Journal Club: Myocardial Reperfusion Injury

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EBM Journal ClubSarah Jean Strube,
D.O.Resident Physician St. Mary Medical
CenterOctober 17, 2008

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Overview

• Topic
• Background
• Defining the patient
• Article
• Methods
• Results
• Statistics
• Authors conclusion
• Statistics discussion

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Topic

• Reperfusion injury status post PCI in acute
  myocardial infarction with and without
  cyclosporine injection on area of infarction.

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Background

• Myocardial infarction is a disabling disease and
  infarct size is considered a major determining
  factor for mortality. Limiting the size of an
  infarct through reperfusion therapy is an
  important strategy in decreasing morbidity
  whether through thrombolysis or PCI. However,
  reperfusion has its own detrimental effects
  through several mechanisms. One of which is via
  mitochondrial dysfunction.

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Background

• Mitochondrial dysfunction has been termed
  permeability transition. It is the opening of
  a nonspecific channel in the inner membrane of
  the mitochondria. This transition results in
  uncoupling of the respiratory chain and collapse
  of the inner mitochondrial membrane potential
  with subsequent efflux of proapoptotic factors
  causing myocardiocyte death.

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BACKGROUND

• Cyclosporine is mostly known for its
  immunosuppressive effects.
• However, it has been found by several researchers
  in experimental models to have potent inhibiting
  effects on mitochondrial permeability transition
  and may prevent ischemia/reperfusion injury.

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PICO Question

• Patient
• Intervention
• Control
• Outcome

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PICO question

• Patient A 65 YO male with a Hx of HTN,
  dyslipidemia and prior tobacco use presented to
  the Emergency Department with prolonged angina
  pectoris. Onset of his CP was six hours prior to
  admission and he was found to have an acute
  ST-segment elevation in two contiguous precordial
  leads along with elevation of CK and troponin I.
  An acute myocardial infarction was Dx and he was
  considered a candidate for urgent PCI.

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PICO QUESTION

• Intervention Administration of cyclosporine via
  IV bolus at time of urgent PCI but prior to
  stenting of an occluded artery (TIMI flow 0) in
  an acute ongoing myocardial infarction

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PICO Question

• Control NS bolus during PCI with stenting alone
  prior to the procedure in an occluded artery
  (TIMI flow 0).

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PICO question

• Outcome did the intervention with pretreatment
  with cyclosporine vs normal saline decrease the
  area of myocardial infarction SP PCI?

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• Article selectedEffect of cyclosporine on
  reperfusion injury in acute myocardial
  infarction. New England Journal of Medicine 2008
  359 473-481.
• Research objective
• To evaluate the efficacy of a therapy

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The article

• Original research, pilot study
• Prospective, multicenter, randomized, single
  blind, controlled trial
• Journal - peer reviewed, general Internal
  Medicine, highly respected
• Sites multicenter
• Patients 58 randomly assigned, 30 CS 28 control

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Patient Criteria

• EXCLUSION
• Cardiac arrest
• Cardiogenic shock
• Vent fibrillation
• Stent thrombosis
• Previous MI
• Angina wi 48h
• Occl LM/Circ or collaterals
• Hypersensitivity to cyclosporine

• INCLUSION
• Male/female 18y or older present wi 12h of CP
• STEMI 0.1 mV 2 cont leads
• PCI eligible
• TIMI flow grade 0 at time of admission

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Other exclusions

• Renal or liver failure
• Uncontrolled hypertension
• Pregnancy
• Women of childbearing age not on contraception
• Any Ds of immunologic dysfunction CA, HIV,
  hepatitis

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Study Population

• July 2005 to October 2006 340 patients at three
  centers were hospitalized for management of acute
  MI
• Approximately 80 men, mean age 58y
• 230 underwent PCI, 24 not enrolled - inadequate
  manpower 148 excluded, see below
• Baseline characteristics of subjects were similar
  

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Study Population

• Similar in ischemia time, myocardium at risk and
  EF prior to PCI - MRI
• Thombolytic therapy failed in 13 patients prior
  to PCI, 8 in control, 5 in CS
• Culprit lesion stented in all patients and only
  infarct related lesions treated
• Four patients, TIMI 2 flow was not achieved SP
  PCI

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Study PopulationBaseline Characteristics

• CS
• Men/women - 25/5 mean age 58 /- 2y
• BMI mean 26 /- 1, dyslipidemia 14, HTN 15, DM 4
• HX CAD 4
• Tobacco 17

• Control
• Men/women 21/7 mean age 57 /- 2y
• BMI mean 27 /- 1, dyslipidemia 12, HTN 13 , DM 4
• HX CAD 4
• Tobacco 16

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Methods

• Randomization after coronary angio, before
  stent, a computer generated sequence assigned
  patients to receive placebo vs cyclosporine

• Intervention
• IV bolus of cyclosporine 2.5mg/kg of BW, control
  given equivalent volume in NS

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Blood Concentration of Cyclosporine during
Reperfusion
Piot C et al. N Engl J Med 2008359473-481
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Statistical Analysis

• Calculated target sample size of 62 pts based on
  prior trial, 31 per group
• Hypothesized that CS would reduce the AUC for CK
  release by 30 for a power of 80
• Probability of a type I error of 0.05 using a two
  sided test
• Between group comparisons for AUC for trop, CK,
  area at risk, and infarct size by MRI evaluated
  with Wilcoxon rank-sum

