A t l t i f th ti f C t t Acetylcysteine for the prevention of

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					Acetylcysteine f th prevention of C t t
A t l    t i for the      ti    f 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
R    lO t         i P ti t U d         i C             d
                 Vascular Angiography

             The    T i l Investigators
             Th ACT Trial I    ti t

          Presenter: Otavio Berwanger (MD; PhD)
                Ch i - S     i Committe
                Chair Steering C      i

                                    Health-
               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
  A i        h


FINANCIAL DISCLOSURE:
None to declare
                        Why do We Need a
                     New Acetylcysteine Trial ?
THE PROBLEM

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

ONE POTENTIAL SOLUTION

                    antioxidant)                   non-
Acetylcysteine (an antioxidant) represents a safe, non-expensive ,
        administer,
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
   D i     Academic Pragmatic R d
   Design: A d i , P
           Academic,                     i d Multicenter T i l of
                              ti Randomized M lti      t Trial f
   Acetylcysteine versus Placebo for the Prevention of Renal
   Outcomes

   Prevention of Bias:

                                      web based
        Concealed allocation (central web-based randomization) and
        Intention-to-treat analysis

        Blinding of patients, investigators, caregivers, and outcome
               g p          ,        g     ,     g     ,
        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 J l 2010
   b t       S t b               d July
* 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               Alexandre Biasi Cavalcanti
Amanda Sousa                   Celso Amodeo
J. Eduardo Sousa               Leda D. Lotaif

Project Office                      Management/e-
                               Data Management/e-CRF
Research Institute HCor        Carlos 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 Brazil      Hospital Bandeirantes (Sao Paulo)
                               Beneficiencia Portuguesa (Sao Paulo)
                                                                       Gerais)
                               Hospital P.S. Mat. Santa Lucia (Minas Gerais)
                                                        (Sta Catarina)
                               Instituto de Cardiologia (Sta Catarina)
2,308 Patients undergoing an angiographic procedure with at least one of
the following risk factors:
            g
                       Age > 70 years;
                       Chronic Renal Failure;
                       Diabetes Mellitus;
                                             <0.45;
                       Heart Failure or LVEF <0 45;
                       Shock



                                        Concealed
                                      Randomization

    Acetylcysteine 1200mg
  Orally Twice Daily for 2 Doses
  Before and 2 Doses After                                        Matching Placebo
  Procedure

                           ITT                                                      ITT

                        Contrast-
      Primary Endpoint: Contrast-induced nephropathy (CIN)
      ( 5% elevation of serum c eat    e abo e baseline 8 96 after angiography)
      (≥ 25% e e at o o se u creatinine above base e 48h-96h a te a g og ap y)
      Secondary Endpoints: Total mortality, CV mortality, Need for dialysis, Doubling of
      serum creatinine, Side effects
                   Baseline Characteristics
                                 Acetylcysteine (1172)          Placebo (1136)
Age – yr                                        68.0 ± 10.4     68.1 ± 10.4
Female sex                                          38.0%          39.3%
Patients fulfilling inclusion criteria
    Chronic Renal Failure*                            15.4%         16.0%
    Diabetes mellitus                                 61.2%         59.7%
    Heart failure                                      9.9%           9.2%
    Shock                                              0.3%           0.2%
Acute coronary syndrome                               35.8%
                                                      35 8%         35.1%
                                                                    35 1%
Coronary diagnostic angiography                       67.1%         68.7%
Percutaneous coronary intervention                    30.1%          28.5%
Glomerular filtration rate                     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                            99.0%           99.4%
  2nd dose                            97.6%           97.3%
  3rd dose                            96.4%           96.1%
      dose
  4th d                               95.6%
                                      95 6%           94.9%
                                                      94 9%
Hydration before procedure
   NaCl 0.9% - 1ml/Kg/h ≥ 6 h         47.1%           47.5%
         0.9%
   NaCl 0 9% - any scheme             94 3%
                                      94.3%           94 3%
                                                      94.3%
   Bicarbonate                         5.1%           4.6%
Hydration after procedure
   N Cl 0 9% - 1 l/K /h ≥ 6 h
   NaCl 0.9% 1ml/Kg/h                 52 3%
                                      52.3%            54.8%
   NaCl 0.9% - any scheme             71.2%            74.1%
   Bicarbonate                        28.8%            28.5%
C t t
Contrast
   High/low/iso-osmolar (%)       22.0/ 75.0 / 3.0 22.9 / 74.3 / 2.9
   Volume (mL)                    100 (70 to 130) 100 (70 to 130)
                                          Results


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


                20


                15
                           12.7
         ents
% of patie




                10
                     Primary Endpoint


                 5                                3.8
                                                                           1.5
                0
                                        Elevation ≥0.5mg/dL       Doubling in serum
                           CIN
                                        in serum creatinine          creatinine
                                               Results


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

                     RR = 1.00 (0.81-1.25)    RR = 1.04 (0.69 -1.57)   RR = 0.74 (0.36 -1.52)
                20   p = 0.97                 p = 0.85                 p = 0.41


                15
                         12.7   12.7
         ents
% of patie




                10
                      Primary Endpoint


                 5                                 3.9     3.8
                                                                             1.1    1.5
                0
                                             Elevation ≥0.5mg/dL        Doubling in serum
                             CIN
                                             in serum creatinine           creatinine
                                Clinical Outcomes at 30 days

                                Acetylcysteine (N=1172)       Placebo (N=1136)
                7


                6


                5
      atients




                4
% of pa




                3
                          2.3
                                                 2.1
                2                                                                     1.6

                1
                                                                     0.3
                0
                    Mortality or need
                                            Total mortality   Need for dialysis   CV mortality
                      for dialysis
                                  Clinical Outcomes at 30 days

                                  Acetylcysteine (N=1172)           Placebo (N=1136)
                7
                    RR = 0.97 (0.57-1.66)   RR = 0.93 (0.53-1.64)   RR = 0.97 (0.20- 4.80)   RR = 0.97 (0.51; 1.85)
                    p = 0.91                      p = 0.80                p = 0.97                 p = 0.93
                6


                5
      atients




                4
% of pa




                3
                         2.2     2.3
                                                 2.0     2.1
                2                                                                                         1.6
                                                                                                  1.5
                                                                                                  15

                1
                                                                         0.3    0.3
                0
                       Mortality or need
                                                Total mortality      Need for dialysis            CV mortality
                         for dialysis
                                Side Effects
                                   Acetylcysteine         Placebo              P
                                        n (%)               n (%)            value
     Adverse events                     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

       Diarrhea                          7 (0 6)
                                           (0.6)              (0 9)
                                                           10 (0.9)          0.43
                                                                             0 43

   Serious adverse events *             15 (1.3)           25 (2.2)          0.09


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.


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


                                   meta-
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.

				
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posted:12/31/2010
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