Management of Coronary Artery Disease

Management of Coronary Artery Disease
Primary Prevention Risk factor modification Life style changes Cholesterol medications – Dr. Woodruff Management of disease Secondary Prevention Medications that decrease future events Aspirin, beta blockers, statins Medications that improve cardiac hemodynamics Ace Inhibitors – Dr. Jeffries, Dr. Hunter

Management of Disease (continued) Medications that improve myocardial oxygen supply and demand Nitrates, beta blockers, calcium channel blockers, Dr. Abel, Dr. Lynch Myocardial Revascularization Medications Thrombolytics, Platelet Inhibitors Surgical Management Percutaneous Management

Myocardial Revascularization
Medications Antiplatelet Agents Oral Aspirin, Clopidrogel, Ticlopidine IV Antiplatelet Agents Glycoprotein IIb/IIIa agents Antithrombotic Agents Unfractionated Heparin Low Molecular Weight Heparin Direct Thrombin Inhibitors

Medications Thrombolytic Agents Streptokinase t-PA Tenecteplase, reteplase Coronary Artery Bypass Surgery (CABG) – Dr. Sugimoto Percutaneous Coronary Intervention (PCI)

Percutaneous Coronary Intervention Balloon Angioplasty Stent Placement Atherectomy Radiation Therapy

Cardiac Catheterization

Coronary Intervention

So how do we decide which method of Myocardial Revascularization? Medications Surgical Management Percutaneous Management

Principle # 1 of Myocardial Revascularization
There are three broad indications for myocardial revascularization in coronary artery disease To treat the symptoms of angina pectoris To improve long term survival To prevent nonfatal events such as nonfatal myocardial infarction, congestive heart failure, or serious ventricular arrhythmias

Principle #2 of Myocardial Revascularization
Stable Angina

Stable Coronary Syndromes
Unstable Coronary Syndromes Unstable Angina Myocardial Infarction

Stable Coronary Syndromes
Blood vessel with atherosclerotic plaque Endothelium Smooth muscle cells Fibrous cap The fundamental process in atherosclerotic disease is the formation of plaque in which the inner layer of arteries becomes thickened by lipid deposits and fibrous tissue. Acute coronary events are triggered by rupture or disruption of atherosclerotic plaque and the subsequent thrombotic process in a coronary artery. Plaque //A&P/241.a.1

Management of Stable Coronary Artery Disease
Medical Therapy Aspirin, Calcium Channel Blockers, Beta Blockers, Nitrates Little role for antithrombotic agents, IV glycoprotein IIb/IIIa agents, thrombolytics Myocardial Revascularization Percutaneous Coronary Intervention Coronary Artery Bypass Surgery Which do we choose?

Coronary Artery Bypass Surgery
CABG vs. Medical Therapy Left Main Coronary Artery Disease Patients with 3 vessel coronary artery disease especially with impaired left ventricular function, LAD involvement, or severe myocardial ischemia Relief of Symptoms Any patient that is unresponsive to medical therapy or percutaneous intervention

CABG vs. Medical Therapy Left Main Coronary Artery Disease Patients with 3 vessel coronary artery disease especially with impaired left ventricular function, LAD involvement, or severe myocardial ischemia

Coronary Intervention

Percutaneous Coronary Intervention vs. Medical Therapy
Patients treated with PTCA achieve greater symptomatic benefit than medically treated patients, particularly those patients with the most severe baseline angina Over time this benefit is not as great No study has ever documented a benefit from coronary revascularization compared with medical therapy on survival or infarction

1. Stable Coronary Syndromes 2. Unstable Coronary Syndromes a. Unstable Angina b. Myocardial Infarction

Unstable Angina

Management of Unstable Coronary Artery Disease
Medical Therapy Aspirin, Calcium Channel Blockers, Beta Blockers, Nitrates Much more important role for antithrombotic agents, IV glycoprotein IIb/IIIa agents, thrombolytics Myocardial Revascularization Percutaneous Coronary Intervention Coronary Artery Bypass Surgery Which do we choose?