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Statistical Analysis

• Analysis of covariance performed on the equality
  of slopes on the regression of infarct size on
  the area at risk in CS and control
• Comparison of incidence of cumulative adverse
  events between groups using Fisher exact test

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END POINTS

• Primary size of the infarct assessed by
  measurements of cardiac biomarkers
• Secondary size of infarct measured by area of
  hyper-enhancement seen on cardiac MRI, assessed
  day 5

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END POINTS

• Other major adverse events first 48h including
  death, MI, heart failure, stroke, recurrent
  ischemia, renal/liver insufficiency, vascular
  complications, and bleeding

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RESULTS

• The cyclosporine and the control group were
  similar in ischemia time, area of myocardium at
  risk and EF prior to PCI

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RESULTS

• Assessment of infarct size by biomarkers
• CK release sig decreased in CS group vs control
  group over time (P0.04)
• Trop I not sig decreased in CS group vs control
  group over time (P0.15)

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RESULTS

• Infarct size as a function of area at risk
• For any given area at risk CS administration was
  associated with a reduction infarct size as
  measured by CK/trop I release (P0.006) /
  (P0.002)

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Assessment of Infarct Size by Biomarker
Measurement
Piot C et al. N Engl J Med 2008359473-481
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Infarct Size as a Function of the Area at Risk
Piot C et al. N Engl J Med 2008359473-481
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MRI or CMR

• MRI has been used since 1984 on imaging of the
  heart and recently improved technology with
  contrast enhancement improves delineation of
  hyper-enhanced regions (acute MI)

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MRI

• Bright is dead

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RESULTS

• Subgroup analysis 27 patients
• Infarct size (absolute mass) decreased on MRI
  day 5 in CS group 37 g vs 46 g control group
  (P0.04)
• Area of infarction
• E A X slice thick X M sd

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Typical Cine Image and Contrast-Enhanced Image
Obtained by MRI before Revascularization
Kim R et al. N Engl J Med 20003431445-1453
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Typical Contrast-Enhanced Images Obtained by MRI
in a Short-Axis View (Upper Panels) and a
Long-Axis View (Lower Panels) in Three Patients
Kim R et al. N Engl J Med 20003431445-1453
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Assessment of Infarct Size by Magnetic Resonance
Imaging (MRI)
Piot C et al. N Engl J Med 2008359473-481
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Authors Conclusion

• The effect of CS in this small pilot study of
  patients having an acute myocardial infarction
  undergoing PCI, showed a decrease in infarct size
  as measured by release of CK and delayed
  hyper-enhancement on MRI.
• Trop I was not significantly reduced by CS

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Evaluation

• Methods
• randomized, but unclear if truly similar in
  ischemia time
• Blinded to full extent allowable
• All patients accounted for
• Subgroup was noted beforehand (MRI) and not added
  later because of Tx effects
• Small population but was a pilot study

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Evaluation

• Outcomes
• Results definitely applied to my patient
• Results are meaningful, however difficult to know
  if truly affected mortality
• CS did show Tx effect especially in MRI group
  with proven validity of acute MI
  hyper-enhancement

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Statistics Discussion

• To review
• Between group comparisons for AUC for trop, CK,
  area at risk, and infarct size by MRI evaluated
  with Wilcoxon rank-sum
• AUC for normal data is a Gaussian distribution
  and the usual parametric stats can be used
• With non normal data (continuous or ordinal data)
  nonparametric stats like Wilcoxin rank sum can be
  used

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Wilcoxin Rank Sum

• A descriptive nonparametric statistic using non
  normal data. Similar to performing a two sample
  t test
• Why use Wilcoxin?
• Appropriate for small population
• Easier to interpret ordinal or continuous data
• No assumption of population distribution
• More robust

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Wilcoxin Rank Sum

• Disadvantages
• Less sensitive
• Less power
• Not appropriate for large N

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Wicoxin Rank Sum

• The procedure
• Arrange observations for both groups into a
  single rank series
• Add up the ranks for both series
• The rank sum is then divided by the number of
  observations
• Observe the rank sum difference, as the magnitude
  tells you how close the groups are

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Wicoxin Rank Sum

• Example
• Imagine choosing an Olympic Team of Karate
  experts from two states, CA and NV. Your
  decision is based on how many boards each athlete
  can break in 5 minutes
• Statistics in a Nutshell

CA NV
4 2
5 3
6 3
6 4
7 4
8 5
9 10
9 10
9 11
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CA NV Rank
2 1
3 2
3 3
4 4
4 5
4 6
5 7
5 8
6 9
49
CA NV Rank
6 2 10
7 11
8 3 12
9 13
9 4 14
9 10 15
5 10 16
10 17
11 18
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CA NV Rank
2 1
3 2.5
3 2.5
4 5
4 5
4 5
5 7.5
5 7.5
6 9.5
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CA NV Rank
7 11
8 12
9 14
9 14
9 14
10 16.5
10 16-5
11 18
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Wilcoxin Rank Sum

• Sum the ranks
• E (CA) 5 7.5 9.5 9.5 11 12 14 14 14
  96.5
• E (NV) 1 2.5 2.5 5 5 7.5 16.5 16.5
  18 74.5
• So I choose the California team to go to the
  Olympics
• Statistics in a Nutshell

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Questions?
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