Acute Coronary Syndromes Adam Oster, R4. Dr. Gill Curry, FRCP Core Rounds. July 8, 2004. Topics Master of the ECG Master of the ECG Evidence for various therapeutic interventions Evidence for various therapeutic interventions NSTEMI Risk Stratification NSTEMI Risk Stratification Thrombolysis Thrombolysis AMI in LBBB AMI in LBBB Pre-hospital lytics Pre-hospital lytics Cardiogenic shock Cardiogenic shock ACS Rounds 55M with atypical chest pain for 60mins Hyperacute T waves Early sign of infarct Early sign of infarct Normal T 8mm Ischemic are more symmetric Ischemic are more symmetric Upgoing side still slopes up gradually Other Causes; Other Causes; Hyperkalemia (steep and sharp) LVH LBBB Master of the ECG Progression of changes Progression of changes STE Evolving STEMI Post-STEMI 3 weeks Case Case Case Role of the 15 lead Inferior MI Inferior MI RV infarct occurs in 25% of inferior MIs Different therapeutic and resuscitation needs Posterior MI Posterior MI Dorsal region of LV Usually LCX or RCA-posterior descending branch Limitations of the ECG Specificity approx 50% for ischemia Specificity approx 50% for ischemia The normal or non-diagnostic ECG Special ECGs LM Disease Wellens Syndrome Wellens Syndrome: T Wave Inversion Pope et al. Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department. New England Journal of Medicine vol. 342, no. 16, patients patients Data collected for 30d (hospitalised patients) or at 24 to 72hrs for non- hospitalised patients Data collected for 30d (hospitalised patients) or at 24 to 72hrs for non- hospitalised patients Outcomes assigned by physicians at study sites using pre-defined criteria Outcomes assigned by physicians at study sites using pre-defined criteria Pope et al. Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department. New England Journal of Medicine vol. 342, no. 16, Final Diagnosis Final Diagnosis 1866 (17%) ACI 894 (8.5%) AMI 972 (9%) unstable angina 21% non-ischemic cardiac problem 55% non-cardiac Pope et al. Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department. New England Journal of Medicine vol. 342, no. 16, missed unstable angina (2.26%) 22 missed unstable angina (2.26%) MC diagnosis; stable angina, atypical chest pain stable angina, atypical chest pain Pope et al. Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department. New England Journal of Medicine vol. 342, no. 16, missed AMIs (2.1% of 894) 19 missed AMIs (2.1% of 894) MC diagnosis; non-cardiac chest pain, pulmonary conditions and stable angina non-cardiac chest pain, pulmonary conditions and stable angina Pope et al. Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department. New England Journal of Medicine vol. 342, no. 16, Factors associated with non-hospitalisation for patients with missed ACI Factors associated with non-hospitalisation for patients with missed ACI female 2 anginal events in 24hrs significant coronary stenosisuse of ASA in last 7d prior MIelevated cardiac markers prior CABGprior history of CHF prior PTCA TIMI Risk Stratification Antman et al. JAMA Vol. 284, No.7 Derivation cohort Derivation cohort 7 variables remained statistically significant after multivariate analysis Age >65 Age >65 at least 3 CAD RF at least 3 CAD RF STD STD severe anginal symptoms severe anginal symptoms prior stenosis >50% prior stenosis >50% use of ASA over previous 7d use of ASA over previous 7d elevated serum cardiac markers elevated serum cardiac markers TIMI Risk Stratification Antman et al. JAMA Vol. 284, No.7 Small numbers of patients in extreme risk scores required combining Small numbers of patients in extreme risk scores required combining criteria of known stenosis >50%, insensitive to missing data and remained a significant predictor criteria of known stenosis >50%, insensitive to missing data and remained a significant predictor TIMI Risk Stratification