Myocardial Oxygen Supply. Ischemic Heart Disease. Autoregulation. Epidemiology of IHD. Myocardial Ischemia. Myocardial Oxygen Supply

Transcription

1 Myocardial Oxygen Supply Ischemic Heart Disease Paul P. Dobesh, Pharm.D., BCPS St. Louis College of Pharmacy Therapeutics I Coronary blood flow coronary perfusion pressure myocardial contraction collateral blood flow Arterial oxygen content Oxygen extraction capacity Epidemiology of IHD Autoregulation Incidence of 1.5 cases per 1000 pt years 20-25% of all deaths in the United States #1 cause of morbidity and mortality in the western world Extravascular compression forces Humoral factors CORONARY BLOOD FLOW Myocardial Ischemia VASCULAR RESISTANCE SUPPLY Autoregulation Metabolic control Neural control Diastolic phase DEMAND HEART RATE CONTRACTILITY Myocardial Oxygen Supply Coronary blood flow coronary perfusion pressure myocardial contraction collateral blood flow Arterial oxygen content Oxygen extraction capacity O 2 -CARRYING CAPACITY SYSTOLIC WALL TENSION

2 Myocardial Oxygen Demand Heart rate Contractility Intramyocardial wall tension preload afterload wall thickness Double Product DP = HR x SBP limitations Differentiating IHD Exertional pain lasting < 20 min, relieved by rest Stable or Exertional Angina CAD, IHD, CHD What are the characteristics of the chest pain? Pain occurring at rest lasting > 20 min Acute Coronary Syndrome Stable Angina Plaque Characteristics Coronary Artery Disease Risk Factors Modifiable Cigarette smoking* HTN* Diabetes mellitus Hyperlipidemia* obesity life style hyperuricemia alcohol ingestion medications Not modifiable Age/gender male 45 yrs female 55 yrs early menopause Family history male < 55 yrs female < 65 yrs Stable Angina Clinical Manifestations (PQRST) Precipitating factors and Palliative measures Quality of pain Region and Radiation of pain Severity of pain Temporal pattern Differential diagnosis Other symptoms Stable Angina: Pharmacotherapy Aspirin Nitrates β-blockers Calcium Channel Blockers (CCB) non-dihydropyridine Dihydropyridine ACE-I

3 Aspirin MOA Dose (325 mg vs. 81 mg) Significant in fatal and non-fatal MI Should be used in all patients with angina that do not have a contraindication organic nitrates GTP Nitrates sulfhydry groups NO (EDRF) stimulates guanylate cyclase cgmp smooth muscle relaxation (vasodilation) Aspirin Contraindications hypersensitivity life-threatening hemorrhage bleeding disorders Adverse effects GI upset occult bleeding tinnitus renal dysfunction bronchospasm Monitoring occult GI blood loss symptoms of anemia hematocrit stool guaiac Coronary events Nitrates Effects O 2 demand due to wall tension (preload) O 2 supply through coronary vasodilation collateral vessels? Antiplatelet activity Diagnostic Test Nitrates Electrocardiogram (ECG or EKG) Exercise - tolerance test Cardiac imaging Coronary angiography Tolerance When? Which products? Management

4 Nitrates: Comments Sublingual tablets for acute attacks patient counseling how to take (3x5) side effects dispensed in original container (dark glass) dry cool storage, avoid sunlight safety cap cotton plug self-life Nitrates: Comments ISDN SL PO chronic therapy tid about 5 hrs apart (tolerance) ISMN ISMO or Monoket: give bid 7 hrs apart Imdur: give qd Nitrates: Comments Nitrates Sublingual spray for acute attacks how to use advantage when low saliva longer self-life more expensive Adverse effects headache flushing postural hypotension syncope reflex tachycardia contact dermatitis Contraindications severe anemia hypotension bradycardia right ventricular infarction Monitoring anginal symptoms adverse effects blood pressure heart rate Nitrates: Comments Ointment how to use / application cosmetically acceptable? gloves Patch application tolerance PO IV for emergency situations (HTN, UA, AMI) tolerance β-blockers MOA O 2 demand HR contractility wall tension Characteristics β 1 selectivity ISA metabolism

