NSTEMI Acute Coronary Syndromes Patrick Hildbrand

Trends and Prognosis in NSTEMI Hospital 1 year Furman MI, JACC 2001, 37:1571-1580

Hospital Outcome by Final Diagnosis

NSTEMI Acute Coronary Syndromes Trends and Prognosis Diagnosis and Risk assessment Initial Management Treatment < Long-Term Management Summary of Treatment Approaches

Diagnosis

Chest Pain

ECG Kaul P, JACC 2001, 38:64-71

Biochemistry

Risk Stratification

Summary Diagnosis and Risk assessment Diagnosis and short-term risk stratification should be based on a combination of Clinical history Symptoms ECG and (10 minutes, 6h, 24h and before hospital discharge) Biomarkers (admission and after 6-12 h) Risk score results Echocardiography is recommended to rule out differential diagnosis Patient without recurrence of pain, normal ECG findings and negative troponins tests > non invasive stress testing

NSTEMI Acute Coronary Syndromes Trends and Prognosis Diagnosis and Risk assessment Initial Management Treatment < Long-Term Management Summary of Treatment Approaches

Therapeutic Options Anti-ischemic agents Anti-platelet agents ASA Clopidrogel GP IIb/IIIa Inhibitors NSTEMI Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin) Revascularization

Anti-Ischemic Agents Aim: Decrease myocardial oxygen consumption and/or induce vasodilatation Betablockers are recommended in absence of contraindications (hypertension and tachycardia; cave inferior MI, acute LV dysfunction) (IB) Nitrates are effective in symptom relief in the acute management of angina episodes (IC) (Cave: Phospodiesterase-5-inhibitors, RV MI) Calcium channel blockers provide symptom relief in patients already receiving betablockers and nitrates; patient with contraindication to betablockers; vasospastic angina (Ic) Nifedipine or other dihydropyridine should not be used (IIIC) unless combined with betalockers (IIa-B)

Anti-ischemic agents Anti-platelet agents Anti-coagulants ASA Clopidrogel GP IIb/IIIa Inhibitors NSTEMI Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin) Revascularization

UFH UFH 33% RR LMWH

Enoxaparin (©Clexane) vs UFH NON REVASC. GP IIb/IIIa Inhibitors GP IIb/IIIa Inhibitors

Enoxaparin was non-inferior to UFH in Reducing death or MI in the Synergy Trial Synergy 14% versus 14.5% p=n.s.

Factor-Xa inhibitors (Fondaparinux, © Arixtra) Oasis 5 Trial Death, MI or refractory ischemia through day 9

Oasisi 5: Major bleeding through d9

Relation between bleeding and mortality in OASIS 5 Bleeding carries a high risk of death Prevention of bleeding is as important as prevention of ischemic events and results in a significant rate reduction of death > Risk stratification of bleeding should be part of the decision making process

Direct thrombin inhibitors (Bivalirudin, ©Angiox) UFH/LMWH

Primary Endpoint Measures Acuity Trial Primary Endpoint Measures Net clinical outcome Cave: hematoma > 5cm never used in any other definition

Summary Anti-coagulants Anticoagulation is recommended for all Patient in addition to anti-platelet therapy Anticoagulation should be selected to the risk of both ischemic and bleeding events Choice of the anticoagulants (UFH, LMWH, fondaparinux and bivalirudin should depend on the strategy. Urgent invasiv UFH (I-C), Enoxaparin (IIa-B) or bivalirudin (I-B) Non-urgent situation Fondaparinux efficacy/safety profile (I-A) Enoxaparin only if bleeding risk is low (IIa-B) >> not LMWH (other then Enoxaparin) / UFH

Anti-ischemic agents Anti-platelet agents Anti-coagulants ASA Clopidrogel GP IIb/IIIa Inhibitors NSTEMI Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin) Revascularization

Anti-platelet agents

ASA GI intolerance 5-40%, bleeding >0.9% in CAPRIE

Primary End Point—MI/Stroke/CV Death CURE Study Primary End Point—MI/Stroke/CV Death 20% Relative Risk Reduction Placebo + ASA* P = 0.00009† N = 12,562 Clopidogrel + ASA* 3 6 9 12 Months of Follow-Up The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

PCI-CURE Study: CV Death or MI .15 Placebo + Aspirin* (n=1345) 12.6% Median time to PCI 31% Relative Risk Reduction .10 8.8% Cumulative Hazard Rate Clopidogrel + Aspirin* (n=1313) .05 P=0.002 .00 10 100 200 300 400 Days of Follow-Up *In combination with standard therapy. Mehta SR, et al. Lancet. 2001;358:527-533.

