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Unstable Angina Treatment & Management

  • Author: Walter Tan, MD, MS; Chief Editor: Eric H Yang, MD  more...
 
Updated: Nov 22, 2015
 

Approach Considerations

Patients with unstable angina require admission to the hospital for bed rest with continuous telemetry monitoring. Intravenous (IV) access should be obtained and supplemental oxygen started. Because the course of unstable angina is highly variable and potentially life-threatening, the aggressiveness of the therapeutic approach must be established expeditiously. The key in this decision-making is to determine whether the initial management strategy will be invasive or conservative (see the images below).

Algorithm for initial invasive strategy. ASA = ace Algorithm for initial invasive strategy. ASA = acetylsalicylic acid (aspirin); GP IIb/IIIa= glycoprotein IIb/IIIa; IV = intravenous; LOE = level of evidence; UA/NSTEMI = unstable angina/non–ST-segment elevation myocardial infarction; UFH = unfractionated heparin. (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines.)
Algorithm for initial conservative strategy. ASA = Algorithm for initial conservative strategy. ASA = acetylsalicylic acid (aspirin); EF = ejection fraction; GP IIb/IIIa= glycoprotein IIb/IIIa; IV = intravenous; LOE = level of evidence; LVEF = left ventricular ejection fraction; UA/NSTEMI = unstable angina/non–ST-segment elevation myocardial infarction. (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines.)

An invasive strategy refers to the routine use of cardiac catheterization with possible revascularization, and a conservative strategy refers to initial medical management with the possible use of cardiac catheterization if indicated by failure of medical therapy or objective evidence of ischemia (dynamic electrocardiographic [ECG] changes or abnormal noninvasive stress test results). Determination of the preferred strategy depends on the patient’s clinical characteristics and clinical risk (see Cardiac Catheterization).

Specific therapy for primary causes of ischemia should be directed at each pathophysiologic origin of unstable angina: increased myocardial rate-pressure product, coronary vasoconstriction, platelet aggregation, and thrombosis.

Several guidelines and decision algorithms are available and are especially helpful in identifying patients at low risk for whom hospital admission can be avoided. In 2012, the ACCF/AHA published a focused update of their 2007 guideline for the management of patients with unstable angina/NSTEMI.[36]  In 2014, they published revisions of their 2007 guidelines on the management of patients with non–ST-elevation ACSs.[37, 38, 39]  The 2014 updates included the following:

  • Because unstable angina and NSTEMI are on a pathophysiologic continuum and are often indistinguishable, they are considered together in the 2014 guidelines
  • Cardiac troponin assays, not yet available in the United States, may improve the diagnosis of myocardial necrosis
  • High-intensity statins should be used in patients with overt cardiovascular disease
  • Risk stratification tools in these patients include the Thrombolysis in Myocardial Infarction (TIMI) risk score and the Global Registry of Acute Coronary Events (GRACE) risk score
  • After discharge, referral to a cardiac rehabilitation program should be made

The level of care and expertise of the different units vary from hospital to hospital. For example, the intermediate care unit in certain tertiary cardiac centers may be equipped and appropriately staffed for treatment of asymptomatic patients, but high-risk patients with unstable angina would be more appropriately cared for in an intensive care unit (ICU) in a community hospital setting.

Indications for intensive care

ICU or emergency revascularization disposition is indicated by the following:

  • TIMI (Thrombolysis In Myocardial Infarction) risk score of 3-7
  • New ECG changes in 2 or more leads
  • ST elevation greater than 1 mm or Q waves 0.04 seconds or longer
  • ST depression greater than 1 mm or T-wave inversion in the context of angina
  • New left bundle branch block
  • Signs and symptoms of incipient or florid heart failure
  • Syncope or sudden death presentation
  • Serious new arrhythmias, including second-degree or complete heart block and ventricular tachyarrhythmias
  • Refractory angina
  • Hypoxia
  • Positive cardiac enzymes (creatine kinase [CK] or troponin)
  • Myocardial infarction or coronary stenting within the last 2 weeks

Indications for immediate care

Patients are admitted to intermediate care units when they are asymptomatic but have any of the following conditions:

