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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 - PowerPoint PPT Presentation
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Acetylcysteine for the prevention of Contrast-induced nephropaThy (ACT) Trial:
The ACT Trial Investigators
Presenter: Otavio Berwanger (MD; PhD)Chair - Steering Committe
A Pragmatic Multicenter Randomized Trial to Evaluate the Efficacy of Acetylcysteine for the Prevention of
Renal Outcomes in Patients Undergoing Coronary and Vascular Angiography
Sponsor: Sponsor: Ministry of Health-BrazilMinistry of Health-Brazil
Presenter Disclosure Information
Presenter: 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:FINANCIAL DISCLOSURE:None to declareNone to declare
Why do We Need a New Acetylcysteine Trial ?
THE PROBLEMTHE PROBLEM
Contrast-induced nephropathy is associated with mortality and Contrast-induced nephropathy is associated with mortality and prolonged hospitalization. The incidence in patients with risk factors prolonged hospitalization. The incidence in patients with risk factors (such as renal failure, diabetes, age > 70 y) varies between 9% and (such as renal failure, diabetes, age > 70 y) varies between 9% and 38%.38%.
ONE POTENTIAL SOLUTIONONE POTENTIAL SOLUTION
Acetylcysteine (an antioxidant) represents a safe, non-expensive , Acetylcysteine (an antioxidant) represents a safe, non-expensive , easy to administer, and widely available drugeasy to administer, and widely available drug
THE EVIDENCETHE EVIDENCE
Low quality (few trials with allocation concealment, blinding, and ITT analysis)Low statistical power (median trial size = 80 patients)Uncertain effects on clinical endpointsLack of standardization of acetylcysteine dose/scheme and co-interventions
Design: Academic,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%
The ACT Trial
Trial Organization
Trial Steering CommitteTrial Steering CommitteOtavio Berwanger Otavio Berwanger Alexandre Biasi Cavalcanti Alexandre Biasi Cavalcanti Amanda Sousa Amanda Sousa Celso Amodeo Celso Amodeo J. Eduardo Sousa J. Eduardo Sousa Leda D. Lotaif Leda D. Lotaif Project OfficeProject Office Data Management/e-CRFData Management/e-CRFResearch Institute HCorResearch Institute HCor Carlos CardosoCarlos CardosoAlexandre Biasi CavalcantiAlexandre Biasi Cavalcanti Andre L.A. FirminoAndre L.A. FirminoAnna Maria BuehlerAnna Maria Buehler Dalmo Silva Dalmo Silva Mariana CarballoMariana Carballo Paulo J. SoaresPaulo J. SoaresAlessandra KodamaAlessandra Kodama Adailton MendesAdailton MendesEliana SantucciEliana Santucci Jose LobatoJose Lobato
Centres Centres Top Recruiting Sites: Top Recruiting Sites: 46 Institutions in Brazil46 Institutions in Brazil Hospital Bandeirantes (Sao PauloHospital Bandeirantes (Sao Paulo))
Beneficiencia Portuguesa (Sao PauloBeneficiencia Portuguesa (Sao Paulo))Hospital P.S. Mat. Santa Lucia (Minas Gerais)Hospital P.S. Mat. Santa Lucia (Minas Gerais)Instituto de Cardiologia (Sta Catarina)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
ITT
ConcealedRandomization
Acetylcysteine 1200mg Orally Twice Daily for 2 Doses
Before and 2 Doses After Procedure
ITT
Matching Placebo
Primary Endpoint: Primary Endpoint: Contrast-induced nephropathy (CIN)Contrast-induced nephropathy (CIN) (≥ 25% elevation of serum creatinine above baseline 48h-96h after angiography)
Secondary Endpoints: Secondary Endpoints: Total mortality, CV mortality, Need for dialysis, Doubling of serum creatinine, Side effects
Flow of patients
1,153 (98.4%) Had data included in the primary outcome analysis
1,171 (99.9%) Had data included in secondary outcome analyses
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
1,172 Allocated to N-acetylcysteine
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
7 (0.6%) did not receive study drug before angiography
2,308 Underwent randomization
12 (1.0%) did not receive study drug before angiography
1,136 Allocated to placebo
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
86.1%
72 (63 to 82)72 (63 to 81)
86.5%
