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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.