Early Management of Acute Coronary Syndrome

Transcription

1 Early Management of Acute Coronary Syndrome Connie Hess, MD, MHS University of Colorado Division of Cardiology Acute Coronary Syndrome (ACS) A range of conditions associated with sudden imbalance in myocardial oxygen supply and demand à myocardial ischemia/infarction Unstable angina Non- ST- segment elevation myocardial infarction (NSTEMI) ST- segment elevation myocardial infarction (STEMI) >780,000 patients with ACS annually in U.S. ~25-40% STEMI In U.S., median age at presentation 68 yo Male- to- female ratio 3:2 STEMI Ischemic symptoms c/w ACS Persistent ST elevations on ECG Subsequent + cardiac biomarkers ACS definitions NSTE- ACS Ischemic symptoms c/w ACS Absence of persistent ST elevations on ECG With or w/o ischemic ECG changes (ST depression, transient ST elevations, T wave inversions) Unstable angina* Negative biomarkers of myocardial necrosis NSTEMI* Positive biomarkers of myocardial necrosis *UA/NSTEMI indistinguishable early on b/c troponin may not be positive for hours

2 Third universal definition of myocardial infarction Cardiac biomarkers JACC Vol. 50, No. 7, 2007 Pathogenesis of ACS Coronary artery disease (CAD) with plaque rupture/erosion most common Other non- atherosclerotic etiologies include spontaneous coronary artery dissection, embolism, arteritis Excessive myocardial oxygen demand with stable flow- limiting coronary lesion Non- coronary supply- demand mismatch (hypotension, anemia, hypertension, tachycardia, aortic stenosis, pulmonary embolism, heart failure)

3 Nature Reviews Cardiology 2016;13: Stable CAD Acute coronary syndrome Stable angina Unstable angina NSTEMI STEMI Non- occlusive thrombus Occlusive thrombus Photos from Davies MJ. Heart 2000;83: NSTEMI STEMI Murray S. Br J Cardiol 2010;17:129-32

4 Clinical presentation Chest discomfort (tightness, pressure, heaviness) at rest or for a prolonged period (>10min) Unstable angina: rest pain, new angina, or worsening of preexisting angina Radiation to back, neck, jaw, arms Associated with shortness of breath, diaphoresis, dizziness, syncope, nausea, vomiting, weakness Women, elderly, patients with diabetes less likely to experience chest pain Differential diagnosis Non- ischemic cardiovascular chest pain Aortic dissection Expanding aortic aneurysm Pericarditis Pulmonary embolism Non- cardiovascular pain Pulmonary (pneumonia, pneumothorax, pleuritis) GI (GERD, esophageal spasm, PUD, pancreatitis) Musculoskeletal (costochrondritis, cervical radiculopathy) Psychiatric (anxiety, somatoform disorders) Other (sickle cell crisis, herpes zoster) Applying Classification of Recommendation and Level of Evidence

5 Initial evaluation 1) What is the likelihood this is ACS? 2) What is the likelihood of adverse clinical outcomes? Early hospital care Is this a STEMI? BMJ 2002;324:831

6 Posterior lead ECG Posterior infarct occurs in 15-20% of STEMIs (typically inferior or lateral infarction) Isolated posterior MI less common (3-11%), often missed b/c electrographically silent High suspicion for ACS but non- diagnostic standard ECG Can help differentiate anterior wall ischemia from posterior STEMI Right ventricular infarct complicates up to 40% of inferior STEMIs STE in V4R most sensitive for RV infarction Patients are preload sensitive AVOID nitroglycerin and other preload- reducing agents Treat with aggressive fluid resuscitation Right- sided ECG

7 Call interventional cardiology for STEMI! Reperfusion therapy for STEMI

8 Fibrinolysis Keeley et al. Lancet 2003; 361: So it s not a STEMI

9 Rationale for early risk stratification in NSTE- ACS Useful for selection of site of care (cardiac ICU, step- down unit, observation unit) Helpful to determine medical therapy and need for early invasive strategy Provides prognostic information

