eMedicine Specialties > Cardiology > Coronary Artery Disease

Unstable Angina: Treatment & Medication

Author: Walter A Tan, MD, MS, Associate Professor of Medicine, Clinical Associate Professor of Surgery, Director of Stroke Interventions, Associate Director of Cardiac Catheterization, Department of Cardiovascular Sciences, Brody School of Medicine, East Carolina University
Coauthor(s): David J Moliterno, MD, Professor of Medicine, Jefferson Morris Gill Professor of Cardiology, Chief, Division of Cardiovascular Medicine, University of Kentucky; Vice Chairman of Internal Medicine, Chandler Medical Center; Medical Director, Gill Heart Institute; Steven James Filby, MD, Fellow in Interventional Cardiology, The Cleveland Clinic Foundation
Contributor Information and Disclosures

Updated: May 13, 2009

Treatment

Medical Care

Patients with unstable angina require admission to the hospital for bed rest with continuous telemetry monitoring. Intravenous access should be obtained and supplemental oxygen started. Because the course of unstable angina is highly variable and potentially life threatening, the aggressiveness of approach needs to be established expeditiously.

The key in this decision-making is to select the initial management approach: invasive or conservative strategy.

Clinical tip: The standard of care dictates that at the minimum, aspirin, beta-blockers, and statins should be given promptly to all patients presenting with acute coronary syndrome unless they have a valid contraindication.

