Course Authors
Romeo A. Majano, M.D., and H. Vernon Anderson, M.D.
Dr. Marjano is Cardiology Fellow and Dr. Anderson is Professor of Medicine, University of Texas Medical.
Dr. Majano reports no commercial conflict of interest. Dr. Anderson reports no commercial conflict of interest.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe the pathophysiology underlying the unstable coronary syndromes
Discuss the rationale for the combination medical therapies employed for unstable coronary syndromes, the common drug agents used and their actions
Discuss the basic elements of clinical risk stratification in unstable coronary syndromes, and the arguments for early invasive or early noninvasive approaches.
Dr. Anderson returns to Cyberounds® with the help of one of our Cardiology Fellows, Dr. Romeo Majano, to give us a superb update on the treatment of unstable coronary syndromes. A number of studies have been published in the past two years, which have dramatically changed how we treat these patients. Two main strategies have emerged as being very important. First, early administration of a glycoprotein IIb/IIIa antagonist seems to be very helpful; second, an early trip to the cathlab for diagnostic (and, frequently, therapeutic) angiographic interventions seems to produce superior outcomes. Please welcome Drs. Anderson and Majano to Cyberounds®!
Richard W. Smalling, M.D., Ph.D., Cardiovascular Moderator
The spectrum of acute coronary syndromes encompasses
- stable angina,
- unstable angina with or with out non Q-wave infarction, also called non-ST-segment elevation MI (NSTEMI), and
- acute ST-segment elevation myocardial infarction.
The focus of this Cyberounds® review is the second portion of this disease spectrum: unstable angina.
Unstable angina (UA) is a relative medical emergency that mandates hospitalization with aggressive medical management to both rule out myocardial infarction, or to prevent MI or subsequent cardiac death. UA is one of the most frequently cited diagnoses for hospital admissions in the United States and the numbers are on the rise.(10) Up to 6% to 8% of patients with UA will have nonfatal myocardial infarction or die one year after diagnosis.(27),(28) The various clinical subsets that are encompassed under the diagnosis of unstable angina are new-onset angina, progressive angina at rest and post-MI angina.
Pathophysiology
The clinical differentiation between UA and acute myocardial infarction can sometimes be difficult. The chest discomfort is typically milder in unstable angina and lasts less than 30 minutes. Nevertheless, measurement of cardiac isoenzymes and serial ECGs are required to distinguish acute MI from unstable angina, as a result the correct diagnosis is made later, after these data are gathered.
At the center of the pathophysiology of unstable angina is atherosclerotic plaque fissuring or ulceration. This leads, in turn, to platelet adhesion and aggregation with subsequent transient thrombosis and dynamic vasoconstriction at the site of plaque disruption.(1),(2),(3)
Platelet activation occurs as the exposed collagen in the arterial wall binds to specific binding sites largely through platelet membrane glycoprotien Ib receptors. Vasoconstriction is mediated by local production of thromboxane A2, serotonin, leukotrienes, adenosine diphosphate, endothelin, platelet-activating factor, thrombin and oxygen-derived free radicals.(4),(5),(6),(7),(8)
In addition, unstable angina may rarely occur when vasospasm without platelet ulceration is superimposed on progressive atherosclerotic disease, leading to decreased blood flow and ischemia.(9) Alternatively, increases in myocardial oxygen demand because of hypertension or conditions that cause tachycardia can precipitate unstable angina if occlusive coronary artery disease is present. Obviously, the pathophysiology of unstable angina is multifactorial, although plaque disruption is the key initiating event in most cases.