10 When to forego formal early risk stratification in NSTE- ACS Patients with any of the following should proceed to urgent coronary angiography: Cardiogenic shock Heart failure Recurrent/persistent angina despite intensive medical therapy Unstable ventricular arrhythmias Ischemia- guided vs. early invasive strategy for NSTE- ACS Ischemia- guided Avoid routine early invasive procedure Plan for noninvasive evaluation to detect severe ischemia at low level of stress Some pts stabilize, may not need angiography Avoids procedural risk/cost Invasive evaluation if Medical therapy failed Ischemia on stress test High clinical risk Early invasive Coronary angiography up front Rapidly risk stratify based on knowledge of coronary anatomy Earlier revascularization Earlier hospital discharge Optimal timing inconclusive W/in 24 hrs vs within hrs, latter may allow antithrombotic therapy to stabilize plaque

11 TACTICS- TIMI 18: Invasive vs conservative strategies in NSTE- ACS 2220 pts with UA/NSTEMI Cannon CP et al. NEJM 2001;344: Routine vs selective invasive strategy in NSTE- ACS: 5 year outcomes

12 Antithrombotic therapy in ACS Antiplatelet therapy Gurbel and Tantry. JACC Heart Fail. 2014;2(1):1-14 Aspirin

13 12,562 pts w/ NSTE- ACS CV death/mi/stroke Relative risk 0.80 (95% CI , p<0.001) NEJM 2001;345: Clopidogrel + ASA and fibrinolysis for STEMI 3491 pts w/ STEMI undergoing lysis CV death, MI, urgent revascularization (%) ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) 45,852 pts randomized w/in 24h of acute MI 93% STEMI or new LBBB 2x2 factorial design: Up to 15 mg IV à 200 mg po metoprolol daily vs. placebo Clopidogrel + ASA vs. ASA alone Lancet 2005; 366:

14 TRITON- TIMI 38: Prasugrel vs clopidogrel in patients with ACS pts (~10,000 w/ NSTE- ACS, ~3500 w/ STEMI) scheduled to have PCI CV death/mi/stroke Major bleeding Wiviott SD et al. N Engl J Med 2007;;357: TRILOGY ACS: Prasugrel vs clopidogrel for ACS w/o revascularization 7243 pts <75 yo w/ NSTE- ACS medically managed Roe et al. NEJM 2012;367: PLATO: Ticagrelor vs clopidogrel in patients w/ ACS pts, ~11,000 w/ NSTE-ACS, ~7000 w/ STEMI CV death/mi/stroke (%) HR 0.84 (95% CI , p<0.001) HR 0.84 (95% CI , p<0.001) Wallentin L et al. N Engl J Med 2009;;361:

15 Early trials NSTEMI Glycoprotein IIbIIIa inhibitors STEMI More recent trials in NSTE- ACS patients treated w/ invasive strategy (EARLY ACS, ACUITY TIMING) have shown increased bleeding without ischemic benefit for routine upstream GPIIbIIIa use vs. delayed provisional use after angiography Am J Med 2000;109: N Engl J Med 2009;360: JAMA 2007;297(6): NSTE- ACS Guideline recommendations: antiplatelet therapy Guideline recommendations: antiplatelet therapy STEMI (undergoing primary PCI)

16 Anticoagulant therapy Gurbel and Tantry. JACC Heart Fail. 2014;2(1):1-14 Unfractionated Heparin Advantages Multiple sites of action in coagulation cascade (IIa,Xa) Long history of successful clinical use Readily monitored by aptt and ACT Very inexpensive Disadvantages Indirect thrombin inhibitor Requires AT for activation Does not inhibit clot- bound thrombin Nonspecific binding to: Plasma proteins Endothelial cells (variable anticoagulation level) Inhibited by platelet factor 4 reduced effect in ACS Causes platelet aggregation Risk of HIT Hirsh J, et al: Circulation 2001;;103: % of composition

17 Benefit of heparins vs placebo in NSTE- ACS Enoxaparin vs. UFH for NSTE- ACS Meta- analysis of ESSENCE and TIMI 11B trials Death/MI/urgent revascularization at day 43 Mainly conservative management, no P2Y12 inhibitor TIMI 11B ESSENCE OVERALL N UFH (%) Enox (%) % 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% B B Day OR % p ( ) UFH ENOX Enox Better Odds Ratio UFH Better Antman EM et al. Circulation 1999;100: SYNERGY: enoxaparin vs. UFH 10,027 patients w/ NSTE- ACS planned for early invasive management % p= Enox (4992) UFH (4982) p= d Death / MI TIMI Major Bleed The Synergy Investigators: JAMA 2004;292:45-54