Medical Management of Unstable Angina
Thrombus formation plays an important role Involves platelet aggregation Involves thrombus formation

Aspirin – decreases platelet aggregation

Heparin – decreases thrombus formation AT 2 1 Thrombin Heparin Pentasaccharide sequence

Low Molecular Weight Heparin

Glycoprotein IIb/IIIa Agents

Could there be a beneficial effect of thrombolytic therapy in patients with non-occlusive thrombus? Studies actually demonstrate a higher mortality with thrombolytic therapy compared to placebo Thrombolysis is known to activate platelets which can lead to progression of the thrombus to total occlusion and MI

Coronary Revascularization
Surgical and Percutaneous revascularizations for Unstable Angina follow the same general guidelines, i. e. Surgery for Left Main, and 3 vessel CAD (especially with proximal LAD involvement, or impaired LV function

Percutaneous Coronary Intervention

Acute ST-Elevation MI Over 1.5 million patients suffer an acute ST-elevation MI in the U.S. each year ST-elevation MI is still the leading cause of mortality in the U.S. —over 500,000 deaths each year 200,000 of all ST-elevation MI patients receive fibrinolytic therapy 5-6% of patients receiving fibrinolytic therapy die within 30 days 1% of patients receiving fibrinolytic therapy experience an intracranial hemorrhage during hospitalization LOW UTILIZATION OF GP IIb-IIIa INHIBITORS IN PCI The high cost of GP IIb-IIIa inhibitor therapy has prohibited generalized acceptance and use of these agents among interventional cardiologists. Safety issues such as bleeding and thrombocytopenia also raised concerns. Importantly, only one trial had prospectively evaluated the combination of stenting and GP IIb-IIIa inhibitor therapy, and that trial was limited to use of Palmaz-Schatz stent, a device useful only in large diameter vessels.

Management of Acute Myocardial Infarction
Primary Goal is to OPEN THE ARTERY Why? Time is muscle and muscle is life

Thrombolytic Therapy Percutaneous Intervention

Goals of Fibrinolytic Therapy
Break-up fibrin mesh that stabilizes the clot Allow normal hemostatic processes to break down remaining clot Restore normal blood flow (TIMI 3 blood flow) through the coronary artery

Medications Thrombolytic Agents Streptokinase t-PA
Tenecteplase, reteplase

Mechanism of Action of Fibrinolytic Therapy
Indirect fibrin degradation Plasminogen Fibrinolytic Plasmin

Thrombolytic Therapy

Management of Acute Myocardial Infarction What Role other antiplatelet and antithrombotic agents?
Aspirin in all patients not allergic, clopidrogel in those that are Heparin (antithrombotics) in those patients receiving selective thrombolytic therapy or those that are at high risk for systemic emboli (large or anterior MI, atrial fibrillation, etc.) Glycoprotein IIb/IIIa agents have no role currently in patients receiving thrombolytic agents, but are beneficial in patients treated with mechanical reperfusion (PCI)

Management of Acute Myocardial Infarction - PCI

A System of Medicine, 1899 Angina Pectoris
Treatment: When first called to a patient in the midst of a paroxysm there is no time for careful observation…(it) urges upon us the immediate use of the vascular antispasmotics. Five to twenty minims of nitrite of amyl may be inhaled. If such means are not at hand some very hot water with a little peppermint essence or brandy may be sipped slowly….