Another point of discussion is the type of atherosclerotic plaque that is vulnerable to the processes outlined above. The degree of luminal narrowing at the site of an atherosclerotic plaque seen on a coronary angiogram does not predict its probability of ulceration or fissuring.(29),(30),(31),(32) Nevertheless, certain morphologic characteristics of the unstable coronary plaque, such as a thin fibrous cap, the presence of numerous inflammatory cells beneath the atherosclerotic plaque surface and a large adjacent lipid core, are all associated with a propensity to rupture/fissure.(33),(34)
The involvement of inflammation in the pathophysiology and prognosis of unstable coronary syndromes is suggested by the fact that the risk for future coronary events seems to be associated with elevations of C-reactive protein, fibrinogen and interleukin 6.(11),(12),(13),(14) Casscells, Willerson and associates have demonstrated temperature heterogeneity in atherosclerotic plaques in human carotid arteries also suggesting inflammation as an important component of this process. In one study by Haverkate et al., 2,121 patients including 1,030 with the diagnosis of unstable angina were followed for two years. The risk of death or MI was approximately twice as great in those patients where the C-reactive protein level was >0.36 mg/dl (highest quintile) compared to the lowest quintile.(44) In a sub-study of patients of the TIMI 11A study, the 14-day mortality was considerably greater among patients with C-reactive protein levels >1.55 mg/dl with or without elevated troponin T's. The strongest predictor of 14-day mortality was an elevated troponin T together with increased C-reactive protein.(45)
Medical Treatment
The goals of therapy in patients with unstable angina are based on optimizing the balance between myocardial oxygen demand, oxygen delivery and stabilization of the atherosclerotic plaque. Modalities of therapy include vasodilators, anti-thrombotics, anti-platelet agents and pharmacology designed to decrease cardiac work. Initial interventions in these patients should include rest, supplemental oxygen and control of high blood pressure, as well as tachycardia if it exists.
Reduction of Demand State
Beta-blockers should be initiated immediately in patients without contraindications. A meta-analysis of studies of patients with unstable angina showed a 13% reduction in the risk of myocardial infarction in beta-blocker treated patients.(46) In addition, even though short-acting and long-acting preparations of these agents have shown benefit, the short acting preparations are usually preferred initially.
Calcium channel blockers may be used in patients with hypertension refractory to initial measures including intravenous nitroglycerin, or in patients for whom beta-blockers are contraindicated. If these drugs are to be used the non-dihydropyridines (i.e., verapamil or diltiazem) offer the benefits of heart rate and contractility reduction over the dihydropyridines like nifedipine. Evidence suggests that patients with unstable angina treated with nifedipine alone have increased mortality probably as a result of the reflex tachycardia that this calcium-channel blocker may produce.(47)
Vasodilators, e.g., nitrates, promote epicardial coronary artery dilatation but more importantly they promote dilatation of venous capacitance vessels, which, in turn, decreases myocardial wall stress and oxygen consumption.
Intravenous nitroglycerin should be initiated, beginning at doses of 5-10 micrograms a minute. The ideal dose will be one that decreases systolic blood pressure by at least 8 to 10 mm Hg, while avoiding systemic arterial hypotension, and/or one that increases heart rate by 5 to 8 beats per minute without increasing it above 90 beats per minute. Intravenous nitroglycerin is initially preferred in the first 24 to 36 hours and replaced (if needed) by an oral regimen.
Antiplatelet Agents
Aspirin is useful in all acute coronary syndromes including unstable angina. The ingestion of one 325 mg tablet is the single most cost-effective adjunctive medication in patient management. This medication has been shown to decrease the risk of death and myocardial infarction.(35),(36),(37) Aspirin interferes with platelet aggregation by inhibiting thromboxane A2 synthesis, and diminishing inflammation and platelet-white blood cell interactions. Contraindications for aspirin therapy include allergies and severe thrombocytopenia. In aspirin-allergic patients, ADP transduction inhibitors like clopidogrel may be used.
Ticlopidine (Ticlid) inhibits platelet aggregation by acting on transduction of the ADP signal. Like aspirin, ticlopidine, given as 250 mg twice a day, has also been shown to decrease the incidence of myocardial infarction and death in patients with unstable angina.(38) Because of a small but potentially catastrophic incidence of Thrombotic Thrombocytopenic Purpura (TTP) with the use of this medication, the newer ADP transduction inhibitor, clopidogrel (Plavix), is currently preferred. One suggested regimen is a loading dose of clopidogrel of 300 mg given orally followed by 75 mg once a day.
