Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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