Osler’s Principles and Practice of Medicine, 1938
Coronary Artery Occlusion Treatment: Absolute rest is essential. Except in the mildest cases complete bed rest for six weeks should be planned from the outset. Every effort should be made to reduce anxiety and sources of irritation. Factors which induce an attack should be avoided. The diet should be simple, and the bowels kept open mildly. Oxygen is often helpful…Nitroglycerine tablets under the tongue may give relief of the pain. If pain is severe morphia should be given hypodermically…

The Principles and Practice of Medicine (Harvey, 1980)
When a patient is admitted to the frightening environment of a CCU, his physician must explain in detail the nature of the illness and the need for cardiac monitoring. Morphine remains the drug of choice for relief of pain…Oxygen administration is a routine measure. During the first 24 – 48 hours the patient should be kept at bed rest. After the first 24 – 48 hours uncomplicated patients may be allowed chair rest. Anticoagulants (heparin and coumadin) are necessary to prevent venous thrombi of the legs…Lidocaine is initiated when premature ventricular beats occur with a frequency of six or more per minute…discharge should be at 10 days to 2 weeks.

Pathophysiology of ST-Elevation Myocardial Infarction
Generally caused by a completely occlusive thrombus in a coronary artery Results from stabilization of a platelet aggregate at site of plaque rupture by fibrin mesh platelet RBC fibrin mesh GP IIb-IIIa

Example Radiation Procedure: PREVENT Pt 133-916: Procedure # 1 Treatment: PTCA/Stent
May 1997 September 1997 4 Months Later Post-PTCA Pre-PTCA Unretouched image from PREVENT Trial Data on file at Guidant

ANGIOMAX® Mechanism of Action
(bivalirudin) ANGIOMAX inhibits both fibrin-bound and circulating thrombin. 2 2 Thrombin Thrombin 1 2 2 1 Thrombin Thrombin Bivalirudin (Angiomax®) can interact with clot-bound thrombin, displacing fibrin. Clot-bound thrombin is an important source of clot extension and platelet activation. 1 1 Fibrin A/E//263.a.1

ANGIOMAX® Mechanism of Action
(bivalirudin) ANGIOMAX binds bivalently to thrombin’s active site and exosite 1. 2 C-terminal dodecapeptide (Exosite 1-binding portion) (Gly)4 D-Phe-Pro-Arg-Pro (active-site-binding moiety) D-Phe-Pro-Arg-Pro (active-site-binding moiety) Thrombin Bivalirudin (Angiomax®) is a synthetic molecule, designed as a bivalent direct thrombin inhibitor. The molecule consists of an N-terminal Gly-Pro-Arg-Pro sequence that binds to the active site of thrombin, linked via a four glycine residue spacer to a dodecapeptide analog of the C-terminal of hirudin (an anticoagulant protein isolated from the medicinal leech). Bivalirudin binds specifically to thrombin and directly to both the active catalytic site and the anion-binding exosite 1 with high affinity. Bivalirudin inhibits both circulating and fibrin-bound thrombin. (Gly)4 1 C-terminal dodecapeptide (Exosite 1-binding portion) Refer to accompanying Package Insert for complete Angiomax prescribing information. A/BR//259.a.1

Heparin’s limitations
The heparin:AT complex inhibits only soluble thrombin… not fibrin-bound thrombin. 2 Heparin AT Thrombin 1 2 2 Thrombin The heparin:AT complex can’t inhibit clot-bound thrombin. Thrombin is bound to fibrin within the developing clot. Free heparin binds simultaneously to thrombin at exosite 2, and to fibrin. Heparin also increases thrombin’s affinity for fibrin. Therefore, the heparin portion of the heparin:AT complex cannot access the occupied thrombin binding site, and cannot form a ternary complex necessary for inhibition. Fibrin-bound thrombin is enzymatically active and is an important factor in clot extension. Thrombin 1 1 Fibrin Heparin increases the affinity of thrombin for fibrin. X/E//257.a.1

Heparin mode of action Indirect effect on thrombin via AT AT Thrombin
2 1 Thrombin Heparin Heparin, the most widely used anticoagulant in PCI, has many limitations resulting from its mechanism of action. Heparin’s anticoagulant effect is indirect, relying on the presence of functional antithrombin (AT). In acute conditions the amount of AT can be depleted. Heparin binds to thrombin at exosite 2, and to AT via a specific pentasaccharide sequence on the heparin chain. Heparin, AT and thrombin form a ternary complex. The affinity of AT for thrombin is potentiated by heparin, which effects a conformational change of AT within this complex. Pentasaccharide sequence X/BR//255.a.1