In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial,(15) clopidogrel (75 mg/d) compared to aspirin (325 mg/d) in 19,185 patients achieved an overall risk reduction for the combined risk of ischemic stroke, myocardial infarction or death from vascular disease (5.3% vs. 5.8%; p-value=0.04). The combination of either ticlopidine or clopidogrel with aspirin has not been fully evaluated but may, theoretically, yield advantages.
In the recent CURE trial (Clopidogrel in Unstable angina to prevent Recurrent Events), the addition of clopidogrel to aspirin in 12,582 patients with unstable angina decreased the incidence of cardiovascular events by 20% (relative risk reduction), as well as producing an increase of 1% in mayor bleeding adverse events. During follow up (3-12 months), the incidence of cardiovascular death, myocardial infarction, or stroke was 11.47% in the aspirin-only group and 9.28% in the clopidogrel plus aspirin group.
Intravenous Platelet Glycoprotein IIb/IIIa Inhibitors
Platelet aggregation at the site of endothelial injury is mediated by cross-linkages of platelet surface membrane receptors, the Glycoprotein (GP) IIb/IIIa receptor. The GP IIb/IIIa receptor is the most abundant on the platelet surface, with approximately 50,000 receptors per platelet.(17) Once a platelet becomes activated, the Glycoprotein (GP) IIb/IIIa receptors on the platelet surface undergo a conformational change, transforming the receptors from a ligand-unreceptive to ligand-receptive state. Ligand-receptive GP IIb/IIIa receptors bind fibrinogen molecules, which bridge adjacent platelets, thereby facilitating aggregation and the formation of a platelet thrombus.
Three intravenous GP IIb/IIIa inhibitors are currently available and all have demonstrated benefit across the spectrum of acute coronary syndromes. Abciximab (Reopro), a monoclonal antibody, tirofiban (Aggrastat), a non-peptide, and the peptide, eptifibatide(Integrilin), all have a rapid onset of antiplatelet activity. Recovery of platelet function after discontinuation is more rapid with eptifibatide and tirofiban because of their reversible binding to the GP IIb/IIIa receptors.(18),(19) Recovery after abciximab is much slower since binding to the receptor is irreversible. Hence, abciximab's effect disappears only as new platelets are incorporated to the blood steam.
The efficacy of GP IIb/IIIa inhibitors in patients with unstable angina has been evaluated in several clinical trials (Table 1).
The benefits at 30 days in prevention of the combined endpoints of mortality and MI are clearly improved over placebo.(20) Therefore, these agents should be considered in the management of patients with UA, especially in those with persistent symptoms, ST-segment depressions and in those patients who will undergo coronary angiography. The recommended doses for these agents are shown in Table 2. It is very important, when using these drugs, to monitor platelet counts, as severe thrombocytopenia may occur in up to 1% of patients treated. Platelet transfusions are indicated in the case of severe bleeding or a platelet count less than 50,000.
Table 2. Currently Available Glycoprotein IIb/IIIa Receptor Inhibitors with Recommended Dosing Regime.
| Table Headline | |
|---|---|
| Abciximab (ReoPro®) | 0.25 mg/kg IV bolus then 0.125 mcg/kg/min (max 10 mcg/min) IV infusion for 12 hours (coronary intervention) |
| Eptifibatide (Integrilin®) | 180 mcg/kg IV bolus, then 2/mcg/kg/min IV infusion for 72 hours (acute coronary syndrome dose) |
| Tirofiban (Aggrastat®) | 0.4 mcg/kg/min IV bolus over 30 minutes, followed by 0.1 mcg/kg/min IV infusion for 48-108 hours or until 12-24 hours after percutaneous coronary intervention |
Antithrombotics
Since both platelet aggregation and thrombin generation are involved in the thrombotic process, there is obvious rationale for the use of anti-thrombotics in the treatment of unstable angina. Weight-based anticoagulation with un-fractionated heparin should be adjusted to maintain a partial thromboplastin time (PTT) between 60 to 80 seconds or an activated clotting time (ACT) of 250 to 35O seconds.