Age > 70 years 52.9%51.3%
History of hypertension
0.2% 0.3%Shock 9.2% 9.9% Known heart failure
68.1 10.4
68.0 10.4Age – yr
Patients fulfilling inclusion criteria
59.7%61.2%Diabetes mellitus
16.0%15.4% Serum creatinine >1.5mg/dL
39.3%38.0%Female sex
Placebo (1136)Acetylcysteine (1172)
Weight - Kg
35.1%35.8% Acute coronary syndrome
Acetylcysteine (1172) Placebo (1136)
Previous Medication
Use of NSAIDS > 7 days
Use of ACE inhibitor
Use of diuretics
5.4%
Use of metformin
37.7%
30.9%
58.3%
29.6%
59.6%
35.4%
5.2%
Glomerular filtration rate
Serum creatinine – mg/dL
60.2 (45.4 to 84.5) 61.4 (45.2 to 83.3)
1.1 (0.9 to 1.4) 1.1 (0.9 to 1.4)
Baseline Characteristics
Acetylcysteine (1172) Placebo (1136)
Compliance with study protocol
Adherence to study drug
1st dose
2nd
dose
99.0%
4th dose
3rd dose
97.6%
96.4%
94.9%
96.1%
95.6%
97.3%
99.4%
Acetylcysteine (1172) Placebo (1136)
NaCl 0.9% - any scheme
NaCl or bicarbonate Hydration before
procedure
Hydration after procedure
NaCl 0.9% - 1ml/Kg/h for 6 h
94.3%94.3%
47.5%
98.5%
71.2%
52.3% 54.8%74.1%
NaCl 0.9% - 1ml/Kg/h for 6 h
NaCl 0.45%
NaCl 0.9% - any scheme
Bicarbonate 0.9%
NaCl or bicarbonate
NaCl 0.45%Bicarbonate 0.9%
4.6%
75.6%
0%
72.7%
0.1%
5.1%
47.1%
0.3%
97.9%
28.5%28.8%
0%
Compliance with study protocol
Acetylcysteine (1172) Placebo (1136)
Characteristics of the angiography
High osmolarity
Contrast type
2.9%
22.0% 22.9%
75.0%
3.0%
74.3%
Iso- osmolar
Low osmolarity
Contrast volume* 100 (70 to 130) 100 (70 to 130)
*Median (interquartile range)
Procedure
67.1% 68.7%
Percutaneous coronary intervention
30.1% 28.5%
Peripheral vascular angiographyCoronary diagnostic angiography
2.8% 2.9%
Results
Primary Endpoint
Acetylcysteine (N=1172) Placebo (N=1136)
Results
Primary Endpoint
Acetylcysteine (N=1172) Placebo (N=1136)
Clinical Outcomes at 30 days
Mortality or need for dialysis
Acetylcysteine (N=1172) Placebo (N=1136)
Clinical Outcomes at 30 days
Mortality or need for dialysis
Acetylcysteine (N=1172) Placebo (N=1136)
Acetylcysteine(n=1172)
Placebo(n=1136)
Relative Risk(95% CI)
PValue
Primary Outcome – 48h-96h 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
Death or Need for dialysis or duplication of serum creatinine
21 (1.8) 26 (2.3) 0.78 (0.44- 1.38) 0.40
Effects on Contrast-Induced
Nephropathy
Acetylcysteine(n=1172)
Placebo(n=1136)
Relative Risk(95% CI)
PValue
Status in 30 days No. of events (% of patients)
Death, need for dialysis or adoubling 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 No. of events (% of patients)
Cardiovascular deaths 18 (1.5) 18 (1.6) 0.97 (0.51; 1.85) 0.93
Other outcomes
Side EffectsAcetylcysteine
n (%) Placebo n (%)
Nausea
Vomiting
89 (7.6)
8 (0.7)
15 (1.3)
7 (0.6)
19 (1.6)
25 (2.1)
4 (0.3)
13 (1.1)
14 (1.2)
14 (1.2)
15 (1.2)
80 (7.0)
Angina
Fatigue
Diarrhea
Serious adverse events * 25 (2.2)
10 (0.9)
Adverse events
P value
0.43
0.33
0.09
0.01
0.12
0.61
0.09
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.Largest acetylcysteine randomized trial conducted to date.
Acetylcysteine does not reduce the short-term risk of CIN nor Acetylcysteine does not reduce the short-term risk of CIN nor other clinically relevant outcomes (30 days) even among the other clinically relevant outcomes (30 days) even among the higher risk subgroups. higher risk subgroups.
These results are consistent with meta-analysis of previous These results are consistent with meta-analysis of previous smaller high quality trials (zero heterogeneity).smaller high quality trials (zero heterogeneity).
These results may help to inform clinical practice and to These results may help to inform clinical practice and to update current guidelines. update current guidelines.
Future Directions
Cystatin C substudyCystatin C substudy
Complete Updtated Systematic Review and Meta-Complete Updtated Systematic Review and Meta-Analysis and Meta-regression analysisAnalysis and Meta-regression analysis
Registries can document impact of ACT Trial Results in Registries can document impact of ACT Trial Results in Clinical PracticeClinical Practice