Plasma Clotting cascade
Thrombus formation Thrombin is the link between tissue injury, coagulation, and platelet response. Thrombin Platelet activation Prothrombin Fibrinogen Fibrin Platelet aggregation ADP TXA2 Plasma Clotting cascade Collagen Tissue Factor THROMBUS Thrombin is a procoagulant that plays a critical, if under-appreciated role in thrombosis through its actions in the coagulation process and as a platelet activator. Thrombin plays a critical and central role in thrombogenesis through: Converting fibrinogen to fibrin strands that hold the clot together, Regulating its own production via positive and negative feedback loops to further promote thrombin generation, Stabilizing the fibrin clot through activation of factor XIII and inhibiting fibrinolytic pathways. Thrombin is the link between tissue injury and cellular response. Thrombin: Is the most effective agonist for platelet activation Elicits multiple responses in platelets, endothelial, and other cells Because of the central role that thrombin plays, and effective thrombin-specific inhibitor is important in thrombosis. Thrombin is a critical mediator in coagulation Elicits multiple responses in platelets //A&P/246.a.1

Thrombus formation Occlusive thrombus
The thrombin bound to fibrin within the developing thrombus serves to amplify the coagulation process, potentially extending the thrombus into an occlusive formation. Thus, thrombin generation, platelet activation and vascular inflammation lead to vessel thrombus formation, which in turn leads to vessel occlusion and downstream passage of clot, myocardial ischemia and infarction. //A&P/245.a.1

Thrombus formation Fibrin strands form Fibrin
Blood coagulation is also triggered as a result of plaque disruption and tissue injury. Coagulation factors assemble and are activated on the surface of platelets. Thrombin is formed, which forms of fibrin strands from fibrinogen. The fibrin enmeshes the platelets in the formation of a thrombus. //A&P/244.a.1

Thrombus formation Disrupted plaques are behind 75% of thrombi responsible for ACS Procedural Injury Spontaneous e.g., balloon deployment or Acute coronary events are triggered by rupture or disruption of atherosclerotic plaque and the subsequent thrombotic process in a coronary artery. Disrupted plaques, which can result in decreased coronary blood flow or obstruction, are a fundamental step in the pathogenesis of acute coronary syndromes and are found beneath 75% of the thrombi responsible for acute coronary syndromes. Arterial injury can result from spontaneous plaque rupture or procedural injury. Percutaneous coronary intervention is inherently thrombogenic. Deep vessel wall injury induced by balloon dilatation and stent implantation triggers thrombosis resulting in thrombin generation, platelet activation and a profound, systemically detectable inflammatory response. Injured endothelium //A&P/242.a.1

Thrombus formation Platelet adhesion, activation, and aggregation
Platelets Exposure of the subendothelial structures as a result of plaque disruption and tissue injury stimulates the formation of a platelet plug. Platelets adhere to the site of injury and are activated. Platelets expose surface receptors that bind fibrinogen and von Willebrand factor, allowing aggregation. Activated platelets also release the contents of their alpha-granules and serve as a surface for assembly of coagulation factors. //A&P/243.a.1

Primary Prevention Risk factor modification Life style changes Cholesterol medications – Dr. Woodruff Management of disease Secondary Prevention Medications that decrease future events Aspirin, beta blockers, statins Medications that improve cardiac hemodynamics Ace Inhibitors – Dr. Jeffries, Dr. HunterMyocardial Revascularization Medications Antiplatelet Agents Oral Aspirin, Clopidrogel, Ticlopidine IV Antiplatelet Agents Glycoprotein IIb/IIIa agents Antithrombotic Agents Unfractionated Heparin Low Molecular Weight Heparin Direct Thrombin Inhibitors

Management of Coronary Artery Disease

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