Management of Acute Coronary Syndromes

Transcription

1 Management of Acute Coronary Syndromes Objectives 1. To outline the approach in managing a patient who presents with an acute coronary syndrome focusing on anti- thrombotic agents. Jenny Chiu, BScPhm, RPh,, ACPR CSHP-Ontario Branch AGM and Educational session Nov 17, To review agents used for secondary prevention of acute coronary syndromes. Case - Mr AC 66 yo male 90kg, 5 10, BMI = 28.4 HPI: He awoke today at 8am with chest pressure, epigastric discomfort, diaphoresis Took some antacids but was getting worried since the chest pressure was getting more intense Presented to ER at 12pm PMH: generally healthy +ve FH for CVD, no DM, no smoking,?cholesterol, social drinker Mr AC NKA No regular meds but does take antacids about times a week (increased use over last month) O/E: diaphoretic, C/P rated 8/10 BP: 160/90; HR = 100; afebrile ECG :ST segment depression in precordial leads Labs: Cardiac enzymes (CK, troponin) ) were positive All other labs were normal Case (cont d) ACUTE CORONARY SYNDROMES What is his diagnosis and what do you do? ST elevation ECG Cardiac Markers negative No ST elevation Unstable Angina positive MYOCARDIAL INFARCTION STEMI NSTEMI Q wave MI Non-Q wave MI

2 Old Terminology: New Terminology: Thrombus Formation and ACS americanheart.org Plaque Disruption/Fissure/Erosion Thrombus Formation UA NQMI STE-MI Non-ST-Segment Elevation Acute Coronary Syndrome (ACS) ST-Segment Elevation Acute Coronary Syndrome (ACS) Definition of an Acute MI Type 1 Ischaemia due to plaque erosion Type 2 Ischaemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, hyper/hypotension Type 3 Sudden unexpected cardiac death, including cardiac arrest with symptoms suggestive of myocardial ischaemia Type 4a Myocardial infarction associated with PCI Type 4b Myocardial infarction associated with stent thrombosis Type 5 Myocardial infarction associated with CABG published online Oct 19, 2007; Circulation Back to our pt Diagnosis of ACS NSTEMI was made IN ER, pt given 160mg ASA to chew Acute treatment : consider NOAH NOAH-B N itrates O xygen A SA, analgesics (eg( eg.. morphine) H eparin or other anti-thrombotic thrombotic Beta-blockers Role of Nitrates Nitroglycerin (NTG) vasodilator result in reduction in myocardial oxygen demand and enhances myocardial oxygen delivery For symptom management only NTG forms Sublingual SL q5min x 3 (spray = 0.4mg) IV infusion of 10 to 200mcg/min topical apply on 24 hours, change daily Oral (eg( eg. isosorbide mono/di di-nitrate) not used Plaque Fissure or Rupture Platelet Adhesion Pathogenesis of Acute Coronary Syndromes: The integral role of platelets Platelet activation COAGULATION CASCADE Prothrombin Thrombin PAF EPI PLATELET CASCADE ADP Thrombin Collagen Platelet Activation 5HT TA 2 Platelet Aggregation Fibrinogen Fibrin GP IIb/IIIa receptor Thrombotic Occlusion STABLE CLOT Platelet Aggregation

3 Which anti-thrombotic thrombotic? Unfractionated heparin (UFH) Low molecular weight heparin (LMWH) Direct thrombin inhibitor Factor a inhibitor Glycoprotein IIb/IIIa inhibitor ASA Thienopyridines The Evolution of Anti-thrombotic thrombotic Use Unfractionated Heparin -MOA COAGULATION CASCADE Prothrombin Fibrinogen Thrombin Heparin Fibrin STABLE CLOT PAF 5HT EPI PLATELET CASCADE ADP Thrombin Collagen Heparin TA 2 GP IIb/IIIa receptor Platelet Aggregation Heparin mix of polysaccharides MW:5,000 MW:5,000-30,000 Daltons binds to a number of plasma proteins Dose: 60 units/kg LD then units/kg/hr Advantages: Can be used in renal dysfunction Short half-life life Protamine for antidote Disadvantages: Need frequent bloodwork for monitoring (aptt( aptt) Unpredictable pharmacokinetics Heparin Low Molecular Weight Heparin Enoxaparin, Dalteparin, Nadroparin Made from enzymatic depolymerization of the polysaccharide chains of UFH Inactivate factor a but not thrombin