Antman et al. JAMA Vol. 284, No.7 Validation Phase Validation Phase different rate of increase for rate of composite endpoint in UFH vs enoxaparin merged the databases TIMI RS and treatment were both significant predictors of risk of the composite endpoint TIMI Risk Stratification Antman et al. JAMA Vol. 284, No.7 Predicting the individual components of the composite endpoint Predicting the individual components of the composite endpoint all statistically sig. all statistically sig. TIMI Risk Stratification Antman et al. JAMA Vol. 284, No.7 Caveats and Critique Caveats and Critique tested on admitted patients with unstable angina/NSTEMI Validation Phase not prospective cohort who qualified for enrolment in a phase III study; ?generalisabilty to all-comers with chest pain enrolment criteria for TIMI 11b changed during the trial duration of treatment different between UFH (3-8d) and enoxaparin (8d or hospital discharge) elevated CKMB was both a predictor of an endpoint as well as part of the definition of an endpoint CKMB was the marker in TIMI but now use Troponin without study to prove similarly predictive TIMI Risk Stratification Antman et al. JAMA Vol. 284, No.7 Support Support consider using on chest pain patients to be admitted simple to use and to communicate to consultants cannot use to determine who is at low risk cannot use to determine who is safe for discharge How Predictive are Routine Historic Features? Goodacre et al. How Useful are Clinical Features in the Diagnosis of Acute, Undifferentiated Chest Pain? Academic Emergency Medicine, vol. 9, no. 3, Goodacre et al. How Useful are Clinical Features in the Diagnosis of Acute, Undifferentiated Chest Pain? Academic Emergency Medicine, vol. 9, no. 3, Prospectively evaluated 893 CPOU (normal ECG, no CHF or arrhythmia) ST seg monitoring, troponin T >6hrs, +/-EST or thallium F/U at 3d and 6mo, 12mo Endpoints: AMI at presentation and ACS (AMI at any time, pos. EST cardiac death, arrhythmia, revascularisation procedure) Assessed predictive power of routine historic features Goodacre et al. How Useful are Clinical Features in the Diagnosis of Acute, Undifferentiated Chest Pain? Academic Emergency Medicine, vol. 9, no. 3, Features Predictive of AMI: Goodacre et al. How Useful are Clinical Features in the Diagnosis of Acute, Undifferentiated Chest Pain? Academic Emergency Medicine, vol. 9, no. 3, Features Predictive of ACS: Once Risk Stratified What to give? ASA ASA Heparin/LMWH Heparin/LMWH hirudin hirudin Bblocker Bblocker CCB CCB Nitro Nitro Morphine Morphine O2 O2 Lytic Lytic Clopidegril (plavix) Clopidegril (plavix) G2b3a G2b3a Bed Rest Bed Rest NSTEMI Acute rupture of plaque Acute rupture of plaque Fibrin and platelets Fibrin and platelets Incomplete occlusion of CA Incomplete occlusion of CA ?chlamydial ?chlamydial Inflammatory reaction Inflammatory reaction Shear forces Shear forces Pharmacology... Better Living Through Chemistry O2 Makes intuitive sense since imbalance between O2 demand of myocardium and supply Makes intuitive sense since imbalance between O2 demand of myocardium and supply Hypoxemia in AMI most likely caused by V/Q mismatch from LV dysfunction Hypoxemia in AMI most likely caused by V/Q mismatch from LV dysfunction Evidence to support routine use is weak Evidence to support routine use is weak Reduces amount of STE in precordial leads with anterior MI Reduces amount of STE in precordial leads with anterior MI Madias, et al. Circulation 1976. Anti-Platelet Therapy ASA ASA Clopidegril Clopidegril 2b3a 2b3a ASA ISIS-2 ISIS-2 Randomised AMI to normal therapy or ASA or streptokinase Reduction in mortality with ASA or strepto ASA RRR 23% NNT 20 to save 1 life in STEMI Benefit and risk profile better than thrombolytic since you can give ASA to virtually all with ACS ASA NSTEMI NSTEMI RRR 50% ARR 3% NNT death/MI 30 ASA