A small percentage of patients treated with un-fractionated heparin can develop heparin-induced thrombocytopenia (HIT), and some may develop the more serious heparin-induced thrombosis syndrome (HITS), which is associated with a high incidence of thomboembolic sequela.(22) The etiology of this reaction is an immune response to heparin-platelet factor-4 complex. Immunoglobulins induced by these complexes may activate platelets by provoking cytokine production and complement activation. The incidence of HIT is about 1.3% of treated patients with porcine heparin and an even higher incidence with bovine heparin.
Low-molecular weight heparins act primarily through antithrombin III-mediated inhibition of Factor Xa as well as through some direct thrombin inhibition.(23) In addition, as is also true with conventional heparin, low-molecular weight heparin promotes the release of tissue factor pathway inhibitor, which may contribute to its anti-thrombotic effect.(23)
Three agents -- dalteparin (Fragmin®), enoxaparin (Lovenox®) and nadroparin (Table 3) -- have been compared to un-fractionated heparin in large studies of patients with unstable angina with or without myocardial infarction.
Table 3. Dosage and Anti-Factor Xa:Anti-Factor IIa Ratios of Low Molecular Weight Heparins Studied in Unstable Angina.
| Preparation | Anti-Factor Xa: Anti-Factor IIa Ratio | Mean Molecular Weight | Dosage |
|---|---|---|---|
| Enoxaparin | 3.8 | 4200 | 1 mg/kg SC q 12 hours or 1.5 mg/kg SC q 24 hours |
| Nadroparin | 3.6 | 4500 | |
| Dalteparin | 2.7 | 6000 | 120 units/kg up to 10,000 units SC q12 hours |
The Fragmin During Instability in Coronary Artery Disease (FRISC trial) found an early reduction (7 days) in death and recurrent MI (1.8% vs. 4.8%) in the dalteparin-treated group.(24) In the Fraxiparin vs. Unfractionated Heparin (FRAXIS trial) of 3,468 patients, nadroparin twice daily was compared to un-fractionated heparin and no significant differences in the occurrence of death, MI, or refractory or recurrent angina were found.(25) The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial and the TIMI 11B trial demonstrated a 20% reduction in the combined end points of death and ischemic events from hour 48 to day 43 without an increase in major hemorrhage.(26)
These last two trials have shown that enoxaparin is clinically more effective than un-fractionated heparin. Therefore, this agent use should be strongly considered in patients with unstable angina. One last point to consider is that the PTT and ACT will not reflect degree of anticoagulation with these agents and that protamine will not completely reverse their effect.
Direct Thrombin Inhibitors
Hirudin, hirilog, efegatran, inogatran and argatroban are direct inhibitors of clot bound thombin. Hirudin has been evaluated in acute coronary syndromes with or without ST-segment elevation in the GUSTO-IIb and OASIS-2 trials. Nevertheless, it is not yet clear if these agents have a role in the routine management of acute coronary syndromes. Their current indications are limited to patients with heparin-induced thrombocytopenia or heparin-induced thrombosis syndrome.
Lipid Lowering Drugs
LDL cholesterol lowering with statins has consistently proven beneficial in the primary and secondary prevention of cardiovascular events. However, patients with unstable coronary syndromes within 3-6 months were excluded from these landmark trials. Nonetheless, new evidence suggests that they are beneficial and that their benefit in patients with acute coronary syndromes might occur very early on.