  • Atrial arrhythmia, supraventricular tachycardia, or low-grade second-degree atrioventricular block
  • Isolated basilar rales
  • Borderline blood pressure
  • Symptoms with minimal activity
  • Presence of major comorbidity (eg, severe pulmonary, renal, or hepatic disease; bleeding history; or dyscrasia)
  • Very advanced age or frailty

Indications for observation

Patients who are otherwise healthy without ischemic ECG changes but who have either of the following should be admitted to observation units:

  • New-onset symptoms at moderate levels of exertion
  • Known coronary artery disease (CAD) with a presentation that does not suggest true worsening but for which further observation is thought to be prudent

Medical management of adverse events

Medications that provide symptomatic relief but that have not been shown to affect long-term major events include nitrates, diltiazem or verapamil, and heparin. Medications that have been convincingly shown to be capable of reducing short- or long-term adverse events are as follows:

  • Aspirin
  • Beta-adrenergic blocking agents
  • Lipid-lowering agents (statins)
  • Angiotensin-converting enzyme (ACE) inhibitors
  • Clopidogrel
  • Glycoprotein (GP) IIb/IIIa antagonists

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.

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Initial Medical Management

Medications used in the initial management of unstable angina include the following:

  • Aspirin
  • Beta-adrenergic blocking agents
  • PSY12 inhibitors (thienopyridines [clopidogrel, prasugrel], nonthienopyridines [ticagrelor])
  • GP IIb/IIIa antagonists
  • Heparin
  • Direct thrombin inhibitors
  • Nitrates

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 (ACS); the peak effect can be observed within as short a time as 30 minutes. Patients with unstable angina/non–ST-segment elevation myocardial infarction (UA/NSTEMI) should continue indefinitely on aspirin, if tolerated.[40]

Pooled data from more than 2000 patients revealed a reduction in the rate of death or myocardial infarction (MI) from 11.8% to 6% with aspirin in cases of unstable angina. Several studies have shown approximately 40-50% risk reductions for death or MI 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 (PCI), oral 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, oral aspirin 75-162 mg should be continued indefinitely.

Beta blockers

Clinical trials of beta blockers in cases of unstable angina have shown decreases in ischemic symptoms and in the occurrence of MIs. 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 to IV agents. Studies have associated IV beta-blocker therapy with an increased risk of cardiogenic shock in patients presenting with heart failure or high-risk features. However, IV beta blockers may still be indicated in select patients with tachycardia or hypertension and ongoing chest pain.

In vitro studies have shown inhibition of platelet aggregation with beta blockers.

Thienopyridines

When the American College of Cardiology (ACC)/American Heart Association (AHA) 2007 guidelines for the management of patients with UA/NSTEMI were released, clopidogrel was the only thienopyridine antiplatelet agent approved by the US Food and Drug Administration (FDA). Subsequently, the FDA approved a second thienopyridine, prasugrel. The 2011 ACC Foundation (ACCF)/AHA focused update of the 2007 guidelines includes recommendations for the use of prasugrel as well as clopidogrel.[40]

The 2011 ACCF/AHA update to the guidelines recommends a loading dose of a thienopyridine for patients with UA/NSTEMI for whom PCI is planned.[40] For patients with UA/NSTEMI who are undergoing PCI, a maintenance dose of a thienopyridine should be given for at least 12 months. Early discontinuance should be considered if the risk of bleeding outweighs the expected benefits of thienopyridine therapy. Dosage and timing for each thienopyridine are specified in the class I recommendations.[40]

Clopidogrel

Clopidogrel is recommended as the antiplatelet of choice in patients who are intolerant to aspirin. It is also used as an adjunctive antiplatelet agent in conjunction with aspirin (dual antiplatelet therapy).[40, 41]

The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial showed that the addition of clopidogrel to aspirin therapy reduced the incidence of cardiovascular death, MI, or stroke from 11.4% to 9.3% at 1 year, with early benefit shown at 24 hours.[42] However, the beneficial results of clopidogrel-aspirin treatment came at the cost of a higher rate of major bleeding (3.7%) than that observed in patients on aspirin therapy plus placebo (2.7%).

The PCI-CURE[42] and the CREDO (Clopidogrel for the Reduction of Events During Observation)[43] trials showed significant benefit from the administration of clopidogrel to patients with unstable angina who undergo coronary intervention; pretreatment with oral clopidogrel 6 hours before intervention was associated with improved outcomes. A loading dose of 600 mg may offer more effective platelet inhibition than one of 300 mg; increasing the loading dose beyond 600 mg has not shown benefit.