5 Adverse effects bradycardia hypotension AV block bronchospasm CHF CNS lipid abnormalities glucose intolerance mask hypoglycemia abrupt withdrawal β-blockers Contraindications bradycardia hypotension severe LV failure signs of peripheral hypoperfusion prolonged PR interval 2 or 3 degree AV block severe COPD history of asthma severe PVD IDDM (hard to control) Calcium Channel Blockers Adverse effects bradycardia reflex tachycardia hypotension AV block constipation peripheral edema gingival hyperplasia Contraindications moderate to severe LV failure 2 or 3 degree AV block unstable angina and AMI hypotension pulmonary congestion β-blockers Monitoring HR BP Double product anginal symptoms signs of CHF adverse effects Calcium Channel Blockers Monitoring HR BP anginal symptoms signs of CHF adverse effects Calcium Channel Blockers MOA O 2 demand wall tension (all agents) contractility (verapamil and diltiazem) HR (verapamil and diltiazem) O 2 supply coronary vasodilation? Exertional Angina: Treatment Modify risk factors non-pharmacologic therapy pharmacotherapy ASA Rest Acute attacks sublingual NTG terminate attack prophylaxis against attack

6 Exertional Angina: Chronic Prophylaxis When? 1 episode / day Impact on patients QOL patient has coexisting condition that would benefit from therapy What? β-blockers Nitrates Calcium Channel Blockers Patients should continue to get SL NTG for breakthrough acute attacks Patients should continue to get ASA Chronic Prophylaxis Nitrates Agents ISDN, ISMN, NTG patch Ideal situations patient already on β-blocker or non-dhp CCB patient at goal or near goal HR heart failure Chronic Prophylaxis β-blockers Best when fixed anginal threshold Goal resting HR exercise HR BP (if hypertensive) double product Ideal situations tachycardia hypertension patient taking DHP CCB or nitrates prior MI Chronic Prophylaxis Combination Therapy β-blocker plus Nitrates CCB plus Nitrates β-blocker plus dihydropyridine CCB β-blocker plus non-dihydropyridine CCB? Nitrates, β-blocker, and CCB Chronic Prophylaxis Calcium Channel Blockers Best for variable exertional threshold Agents dihydropyridine non-dihydropyridine Ideal situations tachycardia (verapamil and diltiazem) hypertension (all agents) patients with heart failure (amlodipine or felodipine) contraindications to β-blockers ACE-I Do not help reduce number or severity of ischemic attacks HOPE Trial Patients with atherosclerosis have mortality benefit when given ACE-I All patients should receive an ACE-I if possible Monitor BP, K +, SrCr, BUN Rash, cough, angioedema

7 Variant Angina Angina from coronary vasospasm Agents CCB (any agent) which one? Nitrates with CCB β-blockers? Refractory Ischemia Combination therapy PTCA therapy ASA heparin abciximab stent - abciximab or eptifibatide with heparin (clopidogrel and ASA) CABG therapy SL NTG ASA lipid lowering agents

8 ACS Spectrum Stable Unstable Angina Angina NSTEMI STEMI Refractory Ischemia Combination therapy PTCA therapy ASA Heparin abciximab stent - abciximab or eptifibatide with heparin (clopidogrel and ASA) CABG therapy SL NTG ASA lipid lowering agents Acute Coronary Syndromes Non-ST-segment elevation Non-ST-segment elevation ACS Ischemic discomfort at rest What does the EKG show? ST-segment elevation ST-segment elevation MI Differentiating IHD Plaque Fissuring and Rupture CAD, IHD, CHD What are the characteristics of the chest pain? Exertional pain lasting < 20 min, relieved by rest Pain occurring at rest lasting > 20 min Stable or Exertional Angina Acute Coronary Syndrome