GP IIb/IIIa Inhibitors Tirofiban Lamifibane Eptifibatide Abciximab Lamifibane

Acuity timing

Summary GP IIb/IIIa Inhibitors Intermediate to high risk (DM, ST segment depression and Troponin pos.) patients, either eptifibatide or tirofibane for initial early treatment is recommended in addition to oral antiplatelet agents (IIa-A) Patient not pre-treated with GP IIb/IIIa inhibitors and proceeding to PCI; abciximab is recommended (IA) GpIIb/IIIa inhibitors must be combined with anticoagulation I-A Bivaluridin may be used as an alternative to GPIIb/IIIa inhibitors plus UFH/LMWH (IIa-B) GPIIb/IIIa inhibitors only for invasive strategy

Coronary revascularization Revascularization for NSTEMI is performed to relieve angina relieve ongoing myocardial ischemia prevent progression to MI or death 30-38% single vessel 44-59% mutlivessel disease (TIMI-3B, FRISC-2)

Anti-ischemic agents Anti-platelet agents Anti-coagulants ASA Clopidrogel GP IIb/IIIa Inhibitors NSTEMI Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin) Revascularization

Coronary revascularization

Randomized trials comparing early invasive (dark bars) vs Randomized trials comparing early invasive (dark bars) vs. conservative strategy (open bars)

Relative Mortality Benefit with the Revascularization vs Relative Mortality Benefit with the Revascularization vs. Gradient in Rates of Revascularization Between both Randomization Arms

Summary Invasive vs. Conservative Strategies New data coming from long-term follow up of RITA-3 and FRISC-2 and Mehta meta-analysis show significant risk reduction for death and „death & MI“ at long-term follow up Early hazard shown in ICTUS Trial Early hazard shown in Mehta meta-analysis ICTUS, Lancet 2007 FRISC 2, Lancet 2000 RITA 3 Lancet 2005 Metha JAMA 2005

Summary Treatment Approaches

Summary Therapeutic Options Anti-ischemic agents Anti-platelet agents ASA Clopidrogel GP IIb/IIIa Inhibitors NSTEMI Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin) Revascularization

NSTEMI Acute Coronary Syndromes Trends and Prognosis Diagnosis and Risk assessment Initial Management Treatment < Long-Term Management Summary of Treatment Approaches

Long-term Post-PCI Management What are our targets ? Prevention of stent thrombosis/restenosis Prevention of plaque rupture

ATC 2002: Indirect Comparisons ASA Doses on Vascular Events in High Risk Patients ASA Dose # Trials OR 500-1500 mg 34 19% 160-325 mg 19 26% 75-150 mg 12 32% <75 mg 3 13% Overall 65 23% 0.5 1.0 1.5 2.0 Antiplatelet Better Antiplatelet Worse Antithrombotic Trialists’ Collaboration BMJ 2002; 324:71-86

Primary End Point—MI/Stroke/CV Death CURE Study Primary End Point—MI/Stroke/CV Death 20% Relative Risk Reduction Placebo + ASA* P = 0.00009† N = 12,562 Clopidogrel + ASA* 3 6 9 12 Months of Follow-Up The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

PCI-CURE Study: CV Death or MI .15 Placebo + Aspirin* (n=1345) 12.6% Median time to PCI 31% Relative Risk Reduction .10 8.8% Cumulative Hazard Rate Clopidogrel + Aspirin* (n=1313) .05 P=0.002 .00 10 100 200 300 400 Days of Follow-Up *In combination with standard therapy. Mehta SR, et al. Lancet. 2001;358:527-533.