• Aspirin
  • Administer chewable aspirin 162-325 mg promptly to patients who are not at high risk for bleeding, who do not have ongoing bleeding, or who do not have true intolerance or allergy.
  • Timeliness of administration is essential because platelet aggregation is central to acute coronary syndrome, and the peak effect of aspirin can be observed within as short a time as 30 minutes.
  • Several studies have shown approximately 40-50% risk reductions for death or myocardial infarction with aspirin at 30-day follow-up and at up to 1-year follow-up in this patient population.
  • In the event of percutaneous coronary intervention, aspirin 162-325 mg should be given for at least 1 month after bare metal stent implantation, 3 months after sirolimus-eluting stent implantation, or 6 months after paclitaxel-eluting stent implantation. Thereafter, aspirin 75-162 mg should be continued indefinitely.
• Beta-blockers
  • Several controlled trials have demonstrated the benefits of beta-blockers in the treatment of myocardial infarction. These benefits have to be counterbalanced by the potential complications of heart failure or cardiogenic shock that have been demonstrated when beta-blockers are used in hemodynamically compromised patients.
  • Oral beta-blockers (eg, metoprolol) are preferred over intravenous therapy. Recent studies have associated intravenous beta-blocker therapy with an increased risk of cardiogenic shock in patients presenting with heart failure or high-risk features.
  • Intravenous beta-blockers may still be indicated in select patients with tachycardia or hypertension and ongoing chest pain.
• HMG coenzyme A reductase inhibitors (statins)
  • Multiple large, randomized, secondary prevention trials including the Heart Protection Study have demonstrated significant mortality benefit from statin therapy.
  • Recent results from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) TIMI trials suggest that early initiation of antilipidemic agents (statins) in patients with ACS can decrease adverse events within a relatively short term.⁸
  • The PROVE-IT TIMI 22 trial demonstrated a benefit from statin therapy even in patients with acute coronary syndrome presenting with relatively low serum LDL-C levels (LDL-C <100 mg/dL suggesting that the target LDL-C level should be less than 80 mg/dL in these patients.
  • Statin therapy should be initiated before hospital discharge to improve patient adherence. Additional clinical benefit may be gained by starting therapy within 24-96 hours of admission.
• ACE inhibitors
  • ACE inhibitors are of particular benefit in patients with large anterior infarctions especially with compromised left ventricular function (eg, from STEMI) but without hypotension. The benefit in patients with unstable angina is less clear.
  • Currently, ACE inhibitors are recommended in patients with left ventricular dysfunction or congestive heart failure, diabetes, and hypertension.
  • ACE inhibitor therapy may be started within 24 hours of admission and titrated for blood pressure effect.
• Clopidogrel
  • Clopidogrel is recommended as the antiplatelet of choice in those patients who are intolerant to aspirin, and it is also used adjunctive antiplatelet agent in addition to aspirin.
  • The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial showed that clopidogrel in addition to aspirin (vs aspirin alone) significantly reduced the composite primary end point of cardiovascular death, myocardial infarction, or stroke with early benefit shown at 24 hours.
  • Percutaneous coronary intervention CURE and Clopidogrel for the Reduction of Events During Observation (CREDO) trials have shown significant benefit in those patients with unstable angina who undergo coronary intervention; pretreatment 6 hours before intervention was associated with improved outcomes. A loading dose of 600 mg may offer more effective platelet inhibition than 300 mg; increasing the loading dose beyond 600 mg has not shown benefit.
  • Patients who later undergo coronary artery bypass graft (eg, those with multivessel disease) while receiving clopidogrel have an increased risk of major bleeding and requirement for surgery for bleeding. Clopidogrel is recommended to be withheld for at least 5 days prior to elective coronary artery bypass graft because of this increased risk of bleeding. Thus, many physicians choose to hold clopidogrel until the patient's coronary anatomy is defined during coronary angiography.
  • Even with the above discussion in mind, patients who are clinically unstable should receive clopidogrel or be taken immediately for coronary angiography.
• Glycoprotein IIb/IIIa antagonists
  • In patients who are undergoing percutaneous coronary intervention (ie, those with high-risk characteristics), therapy should be started with a small-molecule intravenous glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor for medical stabilization.
  • If the patient can be catheterized within the first few hours of presentation and is pain free, an acceptable alternative is to simply commence GP IIb/IIIa inhibitor in the catheterization laboratory in conjunction with percutaneous revascularization.
  • All of the currently available GP IIb/IIIa inhibitors, namely, abciximab, eptifibatide, and tirofiban, have been shown to increase the safety of acute percutaneous coronary intervention, with relative risk reductions in adverse events (including 30-d mortality and infarction) of approximately 30-50%.
