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EBM Journal Club Sarah Jean Strube, D.O. Resident Physician St. Mary Medical Center October 17, 2008.

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Presentation on theme: "EBM Journal Club Sarah Jean Strube, D.O. Resident Physician St. Mary Medical Center October 17, 2008."— Presentation transcript:

1 EBM Journal Club Sarah Jean Strube, D.O. Resident Physician St. Mary Medical Center October 17, 2008

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

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

4 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. 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.

5 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. 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.

6 BACKGROUND Cyclosporine is mostly known for its immunosuppressive effects. 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. 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.

7 PICO Question Patient Patient Intervention Intervention Control Control Outcome Outcome

8 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. 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.

9 PICO QUESTION Intervention: A dministration 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 Intervention: A dministration 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

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

11 PICO question Outcome: did the intervention with pretreatment with cyclosporine vs normal saline decrease the area of myocardial infarction SP PCI? Outcome: did the intervention with pretreatment with cyclosporine vs normal saline decrease the area of myocardial infarction SP PCI?

12 Article selected Effect of cyclosporine on reperfusion injury in acute myocardial infarction. New England Journal of Medicine 2008; 359: Research objective: To evaluate the efficacy of a therapy

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

14 Patient Criteria INCLUSION INCLUSION Male/female 18y or older present wi 12h of CP Male/female 18y or older present wi 12h of CP STEMI 0.1 mV 2 cont leads STEMI 0.1 mV 2 cont leads PCI eligible PCI eligible TIMI flow grade 0 at time of admission TIMI flow grade 0 at time of admission EXCLUSION EXCLUSION Cardiac arrest Cardiogenic shock Vent fibrillation Stent thrombosis Previous MI Angina wi 48h Occl LM/Circ or collaterals Hypersensitivity to cyclosporine

15 Other exclusions: Renal or liver failure Renal or liver failure Uncontrolled hypertension Uncontrolled hypertension Pregnancy Pregnancy Women of childbearing age not on contraception Women of childbearing age not on contraception Any Ds of immunologic dysfunction; CA, HIV, hepatitis Any Ds of immunologic dysfunction; CA, HIV, hepatitis

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

18 Study Population Similar in ischemia time, myocardium at risk and EF prior to PCI - MRI 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 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 Culprit lesion stented in all patients and only infarct related lesions treated Four patients, TIMI 2 flow was not achieved SP PCI Four patients, TIMI 2 flow was not achieved SP PCI

19 Study Population Baseline Characteristics CS CS Men/women - 25/5 mean age 58 +/- 2y Men/women - 25/5 mean age 58 +/- 2y BMI mean 26 +/- 1, dyslipidemia 14, HTN 15, DM 4 BMI mean 26 +/- 1, dyslipidemia 14, HTN 15, DM 4 HX CAD 4 HX CAD 4 Tobacco 17 Tobacco 17 Control 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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21 Methods Randomization: after coronary angio, before stent, a computer generated sequence assigned patients to receive placebo vs cyclosporine Randomization: after coronary angio, before stent, a computer generated sequence assigned patients to receive placebo vs cyclosporine Intervention: Intervention: IV bolus of cyclosporine 2.5mg/kg of BW, control given equivalent volume in NS IV bolus of cyclosporine 2.5mg/kg of BW, control given equivalent volume in NS

22 Blood Concentration of Cyclosporine during Reperfusion Piot C et al. N Engl J Med 2008;359:

23 Statistical Analysis Calculated target sample size of 62 pts based on prior trial, 31 per group 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% 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 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 Between group comparisons for AUC for trop, CK, area at risk, and infarct size by MRI evaluated with Wilcoxon rank-sum

24 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 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 Comparison of incidence of cumulative adverse events between groups using Fisher exact test

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

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

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

28 RESULTS Assessment of infarct size by biomarkers: Assessment of infarct size by biomarkers: CK release sig decreased in CS group vs control group over time (P=0.04) CK release sig decreased in CS group vs control group over time (P=0.04) Trop I not sig decreased in CS group vs control group over time (P=0.15 ) Trop I not sig decreased in CS group vs control group over time (P=0.15 )

29 RESULTS Infarct size as a function of area at risk 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 (P=0.006) / (P=0.002) For any given area at risk CS administration was associated with a reduction infarct size as measured by CK/trop I release (P=0.006) / (P=0.002)

30 Assessment of Infarct Size by Biomarker Measurement Piot C et al. N Engl J Med 2008;359:

31 Infarct Size as a Function of the Area at Risk Piot C et al. N Engl J Med 2008;359:

32 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) 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)

33 MRI Bright is dead

34 RESULTS Subgroup analysis 27 patients: Infarct size (absolute mass) decreased on MRI day 5 in CS group 37 g vs 46 g control group (P=0.04) Area of infarction: E A X slice thick X M sd E A X slice thick X M sd

35 Kim R et al. N Engl J Med 2000;343: Typical Cine Image and Contrast-Enhanced Image Obtained by MRI before Revascularization

36 Kim R et al. N Engl J Med 2000;343: Typical Contrast-Enhanced Images Obtained by MRI in a Short-Axis View (Upper Panels) and a Long-Axis View (Lower Panels) in Three Patients

37 Assessment of Infarct Size by Magnetic Resonance Imaging (MRI) Piot C et al. N Engl J Med 2008;359:

38 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. 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 Trop I was not significantly reduced by CS

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

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

41 Statistics Discussion To review To review Between group comparisons for AUC for trop, CK, area at risk, and infarct size by MRI evaluated with Wilcoxon rank-sum 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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44 Wilcoxin Rank Sum A descriptive nonparametric statistic using non normal data. Similar to performing a two sample t test A descriptive nonparametric statistic using non normal data. Similar to performing a two sample t test Why use Wilcoxin? Why use Wilcoxin? Appropriate for small population Appropriate for small population Easier to interpret ordinal or continuous data Easier to interpret ordinal or continuous data No assumption of population distribution No assumption of population distribution More robust More robust

45 Wilcoxin Rank Sum Disadvantages Disadvantages Less sensitive Less sensitive Less power Less power Not appropriate for large N Not appropriate for large N

46 Wicoxin Rank Sum The procedure: The procedure: 1. Arrange observations for both groups into a single rank series 2. Add up the ranks for both series 3. The rank sum is then divided by the number of observations 4. Observe the rank sum difference, as the magnitude tells you how close the groups are

47 Wicoxin Rank Sum Example 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 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 CA NV NV

48 CA CA NV NV Rank Rank

49 CA CA NV NV Rank Rank

50 CA CA NV NV Rank Rank

51 CA CA NV NV Rank Rank

52 Wilcoxin Rank Sum Sum the ranks Sum the ranks E (CA) = = 96.5 E (NV) = = 74.5 So I choose the California team to go to the Olympics Statistics in a Nutshell

53 Questions?

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