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

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 endpointsLack of standardization of acetylcysteine dose/scheme and co-interventions

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

Trial Organization

Trial Steering CommitteOtavio Berwanger Alexandre Biasi Cavalcanti Amanda Sousa Celso Amodeo J. Eduardo Sousa Leda D. Lotaif Project Office Data Management/e-CRFResearch Institute HCor Carlos CardosoAlexandre Biasi Cavalcanti Andre L.A. FirminoAnna Maria Buehler Dalmo Silva Mariana Carballo Paulo J. SoaresAlessandra Kodama Adailton MendesEliana Santucci Jose 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)

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

I T T

ConcealedRandomization

Acetylcysteine 1200mg Orally Twice Daily for 2 Doses

Before and 2 Doses After Procedure

I T T

Matching Placebo

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

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 10.468.0 10.4Age – 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 angiography

67.1% 68.7%

Percutaneous coronary intervention

30.1% 28.5%

* Serum creatinine >1.5mg/dL (stable measurements)

Acetylcysteine (1172) Placebo (1136)

Compliance and Co-interventions

Adherence to study drug 1st dose2nd

dose

99.0%

4th dose

3rd dose

NaCl 0.9% - any schemeNaCl 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

ContrastHigh/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) 100 (70 to 130)

CIN Elevation ≥ 0.5mg/dL in serum

creatinine

Doubling in serum creatinine

0

5

10

15

20

12.7

3.8

1.5

% o

f p

atie

nts

Elevation ≥0.5mg/dL in serum creatinine

Doubling in serum cre-atinine

Results

Primary Endpoint

Acetylcysteine (N=1172) Placebo (N=1136)

CIN Elevation ≥ 0.5mg/dL in serum

creatinine

Doubling in serum creatinine

0

5

10

15

20

12.7

3.9

1.1

12.7

3.8

1.5

% o

f p

atie

nts

RR = 1.00 (0.81-1.25)p = 0.97

RR = 1.04 (0.69 -1.57) p = 0.85

RR = 0.74 (0.36 -1.52)p = 0.41

Elevation ≥0.5mg/dL in serum creatinine

Doubling in serum cre-atinine

Results

Primary Endpoint

Acetylcysteine (N=1172) Placebo (N=1136)

Mortality or need for dialysis

Total mortality Need for dialysis CV mortality0

1

2

3

4

5

6

7

2.32.1

0.3

1.6

% o

f p

ati

en

ts

Clinical Outcomes at 30 days

Mortality or need for dialysis

Acetylcysteine (N=1172) Placebo (N=1136)

Mortality or need for dialysis

Total mortality Need for dialysis CV mortality0

1

2

3

4

5

6

7

2.22.0

0.3

1.5

2.32.1

0.3

1.6

% o

f p

ati

en

ts

RR = 0.97 (0.57-1.66)p = 0.91

RR = 0.93 (0.53-1.64)p = 0.80

RR = 0.97 (0.20- 4.80)p = 0.97

RR = 0.97 (0.51; 1.85)p = 0.93

Clinical Outcomes at 30 days

Mortality or need for dialysis

Acetylcysteine (N=1172) Placebo (N=1136)

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)

Subgroup Analysis

Also no difference for subgroups:Creatinine ≥ 2mg/dlTime 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.