  • Of the currently used GP IIb/IIIa inhibitors, only eptifibitide and tirofiban have been shown to be of benefit in high-risk patients treated with medical management alone. The relative reduction in adverse events observed in this setting is on the order of 5-7%. In addition, a recent meta-analysis of 6 randomized trials (with 31,400 patients) failed to show a mortality benefit in those patients who did not undergo percutaneous coronary intervention. Judgment is required to decide whether this small benefit offsets the risk of bleeding events.
• Heparin
  • Low molecular weight heparin (LMWH) and intravenous unfractionated heparin (UH) are 2 comparable anticoagulation strategies in the treatment of unstable angina.
  • The many potential benefits of using LMWH include lower rates of bleeding, cost savings, and reduced incidence of heparin-induced thrombocytopenia. Many interventional cardiologists are uncomfortable using LMWH because anticoagulation activity cannot be measured during percutaneous coronary intervention.
  • The Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events (ESSENCE) investigators compared LMWH (enoxaparin) with unfractionated heparin. The revascularization rate in this study was intermediate at about 30%. The 30-day composite rates of death, myocardial infarction, or recurrent angina were significantly reduced for subjects taking LMWH (19.8% vs 23.3%, relative risk reduction of 15%). However, excess minor bleeding occurred in 11.9% versus 7.2% of cases, an important proportion of which were only due to injection site ecchymosis.
  • The Superior Yield of the New strategy of Enoxaparin Revascularization and Glycoprotien IIb/IIIa Inhibitors (SYNERGY) trial randomized high-risk patients with NSTEMI (including those with unstable angina) to unfractionated heparin or enoxaparin. All enrolled patients were treated with an early invasive strategy. No difference in composite end point (death or myocardial infarction by 30 d) was detected. Enoxaparin was associated with more major bleeding episodes than with unfractionated heparin (9.1% vs 7.6%); however, much of this effect was attributed to patients who crossover to unfractionated heparin after receiving an initial dose of enoxaparin.
  • The Organization to Assess Strategies for Ischemic Syndromes-5 (OASIS-5) trial compared fondaparinux and enoxaparin in the treatment of unstable angina and NSTEMI. The number of patients with death, myocardial infarction, or refractory ischemia was similar in both treatment groups. The rate of major bleeding was lower in the fondaparinux group than the enoxaparin group at 9 days; and fondaparinux treatment was associated with significant reductions in death, myocardial infarction, and stroke at 180 days. However, fondaparinux was associated with a low but increased rate of guiding catheter thrombus, and therefore not recommended if urgent percutaneous coronary intervention is foreseen.
  • Enoxaparin, fondaparinux, and unfractionated heparin are safe alternative agents used in the treatment of unstable angina. Switching agents (ie, from LMWH to UH) has been associated with excess bleeding and reduced clinical benefit. In patients with an intended conservative strategy, treatment with LMWH may be preferred.
• Nitrates
  • Intravenous nitrate agents may be used in the treatment of ischemic chest pain, symptoms of heart failure, or hypertension but are not associated with appreciable long-term clinical benefit.
  • These agents are contraindicated for those with right ventricular infarction, hypertrophic cardiomyopathy, and severe aortic stenosis.
• Direct thrombin inhibitors
  • Direct thrombin inhibitors, such as hirudin, lepirudin, or bivalrudin, are potential alternatives to heparin. These agents are much more costly than conventional anticoagulation agents and may be associated with higher rates of bleeding.
  • In a large meta-analysis comparing direct thrombin inhibitors and heparin in the treatment of patients with acute coronary syndrome, there was a slight reduction in myocardial infarction (2.8% vs 3.5%). Treatment with hirudin was associated with an increased risk of major bleeding compared with heparin, whereas treatment with bivalirudin was associated with a lower risk of major bleeding.
  • The benefits of bivalirudin in patients who undergo coronary stent implantation has been demonstrated in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 (REPLACE-2) and Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trials. However, at present, data to recommend routine bivalirudin in patients with unstable angina are insufficient.
  • Direct thrombin inhibitors should not be routinely used in the treatment of unstable angina but may be of clinical benefit in special circumstances (eg, heparin-induced thrombocytopenia).
• Other medications
  • Calcium channel antagonists, antibiotics against Chlamydia pneumoniae, or fibrinolytic agents currently have no established role in the setting of unstable angina.
  • Most of the clinical trials of fibrinolytic therapy showed a tendency for more nonfatal infarctions attributed to procoagulant effects in the context of a nonocclusive thrombus.
  • While the available data suggest similar efficacy of ticlopidine to aspirin, the use of this drug in the United States has been drastically reduced since reports of associated fatal thrombotic thrombocytopenic purpura.