The MIRACL study (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) was a randomized, double-blinded trial, which enrolled 3,086 patients with unstable angina or non-Q-wave Myocardial infarction. Treatment with atorvastatin 80 mg/day or placebo was initiated 24-96 hours after diagnosis of an acute coronary syndrome. There were no significant differences in risk of death, nonfatal myocardial infarction or cardiac arrest between the atorvastatin and the placebo groups, but the atorvastatin group had a lower risk of symptomatic ischemia requiring emergency re-hospitalization in the first 16 weeks of therapy (2% vs. 8.4%; P-value=0.02).(43)
Risk Stratification and Coronary Revascularization Strategies
It is clear that once the diagnosis of unstable angina is entertained the wheels of aggressive medical care should start turning. Nevertheless, taking these patients to the cardiac catheterization laboratory quickly has been a subject of several studies and much debate. Although the majority of patients with UA will do well with standard medical therapy, about 50-60% ultimately will require coronary angiography and revascularization.(57),(58) Therefore, risk stratification to try to identify this group of patients is important and has been centered on clinical presentation, electrocardiographic findings, laboratory markers and stress testing.
Patients admitted with new or reversible ST-segment changes of >0.5 mm or left bundle branch block have a 15.8% incidence of death or myocardial infarction at one year compared with an 8.2% percent in patients with unstable angina and no EKG changes.(48),(49) Noteworthy is the fact that isolated T-wave inversions are not associated with an adverse prognosis.(50),(51)
Serum markers of myocardial necrosis such as creatine kinase (CK), CK-MB isoenzymes, and troponin T and I are also of importance in risk assessment in these patients. In one study of 976 patients with unstable angina or non-Q-wave MI, troponin T levels greater or equal to 0.06 ng/ml were associated with a significant increase in the risk of cardiac death or MI at 5-month follow up.(52) In other studies, the independent prognostic value of troponin T was found to be greater than that of the EKG and creatine kinase-MB prophiles.(53) In addition, the risk of death at six weeks in patients with UA or non-Q-wave MI and troponin I >0.4 ng/ml is increased (3.7% vs. 1%; p-value=<0.001) and continues to increase at higher tropinin I levels.(54) The prognostic value of other laboratory parameters such as C-reactive protein was mentioned above.
Treatment recommendations for patients with unstable angina (non-ST-elevation MI) have been based on trials that have found either no advantage or increased mortality risk with an early invasive approach. Nevertheless, these trials were performed prior to the use of GP IIb/IIIa inhibition and coronary stents. New data from the TACTICS (Treat Angina with Aggrastat + Determine Cost of Therapy with an Invasive or Conservative Strategy)-TIMI 18 trial suggest the contrary. In this trial, 2,220 patients with UA were randomized to tirofiban/medical therapy and early invasive management or conservative care. The composite endpoints of death, MI or re-hospitalization for UA were reported at 15.9% among the invasively managed and at 19.4% in the conservative arm (P-value = 0.025). In addition, the troponin T positive patients appeared to benefit the most from the early invasive approach.(55)
In another recent study, the FRISC II (Fast Revascularization during InStability in Coronary artery disease), it was shown that early invasive treatment (within 7 days), when combined with optimal medical pretreatment with dalteparin, aspirin and anti-anginal medications, is associated with improved clinical outcomes, as compared to a "watchful waiting" approach based on noninvasive therapy.(56)
In conclusion, the data appear to suggest that patients with unstable angina, especially those high-risk patients (who have angina at rest, prolonged angina, dynamic ST-segment changes, hemodynamic instability or positive serum markers of ischemia) appear to benefit from an early invasive approach. Nevertheless, the value of stress testing in the lower risk group of patients who stabilize with medical therapy is still a valued strategy.
Summary
When the diagnosis of unstable angina is a possibility, the patient should be considered as a relative medical emergency. Non-ST-elevation myocardial infarction needs to be excluded with the use of serum markers of myocardial necrosis. Medical management needs to be aggressive and should include interventions to decrease myocardial oxygen consumption and cardiac work, anti-platelet agents, anti-thrombotics, vasodilators and lipid lowering medications (i.e., statins).
This Cyberounds® has reviewed the existing clinical evidence to support these medical interventions. In addition, patients with unstable angina, especially those high-risk patients, appear to benefit from early coronary angiography and intervention. To conclude, with the increasing admission of patients with UA to hospitals around the world, the clinician needs to understand the current evidence surrounding the diagnosis, therapy and prognosis of patients in this portion of the spectrum of acute coronary syndromes.