4 LMWH Advantages better bioavailability less titration of dose (improved dose-response relationship) monitoring of aptt not necessary longer half-life life given SQ vs. continuous infusion possible lower incidence of HIT and osteopenia Disadvantages caution with patients with CrCl < 30ml/min not fully reversible with protamine LMWH cost more than UFH but save money with nursing time and labwork Death, MI or Recurrent Angina ESSENCE Results 30% 25% 20% 15% 10% 5% 0 Unfractionated Heparin Enoxaparin (Lovenox) P = 0.02 Risk Reduction 16.2% Days After Randomization Adapted with permission from Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997;337: Copyright 1997, Massachusetts Medical Society. All rights reserved. Death, MI or Urgent Revascularization TIMI 11B: Enoxaparin vs. Heparin in NSTE-ACS Unfractionated Heparin Enoxaparin (Lovenox) Days Adapted from Antman EM, et al. Circulation. 1999;100: % 14.2 % p = 0.03 Relative Risk Reduction = 15% Enoxaparin Dose: 1mg/kg SC q12h Caution in renal dysfunction (CrCl < 30ml/min) Some recommend 1mg/kg SC q24h Consider monitoring anti-a levels Alternatively 20-30% dose reduction given q12h Duration: up to 8 days or DC or revascularization, cath Direct Thrombin Inhibitor Bivalirudin synthetic analog of hirudin Inhibits free and clot-bound thrombin Advantage No immunogenicity Short half-life life easy to titrate ACUITY trial Acute Catheterization and Urgent Intervention Triage Strategy 13, 800 ACS pts undergoing early invasive procedures Looking at optimal timing and need for GPIIb/IIIa inhibitors Bivalirudin + GP IIb/IIIa vs Bivalirudin + provisional GP IIb/IIIa vs. UFH or Enoxaparin +/- GP IIb/IIIa Hypothesis: Bivalirudin +GPIIb/IIIa inhibitor = non-inferior or superior outcome Bivalirudin alone = non-inferior and less bleeding events

5 Copyright 2007 American College of Cardiology Foundation. Restrictions may apply. ACUITY Clinical Outcomes at 30 D (net clinical outcome = death, MI, revascularization, major bleeding) Role of Bivalirudin Early invasive strategy (w/n( 24-48hrs) 48hrs) Moderate to High risk ACS pts PCI pts with provisional use of GPIIb/IIIa inhibitors Use thienopyridine pre-angio esp. in upstream GPIIb/IIIa pts better results ACUITY PCI substudy Pts with risk for HIT Anderson, J. L. et al. J Am Coll Cardiol 2007;50: Factor a inhibitor: Fondaparinux synthetic pentasaccharide Works upstream on the coagulation cascade Antithrombin AT AT AT Intrinsic pathway a a Extrinsic pathway Fondaparinux Advantage Inhibits thrombin formation upstream Decreased binding to plasma proteins and endothelial cells Long half life Fixed once daily SC dosing (2.5mg) No need for lab monitoring May have a role in patients with HIT Fondaparinux Turpie AGG et al. N Engl J Med ;344:619. II Fibrinogen IIa Fibrin clot Disadvantages No antidote Renally cleared (up to 77%) don t use in CrCl < 30ml/min Long half life: not for surgical pts Does not have any action against thrombin that is already formed May explain why more catheter-associated associated thrombus Fondaparinux- the evidence OASIS-5: 5 th Organization to Assess Strategies in Acute Ischemic Syndromes non-inferiority trial enoxaparin vs fondaparinux 1 o 9 days: death, MI, refractory ischemia May be associated with less bleeding compared to enoxaparin at 9 days Excess bleeding in enoxaparin group may be due to UFH use during PCI More catheter-associated associated thrombus with fondaparinux(3) OASIS Cumulative Risks of Death, MI, or Refractory Ischemia Anderson, J. L. et al. J Am Coll Cardiol 2007;50:

6 Role of Fondaparinux Alternative to UFH or enoxaparin in pts undergoing invasive strategy Need to use supplemental UFH during PCI Alternative to enoxaparin in pts undergoing conservative strategy, especially those with bleeding risks Predictors of Major Bleeding (analysis from ACUITY trial) RR 1.51 Age > Anemia 1.54 CrCl < 60 ml/min 1.90 Female gender 1.21 Diabetes (p = 0.052) 1.67 Hi risk pts (ST, troponins) 1.23 HTN 1.36 No prior PCI Manoukian SV et al. JACC 2007; 49: Glycoprotein IIb/IIIa inhibitor Eptifibatide, Tirofiban, Abciximab GP IIb/IIIa inhibitor GP IIb/IIIa inhibitor GP IIb/IIIa Inhibition for Non-ST ST-Elevation ACS Trial Pooled n 29, Day Death or Nonfatal MI Odds Ratio & 95% CI 0.92 (0.86, 0.995) P= GP IIb/IIIa Better Placebo Better Placebo GP IIb/IIIa PRISM 3, % 5.8% PRISM PLUS 1, % 10.2% PARAGON A 2, % 11.3% PURSUIT 9, % 14.2% PARAGON B 5, % 10.5% GUSTO-IV ACS 7, % 8.7% 11.5% 10.7% Boersma E et al. Lancet. 2002;359: Glycoprotein IIb/IIIa inhibitor Pts with ongoing symptoms despite being on UFH and LMWH Used in combo with UFH or LMWH in ACS in pts going for invasive procedures Agents and Site of action COAGULATION CASCADE PLATELET CASCADE a Bivalirudin ADP Thrombin Fondaparinux Fondaparinux EPI Prothrombin Thrombin Heparin Clopidogrel Collagen PAF Ticlopidine 5HT TA 2 Heparin ASA Fibrinogen TNK, r-tpar Fibrin STABLE CLOT GP IIb/IIIa antagonists GP IIb/IIIa receptor Platelet Aggregation

7 Back to Mr AC Enoxaparin was started at 90mg q12h SC That evening, he developed ongoing chest pain, concomitant meds: ASA 81mg daily Metoprolol 25mg tid Nitro IV at 90mcg/min PRN NTG SL BP: 100/80; HR: s Decision to add GP IIb/IIIa inhibitor with possible angiogram +/- PCI in AM Mechanical intervention Percutaneous coronary intervention (PCI) Mr AC Next am, cath found a 90% LAD lesion which was stented with a bare metal stent (BMS) Eptifibatide was continued until 18 hours post-procedure procedure Enoxaparin was discontinued Clopidogrel was started 600mg load then 75mg daily Mr AC Continued to do well post PCI He developed a hematoma at site of catheterization Plan is to discharge in 2 days if he ambulates ok Echo: grade 2 to 3 LVEF Lipid profile: Total cholesterol : 6 mmol/l LDL: 4.1 mmol/l HDL: 1.0 mmol/l Triglycerides: 2.24 mmol/l Total cholesterol:hdl ratio: 6 What meds should he be discharged on and how long? ABCs s of Secondary Prevention ACC/AHA classification of recommendations for practice guidelines A nti-platelet, A ce-inhibitors B eta-blocker C holesterol lowering agent