Cardiac Catheterization

• Patients with unstable angina and the following clinical characteristics should be referred for immediate cardiac catheterization:
  • Cardiogenic shock
  • Severe left ventricular dysfunction
  • Angina refractory to medical therapy
  • Acute mitral regurgitation
  • New ventricular septal defect
  • Unstable tachyarrhythmias
  • In patients with unstable angina but without the clinical characteristics listed above, whether an invasive strategy yields benefits over conservative management is controversial. The debate has been settled in light of data from large randomized clinical trials.
  • Among patients presenting with unstable angina, approximately 15% have 1-vessel coronary artery disease, 35% have 2-vessel coronary artery disease, and 50% have 3-vessel coronary artery disease. The incidence of left main disease is roughly 5-10%. The rate of thrombus detected at coronary angiography ranges widely from less than 10% among those with chest pain in the previous month to more than 50% among those with rest angina in the preceding 24 hours. This high prevalence of significant disease has led some to advocate routine angiography, whereas the imperfect ability to predict who will develop long-term adverse events has encouraged a tendency toward permissive revascularization.
  • Older clinical trials, such as TIMI III-B, the Veterans Affairs Non–Q-wave Infarction Strategies In-Hospital (VANQWISH) study, and the Medicine Versus Angiography in Thrombolytic Exclusion (MATE) trial did not show superiority of routine catheterization compared with the conservative approach of performing catheterization in only those with recurrent ischemic symptoms or a significantly positive stress test result. This is because of the early hazard observed with angioplasty performed in the acute setting of myocardial ischemia, which resulted in heightened rates of abrupt vessel closure, stent thrombosis, or myocardial infarction.^9,10
  • The introduction of platelet GP IIb/IIIa inhibitors has neutralized most of these periprocedural complications so that an early benefit is now observed with contemporary percutaneous coronary intervention. The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS/TIMI-18) study showed very low 30-day and 6-month composite end point of death, myocardial infarction, or rehospitalization for the early invasive strategy. This entailed the administration of intravenous GP IIb/IIIa (tirofiban) coupled with angiography within 48 hours and a 60% revascularization rate within the index hospitalization compared with 36% for conservative therapy. The benefit of early invasive strategy was more substantial in intermediate- and high-risk patients (ie, those with TIMI score 3).
  • The Fragmin During Instability in Coronary Artery Disease II (FRISC-II) trial showed a significant reduction in death or myocardial infarction at 6 months in patients with unstable angina who underwent early catheterization and revascularization as compared with a noninvasive strategy. This treatment difference was primarily driven by a lower rate of myocardial infarction in the invasive arm (7.8% vs 10.1%). Patients in the invasive arm also had a significant reduction in angina and hospital readmission rates. Again, the treatment benefits were more pronounced in those with ST-segment depression and cardiac marker elevation.¹¹
  • RITA 3 also found benefit with the invasive strategy over conservative management in intermediate- to high-risk patients with NSTEMI and ischemic changes on ECG or elevated troponin levels. The combined end point of death, myocardial infarction, and refractory angina at 4 months was significantly reduced in the invasive arm (9.6%) versus the conservative arm (7.6%) at 4 months. While the two groups showed no difference in the combined end point (death or nonfatal myocardial infarction) at 1 year, a 5-year follow-up analysis revealed that the invasive strategy was associated with significant reductions in death or nonfatal myocardial infarction.
  • With regard to timing of catheterization, the Intracoronary Stenting Angiographic Results Cooling-Off (ISAR-COOL) trial suggested a significant benefit from earlier catheterization. Patients with NSTEMI who underwent coronary angiography within 6 hours had a lower rate of death or large myocardial infarction at 30 days than those who underwent coronary angiography at 3-5 days (5.9% vs 11.6%).
  • In contrast to these trials, the ICTUS trial showed no advantage of an early invasive over a selective invasive strategy in 1200 patients with chest pain and elevated troponin who had either a history of coronary artery disease or the presence of ischemic ECG changes. However, the selective invasive group had a 40% rate of revascularization during initial hospital stay.
  • Two subsequent meta-analyses (one of which included Invasive vs Conservative Treatment in Unstable Coronary Syndromes [ICTUS]) have also supported the use of an early invasive strategy in the management of patients with NSTEMI with the most prominent benefit occurring in those patients with high-risk features.
  • The results of the COURAGE Trial, which suggest that percutaneous coronary intervention is no better at preventing events than medical therapy do not pertain to the management of unstable angina as this trial focused on patients with stable disease.
  • Based on the weight of the current evidence, early invasive strategy benefits high-risk patients with acute coronary syndrome. In keeping with this, the current AHA/ACC Guidelines recommend an invasive treatment strategy for patients with high-risk clinical predictors.^12,13
  • [#Table5]Table 5. AHA/ACC Recommendations for a Preferred Invasive Strategy

Open table in new window

Surgical Care

Patients at moderate-to-high risk for adverse events, such as those with ST depression greater than 1 mm on ECG, troponin positivity or NQMI, or chest pain refractory to medical therapy should be scheduled for cardiac catheterization with likely revascularization within the next 48 hours. The TACTICS/TIMI-18 trial showed that this early invasive strategy reduced 30-day rates of death, myocardial infarction, or rehospitalization for unstable angina from 19.4% to 15.9%, or a relative risk reduction of 18%.