9 ACS Spectrum Stable Unstable Angina Angina NSTEMI STEMI Unstable Angina Definition new onset angina that is severe and/or frequent that markedly limits activity recent acceleration of angina angina at rest that last for > 20 minutes not relieved by rest or SL NTG Pathophysiology abrupt in O 2 supply thrombus formation Risk 10-20% risk of developing AMI Acute Coronary Syndromes Non-ST-segment elevation Non-ST-segment elevation ACS Ischemic discomfort at rest ST-segment elevation ST-segment elevation MI Are there elevated Cardiac Enzymes? Unstable Angina / NSTEMI Goals relieve symptoms reduce the DP prevent complications Supportive care hospitalization bed rest anxiolitics correction of precipitating of complicating factors Acute Coronary Syndromes * Elevated Cardiac Enzymes Are there elevated enzymes? No ST-segment elevation Unstable angina Ischemic discomfort at rest * * * Non-ST-segment elevation MI (non-q-wave MI) What does the EKG show? ST-segment elevation * 80-85% ST-segment elevation MI (Q-wave MI) UA / NSTEMI Pharmacotherapy Antiplatelet agents ASA dose benefit alternatives Heparin LMWH Glycoprotein IIb/IIIa receptor blockers

10 Unstable Angina / NSTEMI Pharmacotherapy Heparin MOA Route / dose Monitoring aptt signs of bleeding platelets angina Benefit Mechanism of Action X TF/VIIa Xa V, Ca ++ Prothrombin Thrombin Advantages of LMWH ESSENCE: Enoxaparin Reduced protein binding More predictable anticoagulant response No monitoring required Resistance to platelet factor 4 SQ dosing (twice a day) Less HIT UA / NSTEMI Enoxaparin 1mg/kg q 12 H Sub Q + ASA UFH IV dose-adjusted + ASA Treatment Phase (min 48H, max 8 Days) Follow-up Visit Day 14 Follow-up Visit Day 14 Follow-up call Day 30/365 Follow-up call Day 30/365 Follow-up Phase Cohen M et al. NEJM 1997;337: Mechanism of Action Unfractionated Heparin Pentasaccharide Sequence Factor Xa Endpoints 14 days ESSENCE Results UFH n=1564 Enoxaparin n=1607 p value Death, MI, recurrent angina 19.8% 16.6% Low-Molecular Weight-Heparin Antithrombin Antithrombin Pentasaccharide Sequence Thrombin Factor Xa 30 days Death, MI, recurrent angina 23.3% 19.8% Revascularization 32.2% 27.0% Major bleeding 7.0% 6.5% NS Any bleeding 14.2% 18.4% Cohen M et al. NEJM 1997;337:

11 UA / NSTEMI TIMI 11B: Enoxaparin Enoxaparin 30 mg IV bolus mg/kg q 12 H Sub Q Heparin 70 U/kg IV bolus + 15U/Kg/h UFH IV Fixed Dose < 65 kg > 65 kg 40 mg 60 mg q 12 H Fixed Dose placebo q 12 H Acute Phase Chronic Phase (min 72H, max 8 Days) 43 days Antman et al. Circulation 1999;100: Days 1-6 Death, MI, Recurrent Angina Death, MI, Recurrent Angina Revascularization Major Bleeding Minor Bleeding FRIC Results Heparin (n=731) 7.6% 12.3% 14.2% 1.0% 3.3% Dalteparin (n=751) 9.3% Days 6-45 (n=561) (n=562) 12.3% 14.3% 1.1% 3.1% p-value Klein et al. Circulation 1997;96: TIMI 11B: Chronic Phase Results % Death/MI/Urgent Revasc 14.5% 12.4% RRR 14.6% p=0.048 ENOXAPARIN UFH 19.7 % 17.3 % RRR 12% p= Days Antman et al. Circulation 1999;100: UA/NSTEMI LMWH Trials Composite Endpoint at Day 14 RRR FRIC (dalteparin) 0% TIMI 11B (enoxaparin) 14.5% (P=0.03) ESSENCE (enoxaparin)) 16.2% (P=0.02) -15% -10% -5% 0% 5% 10% 15% 20% LMWH Better UFH Better Cohen M. Semin Thromb Hemost 1999;25(suppl 3): FRIC: Dalteparin LMWH in UA / NSTEMI UA or NSTEMI Dalteparin 120 IU/kg SC q 12 H UFH 5000 IU bolus 1000 IU/H 48 H then IU SC q 12 Dalteparin 7500 IU SC q 24 H Placebo Dalteparin 7500 IU SC q 24 H Placebo Day 1 6 Day 7-45 Klein, et al. Circulation 1997;96: Enoxaparin has been shown to be superior to UFH in two trials 1 mg/kg SQ q 12 hr for 3 days Dalteparin has been shown to be equivalent to UFH in one trial 120 u/kg q 12 h for 3-5 days Some questions about the trials Both are FDA approved Monitoring

