1. 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: Ministry of Health-Brazil

2. 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: None to declare

3. 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

4. Academic, 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% The ACT Trial

5. Trial Organization Trial Steering Committe Otavio Berwanger Alexandre Biasi Cavalcanti Amanda Sousa Celso Amodeo J. Eduardo Sousa Leda D. Lotaif Project OfficeData Management/e-CRF Research Institute HCorCarlos Cardoso Alexandre Biasi CavalcantiAndre L.A. Firmino Anna Maria BuehlerDalmo Silva Mariana CarballoPaulo J. Soares Alessandra KodamaAdailton Mendes Eliana SantucciJose Lobato Centres Top Recruiting Sites: 46 Institutions in Brazil Hospital Bandeirantes (Sao Paulo ) Beneficiencia Portuguesa (Sao Paulo ) Hospital P.S. Mat. Santa Lucia (Minas Gerais) Instituto de Cardiologia (Sta Catarina)

6. 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 Concealed Randomization Acetylcysteine 1200mg Orally Twice Daily for 2 Doses Before and 2 Doses After Procedure ITT Matching Placebo Primary Endpoint: 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

7. Baseline Characteristics 61.4 (45.2 to 83.3 ) 60.2 (45.4 to 84.5) Glomerular filtration rate 35.1%35.8% Acute coronary syndrome 0.2% 0.3%Shock 9.2% 9.9% Heart failure 68.1  10.4 68.0  10.4 Age – yr Patients fulfilling inclusion criteria 59.7%61.2%Diabetes mellitus 16.0%15.4% Chronic Renal Failure* 39.3%38.0% Female sex Placebo (1136) Acetylcysteine (1172) Coronary diagnostic angiography67.1% 68.7% Percutaneous coronary intervention 30.1% 28.5% * Serum creatinine >1.5mg/dL (stable measurements)

8. Acetylcysteine (1172 ) Placebo ( 1136) Compliance and Co-interventions Adherence to study drug 1 st dose 2 nd dose 99.0% 4 th dose 3 rd dose NaCl 0.9% - any scheme NaCl 0.9% - 1ml/Kg/h ≥ 6 h Hydration before procedure Hydration after procedure NaCl 0.9% - any scheme NaCl 0.9% - 1ml/Kg/h ≥ 6 h Contrast High/low/iso-osmolar (%) 97.6% 96.4% 94.3% 94.9% 96.1% 95.6% 97.3% 99.4% 94.3% 47.5%47.1% 71.2% 52.3% 54.8% 74.1% 22.0/ 75.0 / 3.0 22.9 / 74.3 / 2.9 Bicarbonate 4.6% 5.1% Bicarbonate 28.5% 28.8% Volume (mL) 100 (70 to 130)

9. Results Primary Endpoint Acetylcysteine (N=1172) Placebo (N=1136)

10. Results Primary Endpoint Acetylcysteine (N=1172) Placebo (N=1136)

11. Clinical Outcomes at 30 days Mortality or need for dialysis Acetylcysteine (N=1172) Placebo (N=1136)

12. Clinical Outcomes at 30 days Mortality or need for dialysis Acetylcysteine (N=1172) Placebo (N=1136)

13. Side Effects Acetylcysteine 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) 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)

14. Subgroup Analysis Also no difference for subgroups: Creatinine ≥ 2mg/dl Time of measurement of post-procedure creatinine

15. Updated Meta-Analysis All criteria adequate * = Allocation concealment, double-blind and ITT

16. 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.