Patients who later undergo coronary artery bypass grafting (CABG) (eg, those with multivessel disease) while receiving clopidogrel have an increased risk of major bleeding and are more likely to undergo surgery for bleeding. Because of this increased risk of bleeding, it is recommended that clopidogrel be withheld for at least 5 days before elective CABG. 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. Clopidogrel is a prodrug that must be metabolized into the active form before it is effective. Metabolism of clopidogrel is carried out in the liver by a number of enzymes, including CYP2C19.[44, 45]

Numerous variations of CYP are described, with the wild type being CYP2C19*1. Polymorphisms for *2, *3, *4, and *8 are also described and are associated with lower efficacy of therapy. The results of some studies suggest that an additional polymorphism, designated *17, may increase the efficacy of clopidogrel therapy. However, these studies have not been consistently replicated.[44, 45]

Studies have been conducted to ascertain viable strategies for overcoming the variability in the metabolism and efficacy of clopidogrel.[46] Doubling the dose has been suggested; some studies found this to improve outcomes in poor responders, whereas others failed to show this result. Another suggestion is to add a phosphodiesterase inhibitor, such as cilostazol; some of the initial results of this strategy are promising, and a clinical trial is currently under way.

Finally, switching to more potent inhibiting agents, such as prasugrel (see below), remains a possible strategy. Despite its similarity to clopidogrel, prasugrel is not metabolized by the CYP2C19 system. Consequently, its metabolism would not be influenced by the same genetic factors as that of clopidogrel.[46, 47, 48]

For patients at intermediate or higher risk of adverse cardiovascular events, the National Institute for Health and Clinical Excellence (NICE) recommends discussing the continuation of clopidogrel with the cardiac surgeon before performing CABG so that a decision can be reached based on the balance of ischemic and bleeding risk.[49] It should be noted that although clopidogrel may be less efficacious than the newer P2Y12 inhibitors, it may carry a slightly lower bleeding risk.

Prasugrel

The 2011 ACCF/AHA focused update to the guidelines for UA/NSTEMI recommends prasugrel as an alternative thienopyridine to clopidogrel in conjunction with PCI.[40] Head-to-head comparison has shown that whereas prasugrel is more effective at reducing clinical events than clopidogrel is, it is also associated with a higher risk of bleeding.

Prasugrel is stated to be potentially harmful as part of a dual-platelet regimen in patients with a stroke history for whom PCI is planned.[40] Therefore, it should only be used sparingly in those who weigh less than 60 kg as well as those aged 75 years or older, unless the risk of recurrent cardiac ischemia outweighs the elevated bleeding risk.

It should be noted that prasugrel remains unproven for use in patients with ST-elevation MI (STEMI) or ACS who were treated only medically. In addition, this agent must be withdrawn at least 7 days before planned CABG (compared with 5 days for clopidogrel or ticagrelor).

Nonthienopyridine P2Y12 inhibitor

Ticagrelor

The 2012 focused update of the 2007 guidelines now adds ticagrelor to the armamentarium of antiplatelet therapy for ACS patients.[50] Ticagrelor is indicated to reduce the rate of thrombotic CV events following ACS. Ticagrelor also reduces the rate of stent thrombosis in patients who have undergone stent placement for treatment of ACS. In September 2015, the indication was expanded to include patients with a history of MI more than 1 year previously. It is used in addition to low-dose aspirin (75-100 mg/day).[51]

The key points with respect to ticagrelor are (1) that this agent can also be used for STEMI patients and (2) that improved survival is achieved at 1 year, with all-cause mortality reduced from 5.9% to 4.5%.[19] This 1.4% absolute risk reduction in the death rate is attributed to a possible increase in endogenous circulating adenosine, in that ticagrelor is known to inhibit its uptake into erythrocytes. This may also be the cause of the agent’s unique side effect of transient dyspnea.

