Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Recommendations of the European Society of Cardiology Updated version December 2002

Task Force on management of ACS without persistent ST-segment elevation Developed by the ESC Committee for Practice Guidelines (CPG) Approved by the Board of the ESC This Task Force was entirely supported financially by the European Society of Cardiology and was developed without any involvement of pharmaceutical companies

Task Force Members M.E. Bertrand (FR), Chair M.L. Simoons (NL) L.C. Wallentin (SE) K.A.A. Fox (GB) C.W. Hamm (DE) E.P. McFadden (FR) W. Ruzyllo (PL) P.J. De Feyter (NL) G.Specchia (IT)

ACUTE CORONARY SYNDROMES Different clinical expressions Resulting from a common underlying pathophysiological mechanism: Atherosclerotic plaque rupture (or erosion) Different degrees of superimposed thrombosis Distal embolization

ACS with persistent ST-segment elevation ACS without persistent ST-segment elevation Troponin or CK-MB Troponin elevated or not Myocardial infarction Unstable angina

Epidemiology N Countries Timing STE-ACS Non STE-ACS EuroHeart Survey 10,484 25 Sep 00 42.3% 51.2% Europe May 01 GRACE 11,543 14 Apr 99 30% 63% World Dec 00 Mortality and non-fatal MI at 6-month FU: 13%

Mechanisms Targeted approaches Inflammation Plaque rupture or erosion Stent β-blockers Myocardial Oxygen Supply Myoc demand PCI Luminal narrowing Platelet aggregation Adapted from M.J M Davies Aspirin GpIIb/IIIa receptor inhib Clopidogrel Thrombosis Nitrates Ca antagonists Vasospasm UH Heparin LMWH

ACS without persistent ST-segment elevation Treatment options Five categories of treatment: Anti-ischaemic agents Anti-thrombin agents Anti-platelet agents (Fibrinolytics) Coronary revascularization

Levels of evidence Level of evidence A Level of evidence B Level of evidence C Data derived from multiple randomized clinical trials or meta-analyses analyses Data derived from a single randomized trial or non- randomized studies Consensus opinion of the experts Early benefit ischaemia Early benefit Prevention of Death / MI Sustained Effect of Early benefit Additional Long-term Death / MI

Beta-blockers: Anti-ischaemic agents Three DB randomized trials comparing BB to placebo 13 % RR reduction in progression to Acute MI A B B A Nitrates No RDZ placebo-controlled trials Calcium channel blockers C (-) (-) (-) Small RDZ trials Meta-analysis on death and MI suggests that there is no prevention of death and MI B B (-) (-)

Heparin (UFH or LMWH) vs. Placebo 0.67 Control [95% CI] 7.9 % 10.4% 0.45-0.99 UFH C B (-) (-) LMWH 0.34 Control [95% CI] 1.6 % 5.2% 0.20-0.58 A A A A 0.2 0.6 1 1.4 Heparin better Placebo better

Randomized trials comparing LMWH vs. UFH Randomized trials comparing LMWH vs. UFH Death and non-fatal MI

Death or MI (%) ASA vs. N Placebo Theroux Antiplatelets : Trials ASA vs. Placebo 479 ASA 2.46% Placebo 6.35% Lewis 1266 4.9% 10.1% Cairns 555 6.1% 12.9% RISC 728 6.5% 17.1% Total 3096 5.2% 11.8% 0.41 (-) A A A 0 0.2 0.4 0.6 0.8 1 1.2 ASA better Pl. better

ADP receptor antagonists: Clopidogrel (CURE trial: 12,562 pts ) End-point CV death/mi/stroke Clopidogrel 9.3% Placebo 11.4% 0.80 P <0.001 CV death MI 5.1% 5.2% 5.2% 6.7% 0.77 0.33 0.0004 Death/MI 30-day 3.9% 4.8% 0.007 Death/MI 9-mth 8.6% 10.5% 0.001 Refractory isch. Major bleeding Minor bleeding 8.7% 3.7% 5.1% 9.3% 2.9% 2.4% 1.69 2.12 0.22 0.001 <0.001 NEJM 2001;345:494-502 B B B B 0 0.5 1 1.5 2 2.5 Clopidogrel better Placebo better