• FRISC II showed that even a delayed invasive strategy (mean time to revascularization 4 d, 71% revascularization rate vs 9% in the conservative arm) coupled with LMWH (dalteparin) therapy provides durable benefit for individual hard end points. At 1 year, the invasive group had statistically significant reductions in death (2.2% vs 3.9%, relative risk reduction, 43%) and myocardial infarction (8.6% vs 11.6%, relative risk reduction, 26%).¹¹
  • FRISC II has been the only randomized clinical trial able to show a mortality benefit. This was likely because of the very strict criteria for revascularization, which resulted in only 9% of the conservative arm receiving percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). For example, in the TACTICS/TIMI-18 study and other North American trials, approximately 50% of the patients in the conservative arm had some form of revascularization, and not all in the invasive strategy arm had indications for percutaneous coronary intervention or coronary artery bypass graft. Therefore, the benefits of revascularization were less striking because of the narrower differences in rates of revascularization.
  • Of note, by 1 year, a catch-up phenomenon was observed in patients who had initial conservative management. By then, 52% had undergone angiography, and 43% required revascularization.
    
    

    

    Rate and timing of revascularization for patients with unstable angina using an invasive versus a conservative approach (Fragmin during instability in coronary artery disease [FRISC II]).

    [ CLOSE WINDOW ]

    

    Rate and timing of revascularization for patients with unstable angina using an invasive versus a conservative approach (Fragmin during instability in coronary artery disease [FRISC II]).

  • The cost-benefit ratio of an initial invasive approach based on the FRISC II trial has been estimated. At the cost of 15 extra coronary artery bypass graft and 21 percutaneous coronary intervention procedures, the benefit per 100 patients per year is as follows:
    • 1.7 lives saved
    • 2 myocardial infarctions prevented
    • 20 readmissions prevented
    • Earlier and better symptom relief
  • Coronary artery bypass graft is usually the preferred method for revascularization in patients with the following conditions:
    • Left main trunk artery stenosis
    • Poor left ventricular function
    • Significant 3-vessel coronary artery disease or 2-vessel disease that involves the proximal left anterior descending artery
    • Diabetes mellitus with focal stenosis in more than one vessel
    • Concomitant severe valvular disease that requires open heart surgery
• Continuous observation by Holter monitoring can provide helpful information. Depending on the criteria of ST-segment deviation, the timing of monitoring relative to disease instability, and the intervening medical therapy incidence of abnormal ST-segment shifts has been reported at 11-66% in unstable angina.
  • Up to 92% of these abnormal ST-segment shifts are asymptomatic, and more importantly, patients experiencing such episodes had an associated higher adverse event rate than those without (48% vs 20%).
  • Other studies have documented unfavorable outcomes at up to 6 months with the presence of at least 1 hour of silent ischemia during initial admission

Consultations

• Cardiologist - To assist in risk stratification and decision-making, to expedite further cardiac testing (eg, echocardiography, stress testing, angiography), and to treat unstable patients
• Critical care or telemetry unit specialist - For acute care and monitoring
• Cardiothoracic surgeon - In case coronary artery bypass graft is necessary

Diet

Unstable angina may require patients to take nothing orally if stress testing or an invasive procedure is anticipated. Otherwise, a diet low in cholesterol and saturated fat is recommended. Sodium restriction should be instituted for patients with heart failure or hypertension.