Approval of ticagrelor use beyond 1 year in patients with a history of MI is based on the PEGASUS TIMI-54 study, a large-scale outcomes trial involving over 21,000 patients.[52] PEGASUS TIMI-54 investigated ticagrelor 60 mg twice daily plus low-dose aspirin, compared to placebo plus low-dose aspirin, for the long-term prevention of CV death, heart attack, and stroke in patients who had experienced a heart attack 1-3 years prior to study enrollment. In patients with an MI more than 1 year previously, treatment with ticagrelor significantly reduced the risk of CV death, MI, or stroke compared with placebo.[52]

Glycoprotein IIb/IIIa antagonists

Because of the availability of novel oral P2Y12 platelet inhibitors, IV GP IIb/IIIa inhibitors have been relegated to use in special circumstances when a second antiplatelet agent in conjunction with aspirin cannot be promptly given (as in cases where there is a high likelihood of urgent CABG or where cardiac catheterization is delayed because of consent or staffing issues).[50] The risk must justify the bleeding risk (as in young diabetics with elevated troponin levels).

All of the currently available GP IIb/IIIa inhibitors (ie, abciximab, eptifibatide, and tirofiban) have been shown to increase the safety of acute PCI, with relative risk reductions in adverse events (including 30-day mortality and infarction) of approximately 30-50% in trials prior to the advent of the newer P2Y12 platelet inhibitors.

However, the GUSTO-IV (Global Utilization of Streptokinase and TPA [tissue plasminogen activator] for Occluded coronary arteries IV) randomized clinical trial did not show any benefit for abciximab in medically treated patients who did not undergo PCI.[53, 54] In fact, longer duration of abciximab use was associated with a negative trend in event rates; therefore, abciximab is not recommended for patients who are not undergoing PCI.[40]

Of the currently used GP IIb/IIIa inhibitors, only eptifibatide and tirofiban have been shown to be beneficial 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 meta-analysis of 6 randomized trials (with 31,400 patients) failed to show a mortality benefit in patients who did not undergo PCI.[55] Whether this small benefit offsets the risk of bleeding events is a matter for the physician’s clinical judgment.

Dual and triple antiplatelet therapies

The ACCF/AHA 2011 update to the UA/NSTEMI guidelines recommends dual-antiplatelet therapy (aspirin and a second antiplatelet agent) for medium-risk to high-risk patients with definite UA/NSTEMI for whom an initial invasive strategy is chosen.[40] Before PCI, the second antiplatelet agent may be clopidogrel or an IV GP IIb/IIIa inhibitor (preferably eptifibatide or tirofiban). At the time of PCI, the second antiplatelet agent may be clopidogrel, prasugrel, or an IV GP IIb/IIIa inhibitor.[40]

Precatheterization triple-antiplatelet therapy (aspirin, a thienopyridine, and a GP IIb/IIIa inhibitor) is associated with increased bleeding risk and is recommended only for patients at high risk for ischemic events whose risk of bleeding is not elevated.[40]

Heparin

The use of low-molecular-weight heparin (LMWH) and the use of IV unfractionated heparin (UFH) are 2 comparable anticoagulation strategies in the treatment of unstable angina. The many potential benefits of using LMWH include lower bleeding rates, reduced costs, and decreased incidence of heparin-induced thrombocytopenia. However, many interventional cardiologists are uncomfortable using LMWH because anticoagulation activity cannot be measured during PCI.[56]

In the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events) study, when LMWH (enoxaparin) was compared with UFH, the 30-day composite rates of death, MI, or recurrent angina were significantly reduced for subjects taking LMWH (19.8% vs 23.3%).[57] However, excess minor bleeding occurred in 11.9% of patients in the LMWH group, versus 7.2% of those in the non-LMWH group, many of which were due only to injection site ecchymosis.[57] The revascularization rate was intermediate (~30%).

In the SYNERGY (Superior Yield of the New strategy of Enoxaparin Revascularization and Glycoprotein IIb/IIIa Inhibitors) trial, enoxaparin was associated with more major bleeding episodes (9.1%) than UFH was (7.6%).[58] High-risk patients with NSTEMI (including those with unstable angina) were randomized into groups that received either UFH or enoxaparin. All enrolled patients were treated with an early invasive strategy.

No difference in the composite endpoint (death or MI by 30 days) was detected in the SYNERGY trial.[58] Although more major bleeding episodes occurred in the enoxaparin group, much of this effect was attributed to patients who crossed over to UFH after receiving an initial dose of enoxaparin.

