Thrombolysis failure with Streptokinase in Acute Myocardial Infarction using ECG criteria

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Thrombolysis failure with Streptokinase using ECG criteria in Acute Myocardial Infarct Dr Lee Yeong Yeh MD MMED MRCP (UK) FADUSM Co-Authors Dr Tee Meng Hun, Assoc Prof Dr Zurkurnai Yusof, Dr Sapawi Mohd, Dr Suhairi Ibrahim

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0 5 10 15 20 25 30 Atherothrombosis* Leading Cause Of Death Worldwide1† 1. The World Health Report, 2002, WHO Geneva, 2002 Mortality (%) *Ischemic heart disease, cerebrovascular disease, inflammatory heart disease andhypertensive heart disease †Worldwide defined as Member States by WHO Region (Africa, Americas,Eastern Mediterranean, European, South-East Asia and Western Pacific) Leading Causes of Death Worldwide (% of all deaths)

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Atherothrombosis Significantly Shortens Life Expectancy Analysis of data from the Framingham Heart Study AMI = Acute myocardial infarction Healthy History of CV disease History of AMI History of stroke 1. Peeters et al. Eur Heart J 2002; 23: 458–66 Average Remaining Life Expectancy At Age 60 (men) 0 2 4 6 8 10 12 14 16 18 20 Years -9.2 years -7.4 years -12 years

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Atherosclerosis –Atherothrombosis A Generalized and Progressive disease Adapted from Libby P. Circulation. 2001;104:365-372 Atherosclerosis Stable angina Unstable angina NSTEMI STEMI CV death ACS Thrombosis Atherothrombosis

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Introduction Thrombolysis prevents 20 – 30 deaths per 1000 MI patients with 25% reduction in mortality 1 Streptokinase was shown in MI to achieve 90 minutes arterial patency rate of 50-60% with TIMI-3 flow on angiographic study of only 30% 2 1. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group, Lancet 1994; 343 : 311-322 2. GUSTO investigators, NEJM 1993; 329 : 673-682

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Introduction ECG is a sensitive and cheap non-invasive bedside marker to assess arterial patency after streptokinase Less than 50% resolution of ST segment elevation in the worst infarct lead had sensitivity of 81%, specificity of 88% and positive predictive value of 87% to predict less than TIMI-3 flow 3 3. Sutton AGC et al, Heart 2000; 49 : 149-156

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Primary Objective To assess the failure rate of thrombolysis using streptokinase amongst patients in Hospital Universiti Sains Malaysia (HUSM) with acute myocardial infarct based on electrocardiogram criteria

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Secondary Objectives 1. To compare association between choosen independent variables and thrombolysis failure with streptokinase 2. To compare association between treatment and outcome parameters and failure of thrombolysis with streptokinase

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Methodology Design retrospective and historical cohort observational study Cohorts 192 patients selected from computer registry of Record Department, HUSM from year 1996 till the end of 2005

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Inclusion Criteria ST elevation acute myocardial infarction (WHO criteria) treated with streptokinase at 1.5 Megaunit over 1 hour Exclusion Criteria 1. Bundle branch block acute myocardial infarction 2. Non-ST elevation myocardial infarction 3. Patients who were not given streptokinase

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Electrocardiogram Criteria First ECG recorded before starting streptokinase and second ECG 90 minutes after streptokinase Failure of thrombolysis with streptokinase is defined as less than 50% reduction in ST segment elevation in the worst infarct lead with no idioventricular rhythm 1 1. Sutton AGC et al, Heart 2000; 49 : 149-156

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Electrocardiogram Criteria The ST segment is measured 80ms from J point (defined as the first turning point in the ST segment) Vertical height of ST segment elevation is measured by investigator using a standard ruler in millimeters (mm)

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Statistical Methods Data was entered into SPSS software version 12.0.1 Numerical data was recorded as mean and standard deviation. Categorical data was recorded as frequency and percentages The variables were choosen based on existing clinical studies 1 1. Conor FL et al, J Am Coll Cardiol 1998; 32 : 641 - 647