Activity

• Rehabilitation and preventive services: While secondary prevention is the responsibility of the primary care provider and the cardiologist, some centers have specialized and more effective teams (eg, cardiac rehabilitation, preventive services) that can offer more intensive and perhaps more effective counseling and follow-up.
• Bed rest is indicated until clinical risk stratification is accomplished.
• For patients at high risk for adverse events, bed rest is indicated until definitive therapy is administered.
• For patients at intermediate risk for adverse events, bed rest is indicated until further testing or definitive therapy.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antiplatelet agents

These agents prevent formation of thrombi associated with MI and inhibit platelet function by blocking aggregation. Antiplatelet therapy has been shown to reduce mortality by reducing the risk of fatal MIs, fatal strokes, and vascular death. Pooled data from more than 2,000 patients revealed reduction of death or MI from 11.8% to 6% with aspirin in cases of unstable angina. A recent randomized clinical trial involving 12,562 patients showed a reduction of cardiovascular death, MI, or stroke from 11.4% to 9.3% by adding clopidogrel to aspirin therapy.

Aspirin (Anacin, Bayer Buffered Aspirin, Ecotrin)

Administer as soon as possible. Inhibits cyclo-oxygenase, which produces thromboxane A2, a potent platelet activator. Early administration has been shown to reduce mortality.

Clopidogrel (Plavix)

Selectively inhibits adenosine diphosphate (ADP) binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein llb/llla complex, thereby inhibiting platelet aggregation. This agent is used as an alternative to aspirin or in addition to aspirin after coronary stenting.¹⁴
The randomized clinical trial Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) showed an absolute risk reduction in cardiac death, MI, or stroke of 2.1% (11.4% down to 9.3% at 1 - y) at the cost of increased major bleeding by 1.0% (3.7% vs 2.7%).

HMG-CoA reductase inhibitors

Used to treat hypercholesterolemia. Highly efficacious and very well tolerated.

Atorvastatin (Lipitor)

Can provide up to 60% reduction in LDL-C. Inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), which in turn inhibits cholesterol synthesis and increases cholesterol metabolism. The half-life of atorvastatin and active metabolites is longer than that of all the other statins (ie, approximately 48 h compared to 3-4 h).
The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) clinical trial randomized 3,086 patients with unstable angina to high-dose atorvastatin versus placebo. Therapy resulted in a reduction in the primary end point (ie, death, MI, resuscitated cardiac arrest, severe recurrent symptomatic ischemia) from 17.4% to 14.8% (P = .048) within a relatively short period of 4 mo. The benefit was mostly for recurrent symptomatic ischemia with objective evidence and requiring emergency rehospitalization (8.4% down to 6.2%, P = .02).⁸

Glycoprotein IIb/IIIa receptor antagonists

Up to 80,000 copies of these integrins on the platelet cell surface serve as ligands for fibrinogen cross-linkage, the final common pathway for platelet aggregation and thrombus formation, even under arterial shear stress conditions. To date, more than 40,000 patients have been enrolled in randomized clinical trials evaluating glycoprotein IIb/IIIa antagonists in ACS. These trials have shown 30-day relative risk reductions of 22-56% in composite end points, with beneficial trends in each of the component outcomes, largely in association with percutaneous coronary intervention.

Tirofiban (Aggrastat)

Nonpeptide antagonist of platelet GP IIb/IIIa receptor that reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor, thereby inhibiting platelet aggregation. Effects persist over the duration of maintenance infusion and are reversed after stopping the infusion. Approved by the FDA for use in combination with heparin for patients with ACS who are being managed medically and for those undergoing PCI.
Dose should be halved in patients with severe renal insufficiency (CrCl <30 mL/min).

Eptifibatide (Integrilin)

Cyclic heptapeptide antagonist of the platelet GP IIb/IIIa receptor that reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor, thereby inhibiting platelet aggregation. Effects persist over duration of maintenance infusion and are reversed when infusion ends. Approved by the FDA for use in combination with heparin for patients with ACS, patients who are being managed medically, and for those undergoing PCI.