In the OASIS-5 (Organization to Assess Strategies for Ischemic Syndromes-5) trial, which compared fondaparinux and enoxaparin for treatment of UA/NSTEMI, fondaparinux was associated with a low, but increased, rate of guiding catheter thrombus.[59] Fondaparinux yielded a lower major bleeding rate at 9 days, as well as significant reductions in MI, stroke, and mortality at 180 days.[59] However, this agent is not recommended if urgent PCI is foreseen, because of the increased rate of guiding catheter thrombus.

Enoxaparin, fondaparinux, and UFH are safe alternatives for the treatment of unstable angina. Switching agents (eg, from LMWH to UFH) is associated with excess bleeding and reduced clinical benefit. If a conservative strategy is intended, LMWH may be preferred. The National Institute for Health and Clinical Excellence (NICE) recommends UFH as an alternative to fondaparinux for patients with significant renal impairment (creatinine >265 mmol/L) or for those likely to undergo coronary angiography within 24 hours of admission.[29]

Reactivation of unstable angina after discontinuance of heparin has been documented among subjects not receiving concomitant aspirin therapy.[60]

Direct thrombin inhibitors

Direct thrombin inhibitors, such as hirudin, lepirudin (recombinant hirudin), and bivalirudin, 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 ACS, there was a slightly greater reduction in MI in the inhibitors group (2.8%) than in the heparin group (3.5%).[61] Treatment with hirudin was associated with an higher risk of major bleeding than treatment with heparin, whereas treatment with bivalirudin was associated with a lower risk.[61]

GUSTO IIB investigators compared recombinant hirudin with heparin in 12,142 patients, a third of whom had STEMI.[62] The hirudin group had a 9% relative risk reduction in 30-day death or MI rates (8.9% vs 9.8%) but experienced more moderate bleeding events (8.8% vs 7.7%).[62]

In the international OASIS-2 (Organisation to Assess Strategies for Ischemic Syndromes-2) clinical trial, involving 10,141 patients who were randomly assigned to receive either heparin (activated partial thromboplastin time [aPTT] maintained between 60 and 100 seconds) or lepirudin (0.4 mg/kg bolus, followed by 0.15 mg/kg/hr by IV infusion for 72 hours), investigators found no evidence indicating attenuation of myocardial necrosis (based on CK or troponin measurements), in contrast with GP IIb/IIIa antagonists.[63]

The FDA approved lepirudin for use in patients with heparin-induced thrombocytopenia (HIT) and associated thrombotic disease. The goal is 1.5-2.5 times the control aPTT values. The dosage must be adjusted for patients with renal impairment.

The benefits of bivalirudin in patients who undergo coronary stent implantation has been demonstrated in the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to reduced Clinical Events-2) and ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trials.[63, 64] At present, however, the data are insufficient to support a recommendation of routine bivalirudin use in patients with unstable angina.

Although direct thrombin inhibitors should not be routinely used in the treatment of unstable angina, they may be of clinical benefit in special circumstances (eg, HIT).

Nitrates

IV nitrate agents may be used in the treatment of ischemic chest pain, symptoms of heart failure, or hypertension, but these drugs are not associated with appreciable long-term clinical benefit. Nitrate agents are contraindicated for patients with right ventricular infarction, hypertrophic cardiomyopathy (HOCM), and severe aortic stenosis.

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Further Medical Management

Additional management of unstable angina includes the use of statins (lipid-lowering agents) and ACE inhibitors.

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 in patients with unstable angina.

Results from the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study and the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) TIMI trials suggested that early initiation of antilipidemic agents (statins) in patients with ACS can decrease adverse events within a relatively short term.[65, 66]

The MIRACL trial (including 3086 patients with unstable angina randomized to high-dose atorvastatin vs placebo) demonstrated that therapy with atorvastatin resulted in a reduction in the primary endpoint (ie, death, MI, resuscitated cardiac arrest, severe recurrent symptomatic ischemia) from 17.4% to 14.8% within a relatively short period (4 months) as compared with placebo.[65] The benefit was mostly for recurrent symptomatic ischemia with objective evidence and requiring emergency rehospitalization (from 8.4% to 6.2%).[65]

The PROVE-IT TIMI-22 trial demonstrated a benefit from statin therapy even in patients with ACS presenting with relatively low serum low-density lipoprotein cholesterol (LDL-C) levels (< 100 mg/dL), suggesting that the target LDL-C level should be less than 80 mg/dL in these patients.[66]

To improve patient adherence, statin therapy should be initiated before hospital discharge. Additional clinical benefit may be gained by starting therapy within 24-96 hours of admission.