ASA: mg to chew ASAP All trials have shown mortality benefit that extends to 2 years Contraindications: Allergy?? Allergy?? Active bleeding (GI, retinal) Active bleeding (GI, retinal) Hemophilia Hemophilia Putting it all together Anti-platelet therapy Clopidogrel CAPRIE (1996), RCT ASA vs Plavix (N=19,185) 3 year ischemic stroke, MI or death ARR = 0.5% (NNT = 200) 3 year ischemic stroke, MI or death ARR = 0.5% (NNT = 200) Plavix equal to ASA but increased side effects (diarrhea, rash, GI bleed) Plavix equal to ASA but increased side effects (diarrhea, rash, GI bleed) Anti-platelet therapy Clopidogrel: CURE trial (2001) RCT Plavix + ASA vs ASA UA/NSTEMI within 24 hr UA/NSTEMI within 24 hr Death, MI, or stroke 3 and 12 month ARR = 2.2% (NNT = 45) Death, MI, or stroke 3 and 12 month ARR = 2.2% (NNT = 45) Excess in major bleed of 1% (NNH = 100) Excess in major bleed of 1% (NNH = 100) Risk of bleed with CABG increased in 1 st 5 days Risk of bleed with CABG increased in 1 st 5 days Recommended in UA/NSTEMI when noninvasive course is anticipated Recommended in UA/NSTEMI when noninvasive course is anticipated BOTTOM LINE: appears to work but not for us to start in the ED BOTTOM LINE: appears to work but not for us to start in the ED Anti-platelet therapy GPIIbIIIa Receptor Antagonists: Inhibits the cross-linking of platelets by fibrinogen GPIIbIIIa RA EPIC (abcixamab) NEJM 1994 EPIC (abcixamab) NEJM 1994 PRCT, N=2,099 pts High risk pts going for PCI (AMI, USA) Reopro(bolus, bolus +infusion) vs placebo Placebo vs bolus similar F/U 30 days Bolus/infusion: lower rate triple end-point (Death, MI or urgent revascularization) 8.3% vs 12.8% (ARR 4.5%, RRR 35%) 2 fold increase in major bleeds: 14% vs 6.6 (ARI 7.4%, RRI 112%!!! GPIIbIIIa RA CAPTURE (abcixamab) Lancet 1997 CAPTURE (abcixamab) Lancet 1997 PRCT, N=1050 pts (stopped early) Pts with refractory USA, after cath and before plasty Reopro vs placebo, 18-24hrs before plasty, and 1 hr after F/U 30 days then 6 months Composite endpoint at 30 days(Death, MI, urgent intervention ): 2.6% vs 5.5% (ARR 2.9%, RRR 53%) At 6 months: no difference! (decreased early events only) Major bleeding: 3.8% vs 1.9% (ARI 1.9%, RRI 50%) GPIIbIIIa RA CAPTURE (substudy) CAPTURE (substudy) Predictive value of TnT Increased TnT(>0.1 ng/ml): 30.9% F/U 6 months: Death or MI TnT +ve Reopro 9.5% vs placebo 23.9% (ARR 14.4%, RRR 60% Reopro 9.5% vs placebo 23.9% (ARR 14.4%, RRR 60% TnT ve Reopro 7.5% vs 9.4% (not significant) Reopro 7.5% vs 9.4% (not significant) Conclusion: TnT +ve identifies a high risk population that seems to benefit from GIIb-IIa GPIIbIIIa RA PRISM-PLUS (tirofiban) NEJM 1998 PRISM-PLUS (tirofiban) NEJM 1998 PRCT, N=1,570 pts Non-ST segment elevation ACS and likely to go to catheterization Heparin vs tirofiban vs combination Tirofiban alone arm stopped (increased mortality at 7 days) F/U 7 and 30 days and 6 months Composite endpoint (Death, MI or recurrent ischemia): 7 days: 12.9 vs 17.9% (p=0.004), 30 days: not significant, 6 months: 27.7 vs 32.2% (p=0.02) GPIIbIIIa RA PURSUIT (eptifibatide) PURSUIT (eptifibatide) PRCT, N=10,948 pts Eligible if ECG changes : transient ST elevation, ST depression, T wave inversion, or positive CKMB Eptifibitide vs placebo F/U 30 days and 6 months Double endpoint (Death or MI): 30 days: 14.2 vs 15.7% (ARR 1.5%, RRR 10%), 6 months: 12.1 vs 13.6% (ARR 1.5%, RRR 11%) Medical Management: US benefit, Europe and Latin America no benefit Didnt work in females!!!!! GPIIbIIIa RA GUSTO IV GUSTO IV PRCT, N=7800 pts ECG changes, +ve troponin level Early revascularization strongly discouraged Abcixamab vs placebo (24-48 hr infusion) No difference in MI or Death GPIIbIIIa RA BOTTOM LINE: They are definitely indicated as an adjunct to PCI Role in UA/NSTEMI is questionable, there appears to be a small reduction in death or MI in high risk groups (ongoing or recurrent pain, dynamic ST changes) Not enough evidence for us to start in the ED Heparins Does heparin add anything in addition to ASA? Does heparin add anything in addition to ASA? Ollier, et al. Meta-analysis. JAMA 1996 Ollier, et al. Meta-analysis. JAMA 1996 small 33% RRR in MI NNT Barely statistically significant All high risk patients Anti-thrombotic therapy Unfractionated Heparin: Theroux et al (1993) RCT ASA+hep vs ASA Theroux et al (1993) RCT ASA+hep vs ASA Decreased rates of MI (fatal and nonfatal) 3% (NNT = 33) Decreased rates of MI (fatal and nonfatal) 3% (NNT = 33) RISC (1990) ASA vs UFH vs UFH +ASA RISC (1990) ASA vs UFH vs UFH +ASA ASA + UFH had lowest events in 1 st 5 days ASA + UFH had lowest events in 1 st 5 days Anti-thrombotic therapy LMWH: ESSENCE (1997) RCT enoxaparin vs UFH ESSENCE (1997) RCT enoxaparin vs UFH No difference in mortality Composite endpoint of death, MI or recurrent angina, ARR = 3.2% (NNT=33) TIMI 11B (1999) RCT enoxaparin vs UFH TIMI 11B (1999) RCT enoxaparin vs UFH Composite endpoint death, MI, urgent need for PTCA, ARR = 2.1% (NNT = 50) 2 trials (1 dalteparin, 1 nadroparin) had neutral or unfavorable trends 2 trials (1 dalteparin, 1 nadroparin) had neutral or unfavorable trends Heparin Use in moderate to high risk patients Use in moderate to high risk patients NNH 40 NNH 40 Significant bleed thrombocytopenia B-Blockade Shown to decrease all cause mortality by 2.6% if started within 5-21days of infarct (NNT = 38) early treatment: Metoprolol 15 mg vs placebo f/u at 3 month, 36% RRR of death TIMI IIB showed lower reinfarction or recurrent CP If HR > 70 and BP can tolerate give Metoprolol 5-15 mg iv Nitro Intuitively should help Intuitively should help Combat vasospasm Dilate coronary arteries improving perfursion Reduce pre-load reducing myocardial O2 consumption Afterload reduction Nitro No mortality benefit clearly established No mortality benefit clearly established Shown to decrease post infarct angina Shown to decrease post infarct angina Give sl to patients with ischemic sounding CP unless SBP < 90, HR < 50, tachycardia, or suspected RV infarct Case 64F no known CAD 64F no known CAD 2 hrs atypical chest pain after mowing lawn. No cardiac RF No cardiac RF ECG normal ECG normal c/o 6/10 pain c/o 6/10 pain 3/10 post 3 sprays nitro 3/10 post 3 sprays nitro Response to nitro Annals of Internal Medicine 2003, Dec 16; 139: Annals of Internal Medicine 2003, Dec 16; 139: Enrolled 459 patients prospectively admitted with chest pain. Observational study. Use a combined Gold Standard for and Use a combined Gold Standard for active CAD and no active CAD Defined response to nitro as >50% decline in pain at 5mins post-dose All pts followed for 4 months after index visit Annals of Internal Medicine 2003, Dec 16; 139: Active CAD Active CAD 35% responsive (49/141) No active CAD No active CAD 41% responsive (113/275) Annals of Internal Medicine 2003, Dec 16; 139: Limitations Limitations Self-reported pain (reporting bias) Unvalidated pain-scale (reliability) Non-blinded physicians (work-up bias) 43 pts with chest pain of unclear origin Management of AMI Thrombolytics: Goal door-to-needle time of 30 minutes Goal door-to-needle time of 30 minutes FTT Trial (N=58,000) FTT Trial (N=58,000) No survival benefit after 12 hours ARR 2%, NNT 40-50 Management of AMI Fibrinolytics started First hour Second hour Third hour 3-6 hour 6-12 hour hour Additional lives saved per 1000 pts treated To Lyse? Or not to Lysis? Lysis? Lysis? Lytic Criteria Canadian Consensus Conference on Coronary Thrombolysis: 1994 Recommendations. Canadian Consensus Conference on Coronary Thrombolysis: 1994 Recommendations. Indications: >30mins chest pain and >30mins chest pain and At least 1mm STE in at least 2 limb leads or At least 1mm STE in at least 2 limb leads or At least 2mm in at