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: Sponsor: Ministry of Health-BrazilMinistry of Health-Brazil

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:FINANCIAL DISCLOSURE:None to declareNone to declare

Why do We Need a New Acetylcysteine Trial ?

THE PROBLEMTHE PROBLEM

Contrast-induced nephropathy is associated with mortality and Contrast-induced nephropathy is associated with mortality and prolonged hospitalization. The incidence in patients with risk factors prolonged hospitalization. The incidence in patients with risk factors (such as renal failure, diabetes, age > 70 y) varies between 9% and (such as renal failure, diabetes, age > 70 y) varies between 9% and 38%.38%.

ONE POTENTIAL SOLUTIONONE POTENTIAL SOLUTION

Acetylcysteine (an antioxidant) represents a safe, non-expensive , Acetylcysteine (an antioxidant) represents a safe, non-expensive , easy to administer, and widely available drugeasy to administer, and widely available drug

THE EVIDENCETHE 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,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%

The ACT Trial

Trial Organization

Trial Steering CommitteTrial Steering CommitteOtavio Berwanger Otavio Berwanger Alexandre Biasi Cavalcanti Alexandre Biasi Cavalcanti Amanda Sousa Amanda Sousa Celso Amodeo Celso Amodeo J. Eduardo Sousa J. Eduardo Sousa Leda D. Lotaif Leda D. Lotaif Project OfficeProject Office Data Management/e-CRFData Management/e-CRFResearch Institute HCorResearch Institute HCor Carlos CardosoCarlos CardosoAlexandre Biasi CavalcantiAlexandre Biasi Cavalcanti Andre L.A. FirminoAndre L.A. FirminoAnna Maria BuehlerAnna Maria Buehler Dalmo Silva Dalmo Silva Mariana CarballoMariana Carballo Paulo J. SoaresPaulo J. SoaresAlessandra KodamaAlessandra Kodama Adailton MendesAdailton MendesEliana SantucciEliana Santucci Jose LobatoJose Lobato

Centres Centres Top Recruiting Sites: Top Recruiting Sites: 46 Institutions in Brazil46 Institutions in Brazil Hospital Bandeirantes (Sao PauloHospital Bandeirantes (Sao Paulo))

Beneficiencia Portuguesa (Sao PauloBeneficiencia Portuguesa (Sao Paulo))Hospital P.S. Mat. Santa Lucia (Minas Gerais)Hospital P.S. Mat. Santa Lucia (Minas Gerais)Instituto de Cardiologia (Sta Catarina)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

ITT

ConcealedRandomization

Acetylcysteine 1200mg Orally Twice Daily for 2 Doses

Before and 2 Doses After Procedure

ITT

Matching Placebo

Primary Endpoint: Primary Endpoint: Contrast-induced nephropathy (CIN)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

Flow of patients

1,153 (98.4%) Had data included in the primary outcome analysis

1,171 (99.9%) Had data included in secondary outcome analyses

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

1,172 Allocated to N-acetylcysteine

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

7 (0.6%) did not receive study drug before angiography

2,308 Underwent randomization

12 (1.0%) did not receive study drug before angiography

1,136 Allocated to placebo

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

86.1%

72 (63 to 82)72 (63 to 81)

86.5%

Age > 70 years 52.9%51.3%

History of hypertension

0.2% 0.3%Shock 9.2% 9.9% Known heart failure

68.1 10.4

68.0 10.4Age – yr

Patients fulfilling inclusion criteria

59.7%61.2%Diabetes mellitus

16.0%15.4% Serum creatinine >1.5mg/dL

39.3%38.0%Female sex

Placebo (1136)Acetylcysteine (1172)

Weight - Kg

35.1%35.8% Acute coronary syndrome

Acetylcysteine (1172) Placebo (1136)