FDA safety alerts

On March 1, 2012, the FDA updated healthcare professionals regarding changes to the prescribing information concerning interactions between protease inhibitors (drugs for management of HIV and hepatitis B virus [HBV] infection) and certain statins. The combination of these drugs may raise the blood levels of statins and increase the risk for myopathy. Rhabdomyolysis, the most serious form of myopathy, can cause kidney damage and lead to kidney failure, which is life-threatening.[67]

On February 28, 2012, the FDA approved important safety label changes for statins, including removal of routine monitoring of liver enzymes. Information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels was added to the statin labels. In addition, extensive contraindication and dose limitation updates were added to the lovastatin label in situations when this drug is taken with certain medicines that can increase the risk for myopathy.[68]

On June 8, 2011, the FDA notified healthcare professionals of its recommendations for limiting the use of the highest approved dose (80 mg) of simvastatin because of an increased risk of muscle damage. The FDA required that the simvastatin label be changed to add new contraindications and dose limitations for using simvastatin with certain medicines.[69]

Angiotensin-converting enzyme inhibitors

ACE inhibitors are of particular benefit in patients with large anterior infarctions, especially those with compromised left ventricular function (eg, from ST-elevation MI [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.

Other medications

Calcium-channel antagonists, antibiotics against Chlamydia pneumoniae, and fibrinolytic agents currently have no established role in the setting of unstable angina.

Most of the clinical trials of fibrinolytic therapy have shown a tendency toward more nonfatal infarctions attributed to procoagulant effects in the context of a nonocclusive thrombus.

Although the available data suggest that the efficacy of ticlopidine is similar to that of aspirin, the use of ticlopidine in the United States was drastically reduced after reports appeared of associated fatal thrombotic thrombocytopenic purpura.

Ranolazine, trimetazidine, nicorandil, and ivabradine, which have been shown to reduce myocardial ischemia through various means, have received limited testing in patients with ACS.[70]

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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

Invasive versus conservative therapy

It has been questioned whether patients who have unstable angina but lack the clinical characteristics listed above receive greater benefit from an invasive strategy than from conservative management.

Among patients presenting with unstable angina, approximately 15% have 1-vessel CAD, 35% have 2-vessel CAD, and 50% have 3-vessel CAD. The incidence of left main disease is roughly 5-10%. The rate of thrombus detected at coronary angiography varies widely, ranging 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 so-called permissive revascularization.

Older clinical trials, such as TIMI III-B, the VANQWISH (Veterans Affairs Non–Q-Wave Infarction Strategies in-Hospital) study, and the MATE (Medicine versus Angiography in Thrombolytic Exclusion) trial, did not find routine catheterization to be superior to reserving catheterization for patients with recurrent ischemic symptoms or a significantly positive stress test result. Heightened abrupt vessel closure, stent thrombosis, and MI rates were early hazards observed with angioplasty performed in the acute setting of myocardial ischemia.[71, 72]

The TACTICS (Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy)/TIMI-18 study showed a very low 30-day and 6-month results for the composite endpoint of death, MI, or rehospitalization with the early invasive strategy.[28] The study entailed the administration of IV GP IIb/IIIa (tirofiban), coupled with angiography within 48 hours. The benefit of early invasive strategy was more substantial in intermediate- and high-risk patients (ie, those with a TIMI score of 3).