Events Saved vs Life-threatening Bleeding Over Time: Net Clinical Benefit of Clopidogrel Months of follow-up Events/1000 patients treated -5 5 10 15 20 25 3 6 9 12 Events Saved: CV death, MI, stroke Life-threatening bleeding Yusuf S et al for the CURE Trial Investigators. Circulation. 2003;107:966

EUROPA HOPE PEACE ACE-Inhibitors Placebo Placebo Ramipril Perindopril 14 12 10 8 6 4 2 HOPE EUROPA 20 Placebo annual event rate: 2.4% Placebo Placebo 15 Ramipril Patients Reaching Composite End Point [MI, Stroke, CV Death] (%) 10 CV Death, MI, or Cardiac Arrest (%) Perindopril RRR=22% P=.0003 RRR=20% 5 P<.001 500 1000 1500 1 2 3 4 5 Follow-Up (days) Years N = 12,218 PEACE 30 25 20 15 10 5 Placebo Trandolapril Incidence of Primary End Point (%) HOPE: N Engl J Med. 2000;342:145-153. EUROPA:. Lancet. 2003;362:782-788. PEACE:N Engl J Med. 2004;351:2058-2068. 0 1 2 3 4 5 6 Years After Randomization

Leading and Lagging Hospitals Quartiles: Discharge Care # LVEF < 40% * Known hyperlipidemia Peterson et al, ACC 2004

Discharge Clopidogrel Use in CRUSADE CRUSADE DATA: Q 4, 2004 – Q 3, 2005 (n=35,897)

Proven (mortality or death/MI/stroke) Medical Therapies Following (large*) MI Treated with Stent Treatment RRR Abs benefit Cost/mo+ Aspirin1 23% 2.4% 1.00 Statin2 (simvastatin) 13% 1.8% 125.00 Eplerenone3 15% 2.3% 104.97 ACE-I*4 (ramipril) 13% 1.1% 55.99  blockers*5 (carvedilol) 23% 3.0% 117.93 Clopidogrel**6 27% 3.0% 126.99 Total >70% $531.88 1. ISIS-2, Lancet 1988 2. HPS, Lancet, 2002 3. Pitt NEJM 2003;348;1309-21 4. ACE-I Acute MI Collaborators Overview, Circulation 1998 (ant MI); HOPE. 5. CAPRICORN, Lancet, 2001 6. CREDO, JAMA, 2002 ** death, MI, stroke; all others death costs from www.drugstore.com january 2007

Improving Adherence, Outcome, and Cost by Providing EBM Coverage Post MI: Health Insurance Perspective After 5 years of medicine coverage with good adherence to prevention - $6,500 saved per patient Choudhry N. Health Affairs 2007;26:186-194

Disease Modifying Drugs in Atherothrombosis Statins Prevent CV events Prevent progression of CAD Prevents development of DM ACE-Inhibitors/ARB’s Prevent renal dysfunction in DM Clopidogrel Prevents CV events

Long-term Post-PCI Management There are two key targets in the post-PCI management The lesion and the patient ! The use of ASA with clopidogrel should be used in all patients with PCI Long-term use of the combination appears at least to be safe up to about 3 years Important other therapies include statins, ACE/ARB, and beta-blockers

NSTEMI Acute Coronary Syndromes Trends and Prognosis Diagnosis and Risk assessment Initial Management Treatment < Long-Term Management Summary of Treatment Approaches

Clinical Outcomes for Patients Stratified by Age (Invasive Vs Conservative Strategies) from TACTICS–TIMI-18 Trial

Special Conditions & Populations chronic Kidney Disease Outcomes According to Degree of Renal Function Impairment in NSTE-ACS Patients in GRACE Registry

Special Conditions& Populations Diabetes Treatment Effect on 30-day Mortality Among Diabetic Patients with NSTEMI from Six Randomized Clinical Trials

Special Conditions& Populations Diabetes

Non-ST-segment Elevation Acute Coronary Syndromes Anti-ischemic agents Anti-coagulants UFH or LMWH Factor-Xa inhibitors (Fondaparinux) Direct Thrombin inhibitors (Bivalirudin) Anti-platelet agents ASA Clopidrogel GP IIb/IIIa Inhibitors Revascularization NSTEMI Non-ST-segment Elevation Acute Coronary Syndromes ?

Timing of Intervention Few studies have shown superiority of very early intervention vs. deferred intervention ISAR-COOL (small sample size) JAMA 2003 Many trials have shown early hazard with early intervention vs. deferred intervention ICTUS trial NEJM 2005 Mehta meta-analysis JAMA 2005 Grace and Crusade registries Heart 2007, Arch Intern Med 2006 > Timing of intervention recommended on the basis of risk stratification

Risk Stratification

Summary Management Strategy

Summary Long-Term Management

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