Platelet aggregation inhibitors

Inhibit platelet aggregation.

Abciximab (ReoPro)

Chimeric human-murine monoclonal antibody approved for use in elective/urgent/emergent PCI. Binds to receptor with high affinity and reduces platelet aggregation by 80% for up to 48 h following infusion. The GUSTO-4 randomized clinical trial did not show any benefit for abciximab in medically treated patients who do not undergo PCI. In fact, longer duration of abciximab use was associated with a negative trend in event rates. On the other hand, in the context of PCI, it has been shown to be superior to tirofiban.

Beta-adrenergic blocking agents

Limit heart rate and reduce blood pressure to decrease myocardial oxygen demand, oppose effects of elevated catecholamines, and produce antiarrhythmic properties. Clinical trials of beta-adrenoreceptor blockers in cases of unstable angina have shown decreases in ischemic symptoms and in occurrence of MIs. In vitro studies have shown inhibition of platelet aggregation with this drug class. Infrequent situations in which beta-blocker therapy should be avoided in patients with unstable angina include nonischemic exacerbation of heart failure, cocaine-induced coronary vasoconstriction, and vasospastic angina.

Metoprolol (Lopressor, Toprol XL)

Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During IV administration, carefully monitor blood pressure, heart rate, and ECG.

Esmolol (Brevibloc)

Shown to reduce episodes of chest pain and clinical cardiac events compared to placebo. The very short half-life (8 min) allows a large degree of dosing flexibility, such that cardiovascular benefits are comparable to PO propranolol, yet adverse effects can be managed promptly. It is particularly useful for patients at risk for complications with beta-blockade (eg, reactive airway disease or COPD, severe bradycardia, or poor left ventricular function).

Propranolol (Inderal)

Nonselective beta-blocker that is lipophilic (penetrates CNS). Although generally short-acting agent, long-acting preparations are also available.

Nadolol (Corgard)

Competitively blocks beta-1 and beta-2 receptors. Does not exhibit membrane stabilizing activity or intrinsic sympathomimetic activity.

Antithrombotic agents

Thrombin, the end product of the coagulation mechanism, initiates transformation of fibrinogen to a fibrin clot and activates platelets. Its antagonist, antithrombin III, is the major endogenous inhibitor of the coagulation cascade and is the essential cofactor for heparin.

Heparin

Catalyzes the effect of antithrombin III on coagulative proteinases (eg, factors II, XII, XI, IX, and X; tissue factor VIIa). Prevents reaccumulation of clot after endogenous fibrinolysis. Meta-analysis shows modest benefit (when compared to aspirin alone) and slight increase in bleeding. Reactivation of unstable angina after discontinuation of heparin has been documented among subjects not receiving concomitant aspirin therapy. When unfractionated heparin is used, the aPTT should not be checked until 6 h after initial heparin bolus.

Enoxaparin (Lovenox)

Only LMWH now approved by the FDA both for treatment and for prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism. LMWH has been widely used in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as unfractionated heparin. Except in overdoses, checking PT or aPTT is not useful because aPTT does not correlate with the anticoagulant effect of fractionated LMWH.

Dalteparin (Fragmin)

Enhances inhibition of Factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of Factor Xa.
Except in overdoses, checking PT or aPTT is not useful because aPTT does not correlate with anticoagulant effect of fractionated LMWH.
Average duration of treatment is 7-14 d.