The FRISC-II (FRagmin during InStability in Coronary artery disease-II) trial showed a significant reduction in death or MI at 6 months in patients with unstable angina who underwent early catheterization and revascularization, as compared with patients who were treated with a noninvasive strategy.[73]

This treatment difference was primarily driven by a lower rate of MI in the invasive arm (7.8%) than in the noninvasive arm (10.1%). Patients in the invasive arm also had a significant reduction in angina and hospital readmission rates. The treatment benefits were more pronounced in patients with ST-segment depression and cardiac marker elevation.[73]

Investigators in the RITA-3 (Randomized Intervention Trial of unstable Angina-3) study also reported a benefit with the invasive strategy as opposed to conservative management in intermediate- to high-risk patients with NSTEMI and ischemic changes on ECG or elevated troponin levels.[74]

In this study, the combined endpoint of death, MI, and refractory angina at 4 months was significantly reduced in the invasive arm (9.6%) as compared with the conservative arm (7.6%). Although the 2 groups showed no difference in the combined endpoint (death or nonfatal MI) at 1 year, a 5-year follow-up analysis revealed that the invasive strategy was associated with significant reductions in death or nonfatal MI.[74]

In contrast to these trials, the ICTUS (Invasive vs Conservative Treatment in Unstable coronary Syndromes) trial did not find an early invasive strategy to confer any advantage over a selective invasive strategy in 1200 patients with chest pain and elevated troponin who had either a history of CAD or the presence of ischemic ECG changes.[75] However, the selective invasive group had a 40% rate of revascularization during initial hospital stay.

Timing of catheterization

With regard to the timing of catheterization, the ISAR-COOL (Intracoronary Stenting Angiographic Results COOLing-off) trial suggested that earlier catheterization provides a significant benefit over later use of the procedure.[76] Patients with NSTEMI who underwent coronary angiography within 6 hours had a lower rate of death or large MI at 30 days (5.9%) than did patients who underwent the treatment at 3-5 days (11.6%).[76]

Two meta-analyses (one of which included the ICTUS trial) 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 weight of the current evidence favors the view that an early invasive strategy benefits high-risk patients with ACS. In keeping with this determination, the ACC/AHA 2007 and updated 2011 guidelines recommend an invasive treatment strategy for patients with high-risk clinical predictors (see Table 5 below).[40, 39]

Table 5. ACC/AHA Recommendations for Preferred Invasive Strategy (Open Table in a new window)

Preferred Strategy [39] Patient Characteristics
Invasive Recurrent angina/ischemia at rest or with low-level activities despite intensive medical therapy
Elevated cardiac biomarkers (TnT or TnI)
New or presumably new ST-segment depression
Signs or symptoms of heart failure or new or worsening mitral regurgitation
High-risk findings on noninvasive stress testing
High-risk score (eg, TIMI, GRACE)
Reduced LV systolic function (LVEF < 40%)
Hemodynamic instability
Sustained ventricular tachycardia
PCI within 6 months
Previous CABG
Conservative Low-risk score (eg, TIMI, GRACE)
Patient or physician preference in the absence of high-risk features
ACC/AHA = American College of Cardiology/American Heart Association; CABG = coronary artery bypass grafting; GRACE = Global Registry of Acute Coronary Events; LV = left ventricle; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TIMI = Thrombolysis in Myocardial Infarction Clinical Trial; TnI = troponin I; TnT = troponin T.
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Revascularization

Patients at moderate to high risk for adverse events, such as persons with ST depression greater than 1 mm on ECG, troponin positivity or non–Q-wave myocardial infarction (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, MI, or rehospitalization for unstable angina from 19.4% to 15.9%.[28]

The FRISC II study showed that even a delayed invasive strategy (mean time to revascularization, 4 days; 71% revascularization rate vs 9% in the conservative arm), coupled with LMWH (dalteparin) therapy, provides durable benefit for individual hard endpoints.[73] At 1 year, the study’s invasive strategy group had statistically significant reductions in MI (8.6% vs 11.6%) and death (2.2% vs 3.9%), compared with the noninvasive group.

To date, FRISC II is the only randomized clinical trial showing a mortality benefit—probably because of the very strict criteria for revascularization, which resulted in only 9% of the conservative arm receiving PCI or CABG. In the TACTICS/TIMI-18 study and other North American trials, about 50% of the patients in the conservative arm had some form of revascularization, and not all of those in the invasive arm had indications for PCI or CABG. Consequently, the benefits of revascularization appeared less striking.

Notably, 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 (see the image below).

Rate and timing of revascularization for patients Rate and timing of revascularization for patients with unstable angina using invasive versus conservative approach (FRagmin during InStability in Coronary artery disease [FRISC] II).

