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A cetylcysteine for the prevention of C ontrast-induced nephropa T hy (ACT) Trial:

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

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A cetylcysteine for the prevention of C ontrast-induced nephropa T hy (ACT) Trial:

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  1. 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 The ACT Trial Investigators Presenter: Otavio Berwanger (MD; PhD) Chair - SteeringCommitte Sponsor: Ministry of Health-Brazil

  2. 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

  3. Why do WeNeed a NewAcetylcysteine Trial ? THE PROBLEM Contrast-inducednephropathy is associatedwithmortalityandprolongedhospitalization. The incidence in patientswithriskfactors (such as renal failure, diabetes, age > 70 y) varies between 9% and 38%. ONE POTENTIAL SOLUTION Acetylcysteine (anantioxidant) represents a safe, non-expensive , easy to administer, andwidelyavailabledrug THE EVIDENCE Lowquality (fewtrialswithallocation concealment, blinding, and ITT analysis) Lowstatisticalpower (mediantrialsize = 80 patients) Uncertaineffectsonclinicalendpoints Lackofstandardizationofacetylcysteine dose/schemeandco-interventions

  4. The ACT Trial • Design: Academic,PragmaticRandomizedMulticenter Trial ofAcetylcysteine versus Placebo for thePreventonof Renal Outcomes • Preventionof Bias: • Concealedallocation (central web-basedrandomization) andIntention-to-treatanalysis • Blindingofpatients, investigators, caregivers, andoutcomeassessors • 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%

  5. Trial Organization Trial Steering Committe Otavio Berwanger Alexandre Biasi Cavalcanti Amanda Sousa Celso Amodeo J. Eduardo Sousa Leda D. Lotaif Project Office Data Management/e-CRF Research Institute HCorCarlos Cardoso Alexandre Biasi Cavalcanti Andre L.A. Firmino Anna Maria Buehler Dalmo Silva Mariana Carballo Paulo J. Soares Alessandra Kodama Adailton Mendes Eliana Santucci Jose Lobato Centres Top Recruiting Sites: 46 Institutions in BrazilHospital Bandeirantes (Sao Paulo) Beneficiencia Portuguesa (Sao Paulo) Hospital P.S. Mat. Santa Lucia (Minas Gerais) Instituto de Cardiologia (StaCatarina)

  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 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

  7. 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

  8. Baseline Characteristics (1172) Placebo (1136) Acetylcysteine 68.0  10.4 Age – yr 68.1  10.4 39.3% 38.0% Female sex Patients fulfilling inclusion criteria Serum creatinine >1.5mg/dL 16.0% 15.4% Diabetes mellitus 59.7% 61.2% Known heart failure 9.9% 9.2% Shock 0.3% 0.2% Age > 70 years 51.3% 52.9% History of hypertension 86.5% 86.1% Acute coronary syndrome 35.8% 35.1% Weight - Kg 72 (63 to 81) 72 (63 to 82)

  9. Baseline Characteristics (1172) Placebo (1136) Acetylcysteine 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% 1.1 (0.9 to 1.4) 1.1 (0.9 to 1.4) Serum creatinine – mg/dL 61.4 (45.2 to 83.3) 60.2 (45.4 to 84.5) Glomerular filtration rate

  10. Compliance with study protocol (1172) Placebo (1136) Acetylcysteine Adherence to study drug 99.0% • 1st dose 99.4% 2nd dose 97.6% 97.3% 3rddose 96.4% 96.1% 4th dose 95.6% 94.9%

  11. Compliance with study protocol Acetylcysteine (1172) Placebo (1136) Hydration before procedure NaCl or bicarbonate 97.9% 98.5% 47.5% NaCl 0.9% - 1ml/Kg/h for 6 h 47.1% NaCl 0.9% - any scheme 94.3% 94.3% 0% NaCl 0.45% 0.3% Bicarbonate 0.9% 4.6% 5.1% Hydration after procedure NaCl or bicarbonate 72.7% 75.6% NaCl 0.9% - 1ml/Kg/h for 6 h 52.3% 54.8% NaCl 0.9% - any scheme 71.2% 74.1% 0% 0.1% NaCl 0.45% 28.5% 28.8% Bicarbonate 0.9%

  12. Characteristics of the angiography Acetylcysteine (1172) Placebo (1136) Procedure 2.8% 2.9% Peripheral vascular angiography Coronary diagnostic angiography 68.7% 67.1% Percutaneous coronary intervention 30.1% 28.5% Contrast type High osmolarity 22.0% 22.9% Low osmolarity 75.0% 74.3% Iso- osmolar 3.0% 2.9% Contrast volume* 100 (70 to 130) 100 (70 to 130) *Median (interquartile range)

  13. Results Acetylcysteine (N=1172) Placebo (N=1136) PrimaryEndpoint

  14. Results Acetylcysteine (N=1172) Placebo (N=1136) PrimaryEndpoint

  15. ClinicalOutcomes at 30 days Acetylcysteine (N=1172) Placebo (N=1136) Mortality or need for dialysis

  16. ClinicalOutcomes at 30 days Acetylcysteine (N=1172) Placebo (N=1136) Mortality or need for dialysis

  17. Effectson Contrast-InducedNephropathy

  18. Otheroutcomes

  19. Side Effects Placebo n (%) Acetylcysteine P value n (%) Adverse events 89 (7.6) 0.61 80 (7.0) 8 (0.7) 15 (1.2) Nausea 0.12 4 (0.3) Vomiting 14 (1.2) 0.01 25 (2.1) Angina 14 (1.2) 0.09 Fatigue 13 (1.1) 19 (1.6) 0.33 Diarrhea 10 (0.9) 7 (0.6) 0.43 Serious adverse events * 25 (2.2) 15 (1.3) 0.09 Includes: stroke, pneumonia, sepsis, acute pulmonary edema - (Less then 10 events per endpoint)

  20. Subgroups

  21. Subgroups

  22. Meta-analysis

  23. MainConclusions 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.

  24. Future Directions Cystatin C substudy Complete Updtated Systematic Review and Meta-Analysis and Meta-regression analysis Registries can document impact of ACT Trial Results in Clinical Practice

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