Journal ClubJournal Club

Naudia N. Lauder, M.D.Naudia N. Lauder, M.D.

Evan J. Lipson, M.D.Evan J. Lipson, M.D.

David T. Majure, M.D., M.P.H. David T. Majure, M.D., M.P.H.

Hx of the J-ClubHx of the J-Club

Sir William Osler established the first Sir William Osler established the first formalized journal club at McGill University formalized journal club at McGill University in Montreal in 1875.in Montreal in 1875.

The original purpose of Osler's journal The original purpose of Osler's journal club was "for the purchase and distribution club was "for the purchase and distribution of periodicals to which he could ill afford to of periodicals to which he could ill afford to subscribe.“subscribe.“11

1. The ever-reliable Wikipedia…

Rules of J-clubRules of J-club11stst rule of J-Club: rule of J-Club: Don’t talk about J-club.Don’t talk about J-club.

Incidentally…Incidentally…

Happy 157Happy 157thth birthday, Dr. Osler. (a day birthday, Dr. Osler. (a day late)late)

NN-Acetylcysteine and Contrast-Induced -Acetylcysteine and Contrast-Induced Nephropathy in Primary AngioplastyNephropathy in Primary Angioplasty

NEJM NEJM 354;26 June 29, 2006354;26 June 29, 2006Marenzi et al. at the Institute of Cardiology, University of Milan, ItalyMarenzi et al. at the Institute of Cardiology, University of Milan, Italy

And now, down to business…

BackgroundBackground Patients with acute MI undergoing primary Patients with acute MI undergoing primary

angioplasty are at high risk for contrast induced angioplasty are at high risk for contrast induced nephropathy. nephropathy.

NAC is a scavenger of oxygen-derived free NAC is a scavenger of oxygen-derived free radicals and causes endothelium-dependent radicals and causes endothelium-dependent vasodilation.vasodilation.

Approximately a dozen studies on the Approximately a dozen studies on the prophylactic effect of prophylactic effect of NN-acetylcysteine have -acetylcysteine have been published, with contradictory results.been published, with contradictory results.

BackgroundBackground

Research question: Can the antioxidant Research question: Can the antioxidant NN--acetylcysteine prevent contrast induced acetylcysteine prevent contrast induced nephropathy in patients undergoing nephropathy in patients undergoing primary angioplasty.**primary angioplasty.**

**Primary angioplasty vs. elective PCI (e.g. **Primary angioplasty vs. elective PCI (e.g. after positive stress echo)after positive stress echo)

• Study population: Over 2 years, all patients admitted to the CCU at Centro Cardiologico Monzino in Milan for STEMI who would then undergo angioplasty

• Had to present within 12 hours (18 hours in cases of cardiogenic shock) after the onset of symptoms

• Exclusion criteria were long-term dialysis and known allergy to N-acetylcysteine

• The study was approved by the ethics committee, and written informed consent was obtained from all patients

• Let’s walk through it…

Methods

MethodsMethods

Eligible patients were randomly assigned Eligible patients were randomly assigned to receive standard dose NAC, double to receive standard dose NAC, double dose NAC or placebo.dose NAC or placebo.

Standard dose: Standard dose: 600mg IV 600mg IV bolus NAC bolus NAC before PCI, before PCI, then 600mg po then 600mg po bid for 48 bid for 48 hours after PCIhours after PCI

Double dose:Double dose:1200mg IV 1200mg IV bolus NAC bolus NAC before PCI, before PCI, then 1200mg then 1200mg po bid for 48 po bid for 48 hours after PCIhours after PCI

Placebo

MethodsMethods After intervention, all patients received Normal After intervention, all patients received Normal

Saline at 1ml/kg/hr. (or 0.5ml/kg/hr in cases of Saline at 1ml/kg/hr. (or 0.5ml/kg/hr in cases of overt heart failure) for 12 hours.overt heart failure) for 12 hours.

The use of intraaortic balloon pumps, inotropic The use of intraaortic balloon pumps, inotropic drugs, abciximab, beta-blockers, ACE inhibitors drugs, abciximab, beta-blockers, ACE inhibitors and diuretics was left to the discretion of the and diuretics was left to the discretion of the CCU/Cath cardiologistsCCU/Cath cardiologists

Left ventricular function was evaluated by Left ventricular function was evaluated by echocardiography in all patients within 24 hours echocardiography in all patients within 24 hours after admission. after admission.

Investigators involved in the procedures and Investigators involved in the procedures and those reading echocardiograms were blinded to those reading echocardiograms were blinded to the treatment randomization.the treatment randomization.

Primary end point: occurrence of contrast induced nephropathy, defined as an increase in serum creatinine by ≥25 percent from baseline value within the 72-hour period after PCI.

The major in-hospital clinical events, including death, were recorded.

MethodsMethods

MethodsMethods The contrast used was iohexol (omnipaque)

which is low-osmolar and non-ionic. (versus Visipaque which is iso-osmolar, non-ionic, more expensive, and less damaging to kidneys)

Bare-metal stents (versus drug eluting) were implanted in all patients. Post-stenting antithrombotic treatment consisted of aspirin and either clopidogrel or ticlopidine at standard dosages.

N-acetylcysteine was purchased by the investigators.

MethodsMethods Study was powered assuming a reduction in the average Study was powered assuming a reduction in the average

rate of nephropathy by 50 percent in the treatment arm rate of nephropathy by 50 percent in the treatment arm vs. placebo (e.g. from 30 to 15 percent).vs. placebo (e.g. from 30 to 15 percent).

100 patients in each group allowed for a statistical power 100 patients in each group allowed for a statistical power of 80 percent, with a type I error of 0.05.of 80 percent, with a type I error of 0.05.

80% chance that you will avoid a false null 80% chance that you will avoid a false null hypothesis.hypothesis.

5% chance of a obtaining a statistically 5% chance of a obtaining a statistically significant result and rejecting the null hypothesis significant result and rejecting the null hypothesis when it is in fact is true.when it is in fact is true.

Statistical analysis was done as follows:Statistical analysis was done as follows:

Clinical characteristics of the three groups: Clinical characteristics of the three groups: ANOVA for continuous variables, chi-square test or ANOVA for continuous variables, chi-square test or Fisher's exact test for categorical variables.Fisher's exact test for categorical variables. Time course of creatinine values among the Time course of creatinine values among the three groups: ANCOVAthree groups: ANCOVA Incidence of complications among the three Incidence of complications among the three groups: Wald chi-square test with two degrees of groups: Wald chi-square test with two degrees of freedom and by the Mantel–Haenszel chi-square freedom and by the Mantel–Haenszel chi-square test for trend. test for trend.

A P-value of less than 0.05 was considered to A P-value of less than 0.05 was considered to indicate statistical significance. indicate statistical significance.

Methods