Gp IIb/IIIa receptor inhibitors. Death and MI at 30-day FU Seven Trials comparing GPIIb/IIIa vs Placebo in ACS: Both groups received Heparin +ASA A A A A

GpIIb/IIIa inhibitors and PCI: CAPTURE, PRISM-PLUS, PURSUIT combined 10% N=12,296 p=0.001 N=2,754 p=0.001 N=2,736 p=0.474 8% 6% 4% 2% 0% 4.3% 2.9% Placebo 4.9% 1 2 3 1 2 7 14 21 days PCI 8.0% IIb/IIIa blocker P IIb/IIIa 1.6% 1.3%

GpIIb/IIIa vs. Placebo : Death and non fatal MI at 30 days N patients GpIIb/IIIa Plac. Troponin (+) 4,964 0.84 10.3% 12% Troponin (-) 6,095 1.16 7% 6.2% PCI/CABG 11,986 0.79 14.3% 17.3% No PCI/CABG 19,416 0.97 10.1% 10.5% Diabetes 6,458 0.88 13.7% 22% Diabetes (death) 6,458 0.74 4.6% 6.2% 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 GpIIb/IIIa better Placebo better

ACS without persistent ST-segment elevation Coronary revascularization Indications and approach depend on the extent and angiographic characteristics of the lesions Wide variation among countries In the use of coronary angiography: 52% in EuroHeartSurvey In subsequent revascularization(euroheartsurvey) : 25.4% of PCI (73.5% with stent implantation) 5.4% of CABG

70 Revascularization in contemporary trials % of revascularization 30.8% 28% 61% 37% 58% 37% 60 50 41 44 PCI CABG Percentage 40 30 20 25.4 10 0 5.4 Eur. H. Surv 24 18 13 20 19 15 13 14 Invasive Conservative Invasive Conservative CURE TACTICS FRISC-II

ACS without persistent ST-segment elevation Respective Indications and Strategy! Single VD (30-38%) Usually PCI! LM (4-8%) or MVD (44-59%) Usually CABG! 2VD/3VD Evaluation on an individual basis! Invasive vs. Conservative strategy FRISC II: Revascularization at 4 days for PCI and 8 days for CABG TACTICS: Upstream Treatment with Tirofiban- Cor angio 4-48hrs RITA-3 : upstream enoxaparin At FU significant reduction of Death,or MI or Death/MI/Rec. Isch in favour of the invasive strategy

TACTICS, FRISC-II (6-mths), RITA-3 (1 yr) Invasive vs. Conservative strategy: Death and MI 16 22% p<0.03 14.1 14 Conservative Invasive 12.1 12 9.5 26% p<0.05 10 9.4 9.4 8.3 7.3 7.6 8 6 4 2 0 TACTICS FRISC-II UK MI definitions ACC/ESC MI definitions A A A A RITA-3 Percentage

Levels of evidence of the different therapeutic options Early benefit Reduction ischaemia Early benefit Prevention Death/MI Sustained Effect of Early benefit Additional Long-term Death/MI Beta-blockers A B B A Nitrates C (-) (-) (-) Ca Antagonists B B (-) (-) Aspirin (-) A A A Thienopyridines B B B B IIb/IIIa receptor blockers A A A A Unfractionated heparin C B (-) (-) LWMH A A A C Direct antithrombins (-) A A (-) Revascularization C B B B

ACS Without Persistent ST-segment Elevation Risk stratification: Two types of risk Acute risk i.e. Thrombotic risk Long-term risk Underlying CAD and LV function Inflammation

ACS without persistent ST-segment elevation Risk assessment Thrombotic risk Recurrent ischaemia ST-segment depression Dynamic ST-segment changes Elevated troponins Thrombus on angiography Acute risk Underlying coronary artery disease Clinical markers Age History of prior MI, CABG Diabetes, HF Biological markers CRP, Fibrinogen, IL-6, BNP Renal dysfunction Angiographical markers EF Extension of vessel disease Long-term risk