18 Summary: heparins Enoxaparin and UFH equally efficacious in NSTE- ACS Patients managed w/ conservative strategy may have fewer MACE with enoxaparin (ESSENCE, TIMI 11B) For patients undergoing early invasive strategy, UFH may be preferable due to increased bleeding with enoxaparin (SYNERGY) Do not switch between enoxaparin and UFH (SYNERGY) Direct Thrombin Inhibitors Inhibits soluble and fibrinbound thrombin Inhibits thrombin-induced platelet aggregation No platelet activation No HIT Advantages Disadvantages Short t 1/2 (20 min) Needs continuous infusion No antidote Cost Predictable anticoagulant response ACUITY: Bivalirudin for NSTE- ACS Moderate- to high- risk patients with UA or NSTEMI undergoing an invasive strategy (N = 13,819) Moderate- to high- risk ACS Aspirin in all;; Clopidogrel dosing and timing per local practice R UFH or enox + GP IIb/IIIa n=4,603 Bivalirudin + GP IIb/IIIa n=4,604 Bivalirudin alone n=4,612 Angiography within 72 h Medical management PCI CABG Stone GW, et al: Am Heart J 2004;; 148:

19 ACUITY: Primary End Point Measures Primary EP UFH/Enox + GPI vs Bivalirudin + GPI Risk ratio ±95% CI Bival + GPI UFH/Enox + GPI RR (95% CI) p value (noninferior) (superior) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.8% 11.7% 1.01 ( ) 7.7% 7.3% 1.07 ( ) 5.3% 5.7% 0.93 ( ) < < Bivalirudin + GPI better UFH/Enox + GPI better N Engl J Med 2006;; 355: ACUITY: Primary End Point Measures Primary EP UFH/Enox + GPI vs Bivalirudin alone Risk ratio ±95% CI Bival alone UFH/Enox + GPI RR (95% CI) p value (noninferior) (superior) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 10.1% 11.7% 0.86 ( ) 7.8% 7.3% 1.08 ( ) 3.0% 5.7% 0.53 ( ) < <.001 < Bivalirudin better UFH/Enox + GPI better N Engl J Med 2006;; 355: HORIZONS- AMI: Bivalirudin in primary PCI for AMI 20 % Heparin + GPI (N=1802) RR = 0.76 P sup = RR = 0.60 P sup endpoint 1 endpoint Bivalirudin (N=1800) RR = 0.99 P sup = Net adverse clinical events Major bleeding* MACE** * Non- CABG ** MACE = Death, re- MI, TVR or stroke Stone GW et al: NEJM 2008;; 358:

20 Summary: bivalirudin Bivalirudin has similarly efficacy but less bleeding as UFH/enoxaparin with or without GPIIbIIIa inhibition in NSTE- ACS pts w/ mod- high risk treated w/ an invasive strategy Bivalirudin has similar efficacy but less bleeding in pts w/ STEMI undergoing primary PCI Not studied in pts managed w/ conservative strategy, so not for use in this population Fondaparinux Advantages Synthetic heparin pentasaccharide that exclusively neutralizes factor X SC administration once daily Fixed dose Predictable response No antigenicity Disadvantages Difficult to monitor (no aptt or ACT) Long half- life Catheter thrombosis during PCI Simoons ML: J Am Coll Cardiol 2004;;43: Yusuf S: N Engl J Med 2066;; 354: OASIS- 5: comparison of fondaparinux and enoxaparin in ACS Death, MI, or Refractory Ischemia Major Bleeding % 6 HR: 1.01 (95% CI, ) % HR: 0.52 (95% CI, ) 4 5 p< Fondaparinux 3 3 Enoxaparin 2 2 Enoxaparin 1 1 Fondaparinux Days Days 30 Day and 6 Month Results Event Fondaparinux Enoxaparin p value Mortality (30 day) 2.9% 3.5% 0.02 Mortality (6 mo) 5.8% 6.5% % thrombus on catheter (in fondaparixux group) if no UFH given Yusuf S: et al: N Engl J Med 2006:354:

