1172)
Primary Endpoint
Placebo (N=1136)
Results
Acetylcysteine (N=1172)
Primary Endpoint
Placebo (N=1136)
Clinical Outcomes at 30 days
Acetylcysteine (N=1172)
Mortality or need
for dialysis
Placebo (N=1136)
Clinical Outcomes at 30 days
Acetylcysteine (N=1172)
Mortality or need
for dialysis
Placebo (N=1136)
Effects on
Contrast-Induced Nephropathy
Acetylcysteine
(n=1172)
Primary Outcome – 48h-96h
Placebo
(n=1136)
Relative Risk
(95% CI)
P
Value
No. of events (% of patients)
Elevation ≥ 0.5 mg/dL
in serum creatinine
45 (3.9)
42 (3.8)
1.04 (0.69-1.57)
0.85
Death
7 (0.6)
8 (0.7)
0.85 (0.31-2.33)
0.75
Need for dialysis
2 (0.2)
3 (0.3)
0.65 (0.11-3.86)
0.68
Death or CIN
164 (14.2)
163 (14.5)
0.98 (0.80-1.19)
0.81
Death or Need for dialysis or CIN
152 (13.1)
149 (13.3)
0.99 (0.80- 1.22)
0.92
21 (1.8)
26 (2.3)
0.78 (0.44- 1.38)
0.40
Death or Need for dialysis or
duplication of serum creatinine
Other outcomes
Acetylcysteine
(n=1172)
Status in 30 days
Placebo
(n=1136)
Relative Risk
(95% CI)
P
Value
No. of events (% of patients)
Death, need for dialysis or a
doubling in serum creatinine
in 30 days
45 (3.9)
42 (3.8)
0.90 (0.58 -1.39)
0.63
Deaths or need for dialysis in 30
days
26 (2.2)
26 (2.3)
0.97 (0.57-1.66)
0.91
Deaths in 30 days
23 (2.0)
24 (2.1)
0.93 (0.53 -1.64)
0.80
Need for dialysis in 30 days
3 (0.3)
3 (0.3)
0.97 (0.20 -4.80)
0.97
Doubling in serum creatinine
13 (1.1)
17 (1.5)
0.74 (0.36 -1.52)
0.41
Status after 30 days
Cardiovascular deaths
No. of events (% of patients)
18 (1.5)
18 (1.6)
0.97 (0.51; 1.85)
0.93
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)
Subgroups
Subgroups
Meta-analysis
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.
Future Directions
Cystatin C substudy
Complete Updtated Systematic Review and MetaAnalysis and Meta-regression analysis
Registries can document impact of ACT Trial Results in
Clinical Practice