Death/MI, Ref Ang at 30days 25 20 15 10 5 0 21 ST-depression Inverted T- waves ECG: Risk predictor 10 10 Normal 7 Transient STelevation Death/MI at 30 day s 25 20 15 10 5 0 Death & MI 22.1 9.1 6.7 No ST ST 1 mm ST > 2mm Death/MI at 30 day s 25 20 15 10 5 0 Death & MI 19.7 12.7 9.5 0-2 episodes /d 2-5 episodes /d >5 epidodes /d

Comparison Troponin (+ ) vs. Troponin (- ) T+ T- Death Death/MI short-term short-term 5.7% 13.4% 0.9% 3.0% 7.7 9.9 N=3091 Death Death/MI long-term long-term 7% 20.2% 3.5% 9% 2.74 2.9 N=4273 0 2 4 6 8 10 12 14 16 18 Ottani et al Am Heart J 2000; 140:917 x (risk if TnT +)

Admission Working diagnosis Chest pain Suspicion of Acute Coronary Syndrome ECG Biochemistry Risk stratification Persistent ST elevation CK-MB Troponin No persistent ST elevation Troponin High Risk Low Risk Normal or atypical ECG changes Troponin Twice negative Probably not ACS Treatment Secondary prevention

Patients judged to be at high risk for progression to MI or death Heparin (LMWH or UFH), ASA, Clopidogrel, Betablockers, Nitrates 0 2 4 48h Patients with recurrent ischaemia Recurrent chest pain Dynamic ST-segment changes (ST-segment depression or transient ST segment elevation) Elevated troponin levels Diabetes Early post infarction unstable angina Haemodynamic instability Major arrhythmias (VF, VT) GpIIb/IIIa blocker & Coronary angiography In Emergency

Patients judged to be at low risk for progression to death or MI Heparin (LMWH or UFH), ASA, Clopidogrel, Beta-blockers, Nitrates No recurrence of chest pain within observational period No elevation of troponin or other biochemical markers of thrombosis No ST-segment depression (Negative or flat T-waves, normal ECG Repeat troponin measurements between 6 and 12 hours No ECG changes and second troponin measurement: negative Heparin discontinued Oral treatment with ASA, Clopidogrel, Beta-blockers, Nitrates) Stress test to to confirm or or to to establish a diagnosis of of CAD To assess the risk of of future events

Clinical suspicion of ACS Physical examination, ECG monitoring, Blood samples Persistent ST-Segment elevation Thrombolysis PCI No persistent ST-Segment elevation Heparin (LMWH or UFH), ASA, Clopidogrel*, Betablockers, Nitrates Undetermined diagnosis ASA High risk Low risk GPIIb/IIIa Cor. Angiography PCI, CABG or medical management Second troponin measurement Positive Depending upon clinical and angiographic features * omit clopidogel if the patient is likely to go to CABG within 5 days Twice negative Stress test Cor. angiography

ACS without persistent ST-segment elevation Long-term management Aggressive and extensive risk factor modification Patients should quit smoking ASA (75-100 mg for life), Clopidogrel (9 months, possibly 12 months) Betablockers Lipid lowering drugs: HMG-CoA reductase inhibitors HPS, 4S, CARE, LIPID, (A to Z ongoing) ACE inhibitors (HOPE), (EUROPA, PEACE ongoing)

Guidelines: ACS without persistent ST-segment elevation Caveats Guidelines are based upon evidence resulting from many clinical trials: These trials were restricted to selected populations Guidelines describe the current knowledge but They do not give the solution for an individual patient Clinical science is different from Practice

Conclusion (1) Importance of risk-stratification To perform the triage To choose the best strategy To predict the prognosis

Conclusion (2) High-risk patients require: Aggressive anti-thrombotic treatment Antithrombin agents Aggressive antiplatelet treatment: blockade of the three principal pathways ASA Clopidogrel GpIIb/IIIa Invasive strategy PCI prepared by upstream treatment Rapidly evolving field: frequent update Needs for implementation programme across Europe

The End