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Statistical Methods Univariate analysis Chi-square test or Fischer-exact test for categorical data and student-t test for numerical data were used to test association Multiple logistic regression analysis was used to test association between multiple variables

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Results

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* p value < 0.05

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Standard Error Chart showing Odds Ratio and Confidence Interval of variables in Multiple logistic Regression analysis Favour Streptokinase Failure Yes No Variable P 95% CI OR Ant MI <0.001 0.03 to 0.16 0.07 Door-to- Needle time 0.02 1.00 to 1.02 1.01 Diabetes 0.03 1.13 to 8.69 3.13 Hypertension 0.08 0.92 to 4.60 2.06 TW count 0.03 1.01 to 1.24 1.12 6 4 2 0 -2 Odds Ratio (95% Confidence Interval) P= p value, Ant=anterior, TW= total white, CI=confidence interval, OR=odds ratio

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Primary End Point Our study showed that failure rate of thrombolysis with streptokinase was 56.8% (N = 105) in acute myocardial infarction using ECG criteria in HUSM

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Secondary End Points Failure of thrombolysis with streptokinase was associated with : 1. Higher rate of recurrent acute coronary syndrome (OR 2.49, 95% CI 1.16 – 5.32) 2. Mortality after one year (OR 7.61, 95% CI 0.95 - 61.24)

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Limitations of Study Retrospective design Difficulty in recruitment of different races (predominant Malay) and gender (less female) Sample size was affected by poor ECG recordings, poor records documentation and exclusion criteria Low number of subjects (36 or 18.7%) were subjected to coronary interventions (newly established cardiac lab 2002) A total of 56 or 29.2% patients were lost to follow-up

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Reasons for high failure rate of thrombolysis with streptokinase in AMI Streptokinase is a first generation thrombolytic agent. It acts by complexing with plasminogen and it is not fibrin specific Phenomenon of depletion of plasminogen “plasminogen steal” which limit the fibrinolytic action 1 1. Ijaz AK, Ramesh MG; International Journal of Cardiology 2003; 91 : 115-127

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Reasons for high failure rate of thrombolysis with streptokinase in AMI Streptokinase was shown to have the highest paradoxical thrombin activation “thrombolytic paradox” among thrombolytic agents 2 The pro-coagulant effect was due to plasmin-mediated activation of the contact system of the coagulation pathway (Kallikrein/factor XII) 3 2. Hans Martin Hoffmeister et al; Thrombosis Research 2001; 103 : 51-55 3. Ewald GA et al; Circulation 1995; 91 : 28-36

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Implications of Study Results Consider other newer and more efficacious thrombolytic agents especially recombinant tPA 1 eg reteplase and alteplase Consider primary angioplasty 2 Consider rescue angioplasty 3 Emergency coronary artery bypass surgery may have a role 4 (time delay, slower reperfusion rate compared to thrombolytic agent and lack of supporting staffs) 1. Ijaz AK, Ramesh MG; International Journal of Cardiology 2003; 91 : 115-127 2. Keeley EC et al; Lancet 2003; 361 : 36 3. Vermeer F et al; Heart 1999; 82 : 426 4. Berger PB et al; Am J Cardiol 1995; 76 : 565

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Conclusion Thrombolysis failure rate using streptokinase with ECG criteria in AMI among 192 cohorts in HUSM was 56.8% Multivariate analysis implicated history of diabetes (OR 3.1 95% CI 1.1 – 8.7) and hypertension (OR 2.1 95% CI 0.9 – 4.6) as strong predictors of thrombolysis failure

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Conclusion Failure of thrombolysis with streptokinase was associated with higher rate of recurrent acute coronary syndrome (OR 2.49, 95% CI 1.16 – 5.32) and mortality after one year (OR 7.61, 95% CI 0.95 - 61.24) This study suggests consideration for other methods of thrombolysis in high risk AMI patients

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