8 Probability of Death or MI Aspirin in the Treatment of NSTE-ACS Months Wallentin LC et al. JACC. 1991;18: Placebo Aspirin 75 mg Risk ratio, % CI, CV death, MI, stroke (%) CLOPIDOGREL Placebo (n=6,259) Clopidogrel (n=6,303) Days After Enrollment RR = 0.80 P< CURE investigators. N Engl J Med. 2001;345(7): ACC/AHA: Antiplatelet Therapy Medical therapy without stenting ASA mg/d indefinitely (I, A) + clopidogrel 75 mg/d, at least 1 mo (I, A), ideally up to 1 yr (I, B) Bare metal stent ASA mg/d at least 1 mo, mg/d indefinitely (I, A) + clopidogrel 75 mg/d, at least 1 mo (I, A), ideally up to 1 yr (I, B) Drug-eluting stent ASA mg/d at least 3 mths (sirolimus)) to 6 mths (paclitaxel), mg/d indefinitely (I, A) + clopidogrel 75 mg/d at least 1 yr (I, B) Beta Blockers reduces reinfarction and ventricular fibrillation Pooled results in ACS pts undergoing PCI shown reduced death 30 d (0.6% vs. 2.0%) 6 months (1.7% vs. 3.7%) both p less than All pts should be on B-blockers B post UA/STEMI (I,B) Ellis K et al. Interv Cardiol 2003;16: ACE Inhibitors Helps with remodelling Continue indefinitely Pts with HF, LV dysfunction (LVEF < 0.40), hypertension or diabetes (I, A) Reasonable in absence of LV dysfunction, hypertension or diabetes (IIa( IIa,, A) Reasonable with HF and LVEF >0.40 (IIa( IIa,, A) Consider ACE/ARB combination with persistent HF and LVEF <0.40 despite conventional therapy including ACE or ARB (IIb( IIb,, B) Angiotensin Receptor Blocker If ACE inhibitor intolerance and signs of HF with LVEF < 0.40 (I, A)

9 CHOLESTEROL LOWERING AGENTS (2.46 mmol/l) (1.6 mmol/l)

10 A to Z trial - Estimates of the Rate of the Primary End Point 3.18 mmol/l 2.0 mmol/l 1.6 mmol/l 1.7 mmol/l De Lemos J et al. JAMA 2004;292: Coronary heart disease (CHD) event rates in secondary prevention trials CHOLESTEROL LOWERING AGENTS Statin regardless of baseline LDL-C C (I, A) initiated prior to discharge (I, A) Goal LDL-C C < 2 mmol/l (I, A) Goal TC/HDL-C C < 4 (IIa( IIa,, A) O'Keefe, J. H. et al. J Am Coll Cardiol 2004;43: AHA/ACC 2007 UA/STEMI guidelines CCS position statement on dyslipidemia. Can J Cardiol (11): Mr AC s discharge meds ECASA 81mg od (indefinitely) Clopidogrel 75mg od for 1 year Metoprolol 50mg bid Ramipril 2.5mg qhs Atorvastatin 80mg qhs NTG spray 0.4mg SL q5min prn x 3 for C/P (I,C) Role of pharmacist Counsel on meds Monitor tolerability of meds Anti-platelets: bleeding side effects Rash, CBC Beta Blockers: Dizziness, potential sexual dysfunction, CNS ACE inhibitors Cough, dizziness, angioedema Statins GI side effects, myopathy,, liver enzymes

11 Role of pharmacist Ensure compliance esp. with clopidogrel in stented patients Ensure patient meeting target goal Optimization of lipids Optimization of ACE inhibitor and B-blockersB For patients with no drug coverage, strategize ways to afford medication Participate in smoking cessation program with patients Guideline resources ACC/AHA 2007 guidelines for management of UA/STEMI ACC/AHA 2002 guidelines for management of UA/STEMI CCS position statement recommendations for diagnosis and treatment of dyslipidemia and prevention of CV disease Can J Cardiol (11)