Previous Medication

Use of NSAIDS > 7 days

Use of ACE inhibitor

Use of diuretics

5.4%

Use of metformin

37.7%

30.9%

58.3%

29.6%

59.6%

35.4%

5.2%

Glomerular filtration rate

Serum creatinine – mg/dL

60.2 (45.4 to 84.5) 61.4 (45.2 to 83.3)

1.1 (0.9 to 1.4) 1.1 (0.9 to 1.4)

Baseline Characteristics

Acetylcysteine (1172) Placebo (1136)

Compliance with study protocol

Adherence to study drug

1st dose

2nd

dose

99.0%

4th dose

3rd dose

97.6%

96.4%

94.9%

96.1%

95.6%

97.3%

99.4%

Acetylcysteine (1172) Placebo (1136)

NaCl 0.9% - any scheme

NaCl or bicarbonate Hydration before

procedure

Hydration after procedure

NaCl 0.9% - 1ml/Kg/h for 6 h

94.3%94.3%

47.5%

98.5%

71.2%

52.3% 54.8%74.1%

NaCl 0.9% - 1ml/Kg/h for 6 h

NaCl 0.45%

NaCl 0.9% - any scheme

Bicarbonate 0.9%

NaCl or bicarbonate

NaCl 0.45%Bicarbonate 0.9%

4.6%

75.6%

0%

72.7%

0.1%

5.1%

47.1%

0.3%

97.9%

28.5%28.8%

0%

Compliance with study protocol

Acetylcysteine (1172) Placebo (1136)

Characteristics of the angiography

High osmolarity

Contrast type

2.9%

22.0% 22.9%

75.0%

3.0%

74.3%

Iso- osmolar

Low osmolarity

Contrast volume* 100 (70 to 130) 100 (70 to 130)

*Median (interquartile range)

Procedure

67.1% 68.7%

Percutaneous coronary intervention

30.1% 28.5%

Peripheral vascular angiographyCoronary diagnostic angiography

2.8% 2.9%

Results

Primary Endpoint

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

Results

Primary Endpoint

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

Clinical Outcomes at 30 days

Mortality or need for dialysis

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

Clinical Outcomes at 30 days

Mortality or need for dialysis

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

Acetylcysteine(n=1172)

Placebo(n=1136)

Relative Risk(95% CI)

PValue

Primary Outcome – 48h-96h 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

Death or Need for dialysis or duplication of serum creatinine

21 (1.8) 26 (2.3) 0.78 (0.44- 1.38) 0.40

Effects on Contrast-Induced

Nephropathy

Acetylcysteine(n=1172)

Placebo(n=1136)

Relative Risk(95% CI)

PValue

Status in 30 days No. of events (% of patients)

Death, need for dialysis or adoubling 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 No. of events (% of patients)

Cardiovascular deaths 18 (1.5) 18 (1.6) 0.97 (0.51; 1.85) 0.93

Other outcomes

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)

Subgroups

Subgroups

Meta-analysis

Main Conclusions

Largest acetylcysteine randomized trial conducted to date.Largest acetylcysteine randomized trial conducted to date.

Acetylcysteine does not reduce the short-term risk of CIN nor Acetylcysteine does not reduce the short-term risk of CIN nor other clinically relevant outcomes (30 days) even among the other clinically relevant outcomes (30 days) even among the higher risk subgroups. higher risk subgroups.

These results are consistent with meta-analysis of previous These results are consistent with meta-analysis of previous smaller high quality trials (zero heterogeneity).smaller high quality trials (zero heterogeneity).

These results may help to inform clinical practice and to These results may help to inform clinical practice and to update current guidelines. update current guidelines.

Future Directions

Cystatin C substudyCystatin C substudy

Complete Updtated Systematic Review and Meta-Complete Updtated Systematic Review and Meta-Analysis and Meta-regression analysisAnalysis and Meta-regression analysis

Registries can document impact of ACT Trial Results in Registries can document impact of ACT Trial Results in Clinical PracticeClinical Practice