12 UA / NSTEMI Pharmacotherapy Antiplatelet agents ASA dose benefit alternatives Heparin LMWH Glycoprotein IIb/IIIa receptor blockers Unstable Angina / NSTEMI Pharmacotherapy Calcium Channel Blockers not 1 st line agents ideal situations ongoing ischemia on nitrates and β- blockers intolerance to nitrates and/or β-blockers variant angina avoid pulmonary edema LV dysfunction GP IIb/IIIa Receptor Blockers Very potent antiplatelet agents also very expensive Use in high risk patients elevated troponin EKG changes (ST-segment depression, flipped T-waves) Which agent patient going directly to PCI - abciximab patient going PCI later tirofiban, eptifibatide, or abciximab now and during PCI LMWH now, GP IIb/IIIa during PCI not going to PCI - UFH or LMWH Monitoring Unstable Angina / NSTEMI Pharmacotherapy Morphine sulfate MOA analgesia SBP, and may HR Use Monitoring pain vital signs (SBP, HR, respiration) and mental status Allergy Avoid Unstable Angina / NSTEMI Pharmacotherapy β-blockers choice of agent dosing goal of therapy Nitrates agents dose goal of therapy patient management benefit? Unstable Angina / NSTEMI Pharmacotherapy Coronary intervention all patients should go to cardiac catheterization within hours sooner the better Thrombolytic therapy

13 ST-Segment Elevation AMI Acute Myocardial Infarction Diagnosis: at least 2 or the 3 Prolonged chest pain ECG changes Elevation of cardiac enzymes Acute Coronary Syndromes Cardiac Enzymes No ST-segment elevation Unstable angina Ischemic discomfort at rest * * * Non-Q-wave AMI ST-segment elevation * Q-wave AMI X Upper limit of normal Myoglobin Total CK CK-MB LDH Troponin I Hours from onset of infarcion Epidemiology 900,000 AMI / year in US 30% mortality mortality is higher in the elderly cost to the US health system: $ 50 billion / yr. Pathophysiology 85% occlusion of coronary artery wavefront ischemia hibernating or stunned myocardium Enzyme CK CK-MB LDH Troponin I/T Myoglobin Cardiac Enzymes Onset to Rise Time to Peak Normalization 4-8 hrs 4-8 hrs hrs 3-12 hrs 1-4 hrs 20 hrs 20 hrs 3-6 days 24 hrs 6-7 hrs 2-3 days 2-3 days 8-14 days I: 7-10 days T: days 24 hrs