Thrombin inhibitors

Lepirudin and bivalirudin are direct thrombin inhibitors. Advantages over heparin are efficacy against clot-bound thrombin, resistance to inactivation by platelet factor 4 and thrombospondin, and nondependence on antithrombin III pathways. Data to date suggest only a modest reduction in adverse events at the cost of increased nonmajor bleeding complications. GUSTO IIB investigators compared recombinant hirudin and heparin in 12,142 patients, a third of whom had ST elevation MI. The hirudin group had a 9% relative risk reduction in 30-d death or MI rates (8.9% vs 9.8%), but more moderate bleeding events occurred (8.8% vs 7.7%).¹⁵

OASIS-2 was an international randomized clinical trial that involved 10,141 patients. Patients were randomized between heparin (aPTT maintained between 60 and 100 seconds) or lepirudin, which is recombinant hirudin (0.4 mg/kg bolus followed by 0.15 mg/kg/h 72-h IV infusion). Unlike for GP IIb/IIIa antagonists, no evidence indicates attenuation of myocardial necrosis (based on CK or troponin measurements). Approved by the FDA in patients with heparin-induced thrombocytopenia and associated thrombotic disease. Goal is 1.5-2.5 times the control aPTT values. Dose needs to be adjusted for patients with renal impairment.

Bivalirudin (Angiomax) is a thrombin inhibitor used as alternative anticoagulation in patients with unstable angina undergoing PTCA.

Bivalirudin (Angiomax)

Synthetic analogue of recombinant hirudin. Inhibits thrombin. Used for anticoagulation in patients with unstable angina undergoing PTCA. With provisional use of GP IIb/IIIa inhibitor indicated for use as anticoagulant in patients undergoing PCI. Potential advantages over conventional heparin therapy include more predictable and precise levels of anticoagulation, activity against clot-bound thrombin, absence of natural inhibitors (eg, platelet factor 4, heparinase), and continued efficacy following clearance from plasma (because of binding to thrombin).

Lepirudin (Refludan)

Recombinant hirudin derived from yeast cells. Highly specific direct inhibitor of thrombin. Natural hirudin is produced in trace amounts as a family of highly homologous isopolypeptides by the leech Hirudo medicinalis. Biosynthetic lepirudin is identical to natural hirudin except for substitution of leucine for isoleucine at the N -terminal end of the molecule and the absence of a sulfate group on the tyrosine at position 63.
Activity of lepirudin is measured in a chromogenic assay. One antithrombin unit (ATU) is the amount of lepirudin that neutralizes one unit of WHO's preparation 89/588 of thrombin. Specific activity of lepirudin is >16,000 ATU/mg. Mode of action is independent of antithrombin III. Platelet factor 4 does not inhibit lepirudin. One molecule of lepirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected (eg, aPTT values increase in a dose-dependent fashion).
Goal is 1.5-2.5 times the control aPTT values. Dose needs to be adjusted for patients with renal impairment.

Vasodilators

Relieve chest discomfort by improving myocardial oxygen supply, which in turn dilates epicardial and collateral vessels, improving blood supply to the ischemic myocardium. Opposes coronary artery spasm, which augments coronary blood flow and reduces cardiac work by decreasing preload and afterload. Effective in the management of symptoms in acute MI but may reduce mortality only slightly. Nitroglycerin can be administered sublingually by tablet or spray, topically, or by IV. In acute MI, topical administration is a less desirable route because of unpredictable absorption and onset of clinical effects.

Nitroglycerin (Minitran, Nitrogard, Nitrol, Nitrolingual, Nitrostat, Nitro-Dur)

Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. Whether administered topically, SL, PO, or IV, nitrates ameliorate several pathways of unstable angina and reduce the incidence of symptomatic ischemia. Nitrates lower systemic arterial pressure and decrease venous return to the heart, both of which reduce myocardial wall stress. Similarly, nitrates are excellent coronary vasodilators. Other possible beneficial effects include transient inhibition of platelet aggregation, increase in coronary collateral blood flow, and a favorable redistribution of regional flow. Of note, induction of heparin resistance has been reported.

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• The Paradoxical Use of Cardiac Catheterization in Patients With Non-ST-Elevation Acute Coronary Syndromes: Lessons From the Can Rapid Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC /AHA Guidelines (CRUSADE) Quality Improvement Initiative