21 Summary: fondaparinux Fondaparinux is a reasonable option for patients w/ NSTE- ACS managed with a conservative strategy Fondaparinux might be better if increased bleeding risk If pt on fondaparinux undergoes PCI, need to switch to another anticoagulant to avoid catheter thrombosis NSTE- ACS Guideline recommendations: anticoagulants STEMI Guideline recommendations: anticoagulants

22 84 pts treated for 1 year w/ beta- blockers after MI to prevent one death ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) 45,852 pts randomized w/ 24h of acute MI 93% STEMI or LBBB 2x2 factorial design: Up to 15 mg IV à 200 mg po metoprolol daily vs. placebo Clopidogrel + ASA vs. ASA alone Fewer reinfarctions and fewer VF BUT more cardiogenic shock, especially with initial hemodynamic instability (first 24 h) Moderate late benefit after relative stability Lancet 2005; 366: Guideline recommendations: beta- blockers NSTEMI Initiate oral beta- blockers w/in first 24 hrs in the absence of HF, low output state, risk for cardiogenic shock, or other contraindications (Class I, LOE A) Use metoprolol succinate, carvedilol, or bisoprolol in pts w/ stabilized HF and reduced EF (Class I, LOE C) Reasonable to continue beta- blockers w/ normal LV function in NSTE- ACS (Class IIa, LOE C) STEMI Beta blockers should be continued during/after hospitalization in all STEMI pts w/o contraindications (Class 1, LOE B) Pts w/ initial contraindications during first 24h after STEMI should be reevaluated for subsequent eligibility (Class I, LOE C)

23 MIRACL: effects of atorvastatin on recurrent ischemic events in NSTE- ACS 15 Placebo (n = 1548) LDL-C 135 mg/dl (3.5 mmol/l) 17.4% 14.8% 16% RRR Cumulative Incidence*, % 10 5 Atorvastatin 80 mg (n = 1538) LDL-C 72 mg/dl (1.9 mmol/l) RR = 0.84 (95% CI , p=0.048) Time Since Randomization, weeks *Death (any cause), nonfatal MI, resuscitated cardiac arrest, worsening angina with new objective evidence and urgent rehospitalization. Schwartz GG et al. JAMA. 2001;;285: PROVE IT: Intensive vs. moderate lipid lowering w/ statins after ACS 4162 patients w/ ACS (one- third w/ STEMI) Death, MI, UA rehosp, revasc, or stroke % Pravastatin 40 mg (n = 1548) 95 mg/dl (2.5 mmol/l) Atorvastatin 80 mg (n = 2099) 62 mg/dl (1.6 mmol/l) 26.3% 16% RRR 22.4% 35% LDL reduction (P =.005) Months of Follow-up Cannon CP et al. N Engl J Med. 2004;;350: % proportional reduction in 30d mortality à 4.8 deaths/1000 pts avoided Circulation 1998;97:

24 Effect of ACE Inhibitors on Mortality in Patients with CHF Garg R and Yusuf S. JAMA 1995;273: Guideline recommendations: statins and ACEI Initiate or continue high- intensity statin if no contraindications (Class I, LOE A) ACEI should be used in all NSTE- ACS patients with LVEF <40 or in those with HTN, DM, or stable CKD unless contraindicated (Class I, LOE A) ACEI w/in 24 hours for STEMI pts w/ anterior infarct, HF, or EF <40 unless contraindicated (Class I, LOE A) ACEI reasonable for all pts w/ STEMI and no contraindications (Class IIa, LOE A) ARBs are recommended if pt cannot tolerate ACEI (Class I, LOE A) Conclusions ACS is a spectrum of clinical conditions most commonly due to atherosclerosis and plaque rupture Early recognition and risk stratification key for selection of appropriate treatment Cornerstones of early management include antiplatelet therapy, anticoagulation, and revascularization Beta- blockers, statins, and ACEI/ARB also important components of early ACS treatment