least 2 adjacent precordial leads or At least 2mm in at least 2 adjacent precordial leads or Complete BBB Complete BBB Within 12 hrs of symptoms Within 12 hrs of symptoms Target time 80% sensitive > 90% sensitive Patients with TnT + and CKMB have worse prognosis (increased death and CV events at 30 days) Patients with TnT + and CKMB have worse prognosis (increased death and CV events at 30 days) Case 55M with ESRD 55M with ESRD HD 3/week No previous IHD Cath 4 years ago demonstrated non- occlusive disease 6hrs atypical chest pain TnT.15 TnT in RF Tricky Tricky Some research in the area Some research in the area Starting points Starting points Cardiovascular death makes up 50% of death in ESRD Prevalence of CAD is approx 75% Higher risk of silent ischemia and atypical presentations ECG may also be difficult to interpret d/t LVH TnT in RF Hypotheses on why elevated Hypotheses on why elevated Uremic cardiomyopathy Clinically silent micro-infarctions LVH Unlikely d/t decreased renal clearance Similar molecular wt as albumin Similar molecular wt as albumin Post-Tx still have elevated TnT Post-Tx still have elevated TnT TnT in RF Elevation: What does it mean? Elevation: What does it mean? No true GS of IHD in ESRD Lower sens/spec of stress testing Lower sens/spec of stress testing Less prevalence of cath in this population Less prevalence of cath in this population Have to rely on outcomes Have to rely on outcomes TnT in RF: Elevation: What does it mean? No suspicion of ACS. Significant difference in 1 yr cardiovascular mortality >0.1 Nephrol Dial Transplant 1999;14:19617 102 patients with ESRD without any clinical evidence of acute ischemic heart disease Troponin T > 0.1 ng/ml was strongly associated with all cause mortality TnT 0.05 ng/ml was associated with fatal cardiovascular events. This association was independent of baseline presence of heart disease. All patients with non-detectable TnT were alive at follow up. Circulation 2000; 102:19649 TnT in RF: Elevation: What does it mean? No suspicion of ACS. 244 patients on chronic hemodialysis for up to 34 months. Troponin T significantly associated with death from all causes strongest association for TnT values above 0.1 A trend of increasing TnT measurements during longitudinal follow up was also predictive of progression of cardiac disease and all-cause mortality TnT in RF: Elevation: What does it mean? Suspicion of ACS. 7,033 patients from the GUSTO-IV prognostic value of cardiac TnT was not diminished in patients presenting with renal insufficiency and suspected ACS Patients with positive TnT and renal insufficiency had the highest overall risk of cardiac death or acute MI N Engl J Med 2002;346: TnT in RF: Elevation: What does it mean? Suspicion of ACS. Case 60M with chest pain for 12hrs 60M with chest pain for 12hrs STE anteriorly BP 80/50, HR= 120 Sats 90% NRB Cardiogenic shock Complicates 7-10% of AMI Complicates 7-10% of AMI 70-80% mortality 70-80% mortality Diagnosis: Diagnosis: SBP< 90mmHg Evidence of end organ hypoperfusion (cool extremities, oliguria, altered mentation) Management cardiogenic shock Oxygenation and ventilation Oxygenation and ventilation Improve systolic function Improve systolic function Catecholamines (dopamine, dobutamine if BP tolerates) IABP revascularization revascularization Cardiogenic shock PTCA vs lytic SHOCK (1999) RCT PTCA vs lytic, N= 302 RCT PTCA vs lytic, N= % cross over to PTCA group within 54 hrs 2.7% cross over to PTCA group within 54 hrs 9.8% ARR at 30 day mortality (not stat sig) 9.8% ARR at 30 day mortality (not stat sig) 13% ARR at 6 month mortality (NNT = 8) 13% ARR at 6 month mortality (NNT = 8) Pre-hospital Lytics 45M with 45mins severe RSCP 45M with 45mins severe RSCP Medics patch in that this guy has widespread anterior STE and they want to give lytic Transport time 30-45mins What do you say?