14 Risk Stratification Goals of therapy reduce mortality minimize infarct size salvage ischemic myocardium prevent or minimize complication Reperfusion Therapies Goals obtain and maintain vessel patency prevent recurrent ischemia prevent reocclusion / reinfarction preserve LV function reduce mortality History of Therapy PRE CURRENT THERAPY: Bed Rest Cardiac rehabilitation Pharmacologic reperfusion Sedation CCUs Revascularization procedures Coronary Patency TIMI grade flow TIMI grade 0 flow: no flow TIMI grade 1 flow: minimal flow TIMI grade 2 flow: moderate flow TIMI grade 3 flow: normal flow EFFECT ON PROGNOSIS: Observation Dysrhythmia and CHF control Minor (negative) Moderate Major Goal of any reperfusion therapy is to obtain TIMI grade 3 flow Supportive Care hospitalization bed rest oxygen when? how long? monitoring Reperfusion Therapies Emergency PTCA may be better than fibrinolytics should be done within minutes must be in high volume centers abciximab is only GP IIb/IIIa inhibitor studied in patients with STEMI Fibrinolytics MOA benefit open 60-90% of occluded arteries result in 20% reduction in mortality should be given within 30 minutes

15 Fibrinolytic System Thrombin Fibrin Fibrinogen Plasminogen FDP PAs Thrombus Plasmin Trial # Patients Patient Population GISSI-2 12,381 within 6 hr AMI ISIS-3 41,299 within 24 hr AMI GUSTO 41,021 within 6 hr AMI Agents Mortality Stroke t-pa 100mg /3 hr 1.5 MU SK +/- heparin SQ Duteplase 0.6 MU over 4 hr SK 1.5 MU APSAC 30 U accel t-pa / IV heparin SK / IV heparin SK / SQ heparin t-pa and SK / IV heparin t-pa 8.9% SK 8.5% Duteplase 10.3% SK 10.6% APSAC 10.5% accel t-pa / IV heparin 6.3% SK / IV heparin 7.4% SK / SQ heparin 7.2% t-pa and SK / IV heparin 7.0% t-pa 1.3% SK 0.9% 6.9% 7.9% 7.7% 7.6% Fibrin Degradation Products (FDP) Fibrinolytic Agents Steptokinase t-pa (alteplase) r-pa (reteplase) TNK (tenecteplase) GUSTO III Design: Superiority trial STEMI, lytic eligible, < 6 h ASA r-pa (10 U + 10 U) + heparin Primary Endpoint: mortality at 30 days t-pa (15 mg bolus; 0.75 mg/kg over 30 min.; 0.5 mg/kg over 60 min.) + heparin N Engl J Med 1997;337: Major Thrombolytic Trials GISSI-2 ISIS-3 GUSTO GUSTO III ASSENT II GUSTO III: Results r-pa t-pa p-value 30-Day mortality 7.47% 7.24% NS Time to treatment 0-2 hours (n=4,217) 5.9% 6.2% NS 2-4 hours (n=7,379) 7.7% 7.7% NS 4-6 hours (n=3,464) 10.1% 7.5% NS * * P = Hemorrhagic stroke 0.91% 0.87% NS

16 TNK single bolus weight-adjusted ASSENT-2 Design: Equivalence trial STEMI < 6 h ASA Heparin (aptt 50-75s) 1:1 (double-blind) Primary endpoint All cause mortality (30 days) t-pa <100 mg/90 min n=16,500 pts Fibrinolytic Therapy Indications Best situation ST segment elevation or BBB present within 12 hours age < 75 years Other indications age 75 years present in hours elevated BP Lancet 1999;354: Total Pop Age (years) 75 >75 ASSENT-2: Results 30 day mortality: Subgroups Time to Rx (hrs) > > TNK t-pa Relative Risk (n=8,461)(n=8,488) (95% CI) % 6.18 % (0.89,1.12) Lancet 1999;354: (0.92,1.24) 0.90 (0.75,1.08) 1.02 (0.80,1.30) 1.16 (0.97,1.38) 0.77 (0.62,0.95) TNK better t-pa better p- value NS NS NS NS NS SS 1.4 Choice of Fibrinolytic < 6 hours from onset < 75 years, anterior MI, or inferior wall MI with poor prognosis t-pa, TNK, or r-pa Other patients t-pa, TNK, r-pa, or SK > 6 hours from onset most patients 7-12 hours, some hours t-pa, r-pa, TNK, or SK ASSENT-2: Results Bleeding events Total bleeds Major bleeds Units transfused TNK (n=8,461) % t-pa (n=8,488) % p- value SS SS SS Fibrinolytic Therapy Absolute Contraindications Active internal bleeding Suspected aortic dissection Previous hemorrhagic stroke Other strokes or CVA within 1 year Known intracranial neoplasm Lancet 1999;354:

17 Fibrinolytic Therapy Relative Contraindications Severe uncontrolled HTN on presentation Hx of CVA or intracerebral pathology Current use of anticoagulants Known bleeding diathesis Recent trauma Prolonged CPR Major surgery Noncompressible vascular punctures Recent internal bleeding Prior SK/anistreplase Pregnancy Active peptic ulcer Hx of chronic severe HTN Conjunctive Treatment Heparin PTCA and CABG t-pa, TNK, or r-pa 60 units/kg bolus, followed be a 12 units/kg/min infusion (max 5000 U bolus/ 1000 U/hr infusion continued for 48 hours with a goal aptt sec Streptokinase or anistreplase: high-risk large anterior MI, mural thrombus, CHF, previous embolus, atrial fibrillation Streptokinase or anistreplase: not high-risk Without thrombolytic therapy Conjunctive Treatment ASA dose given to all AMI patients without contraindications continued indefinitely benefit ISIS-2 Conjunctive Treatment Warfarin patients at high-risk of thromboembolism mural thrombus INR 2.5 ( ± 0.5 ) for 3 months use with heparin INR 2.5 ( ± 0.5 ) atrial fibrillation Aspirin Prevention of recurrent MI INR 3.0 ( ± 0.5 ) indefinitely Mortality ISIS-2 Results Days from Randomization Placebo 13.2% ASA 10.7% SK 10.4% ASA + SK 8.0% Adjunctive Treatment: β-blockers Dose Contraindications Early therapy within 12 hours benefit: ischemic events, nonfatal reinfarction, and mortality ideal candidates tachycardia / tachyarrhythmias and/or HTN continued or recurrent ischemia post-infarction angina given with or without thrombolytics

18 Adjunctive Treatment: β-blockers Adjunctive Treatment: ACE-I Late therapy start with oral therapy goal: secondary prevention still risk of death MOA Dosing When? Within 24 hrs Who? Everyone who can tolerate it Adjunctive Treatment Nitroglycerin dosing IV hrs most benefit CHF large anterior MI persistent ischemia HTN treatment beyond 48 hours avoid Other Treatments Magnesium Major studies LIMIT-2 ISIS-4 Uses Magnesium deficiency treatment of tosades de pointes Morphine Stool softeners ACE-I Trials in AMI Patients TRIAL AGENT # of PATIENTS DURATION Relative Risk of P-value Death During Infarction ISIS-4 captopril 58, days 0.93 ( ) 0.02 GISSI-3 lisinopril 19, days 0.88 ( ) 0.03 CONSENSUS II enalaprilat 6, days 1.11 ( ) 0.26 After Infarction, pts with LV SAVE captopril 2, mon 0.81 ( ) 0.02 AIRE ramipril 2, mon 0.73 ( ) TRACE trandolapril 1, mon 0.78 ( ) <0.001 Other Treatments Calcium Channel blockers use should be limited verapamil and diltiazem contraindications to β-blockers ongoing ischemia non-st-elevation infarction without LV dysfunction without pulmonary congestion add after 24 hrs, continue for 1 year avoid dihydropyridines

19 Other Treatments Antiarrhythmics not for routine use (CAST trial) do not treat isolated PVC runs of accelerated idioventricular rhythm nonsustained VT treat sustained VT treatment