Cost-to-benefit ratio of revascularization

Wallentin et al estimated the cost-to-benefit ratio of an initial invasive approach based on the FRISC II trial.[77] At the cost of 15 extra CABG and 21 PCI procedures, the benefits per 100 patients per year were as follows:

  • 1.7 lives saved
  • 2 MIs prevented
  • 20 readmissions prevented
  • Symptoms relieved earlier and better

CABG 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 CAD or 2-vessel disease that involves the proximal left anterior descending (LAD) artery
  • Diabetes mellitus with focal stenosis in more than 1 vessel
  • Concomitant severe valvular disease that necessitates open heart surgery

Patient monitoring

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, the incidence of abnormal ST-segment shifts has been reported to be 11-66% in unstable angina. As many as 92% of these abnormal ST-segment shifts are asymptomatic; more important, patients who experienced such episodes had an associated higher adverse event rate than those who did not (48% and 20%, respectively).

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.

Follow-up

The ACC/AHA 2007 UA/NSTEMI guideline recommended that aspirin (75-162 mg/day) be continued indefinitely for patients with UA/NSTEMI who tolerate it.[39] For patients with UA/NSTEMI who are treated medically without stenting, clopidogrel (75 mg/day) should be prescribed for at least 1 month and ideally for up to 1 year.

The 2011 update to the ACCF/AHA guideline for UA/NSTEMI stated that for patients treated with PCI, clopidogrel or prasugrel (10 mg/day) should be given for at least 12 months. For post-PCI patients with a drug-eluting stent, clinicians may consider continuing clopidogrel or prasugrel beyond 15 months.[40]

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Prevention

Approximately 1-3 months after the acute phase of unstable angina, the risk of major adverse events typically declines to that observed in patients with chronic stable angina. The goals are to prepare patients for resumption of their normal activities as safely as possible, to preserve left ventricular function, and to prevent future events.

Although secondary prevention is the responsibility of the primary care provider and the cardiologist, some centers have specialized teams (eg, cardiac rehabilitation and preventive services) that offer more intensive, and perhaps more effective, counseling and follow-up.

Smoking cessation

Aggressive attempts should be made to convince the patient and the rest of his or her household to cease smoking. The target is for the patient and his or her cohabitants to abstain completely from all tobacco products for 12 months or longer. Patients who have expressed a decision to quit should be supported with counseling, follow-up, and pharmacotherapy, and possibly with acupuncture or hypnosis (if necessary). Patients should avoid secondhand smoke.

Lipid lowering

The target is an LDL-C level of 70 mg/dL or lower, a high-density lipoprotein cholesterol (HDL-C) level higher than 35 mg/dL, and a triglyceride level below 200 mg/dL. Diet modification, exercise, and drug therapy are indicated as per National Cholesterol Education Program (NCEP) guidelines.

Control of hypertension

The target blood pressure is below 140/90 mm Hg or below 130/80 mm Hg if the patient has diabetes mellitus or chronic kidney disease. Diet modification, moderation of sodium and alcohol intake, exercise, smoking cessation, and pharmacotherapy are indicated.

Diabetes mellitus management

The ACCF/AHA 2011 update to the UA/NSTEMI guideline states that it is reasonable to achieve and maintain glucose levels lower than 180 mg/dL for hospitalized patients, avoiding hypoglycemia.[40] Thereafter, the guideline defers to the 2010 American Diabetes Association standard of care guideline.[40, 78] Diet modification, exercise, pharmacotherapy (including ACE inhibitor therapy), preventive counseling regarding foot care, and ophthalmic examinations are indicated.

Weight management and nutritional counseling

The target body mass index (BMI) is below 25 kg/m2, in conjunction with a waist circumference of less than 40 inches in men and of less than 35 inches in women. Diet modification with adequate intake of fruits and vegetables, exercise, and behavioral modification and counseling are indicated.

Psychosocial management

The targets in psychosocial management are lifestyle modification, recognition and treatment of substance abuse (whether involving alcohol or psychotropics), management of depression or hostile attitude, and compliance with health maintenance. Education, counseling, support groups, and social or religious resources are indicated.

Activity management

Patients at risk for MI should avoid sudden strenuous activities, especially in cold weather (eg, shoveling snow).

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Consultations

When a clinician is presented with a patient with suspected or confirmed unstable angina, consultation with a cardiologist is indicated to assist in risk stratification and decision making, to expedite further cardiac testing (eg, with echocardiography, stress testing, or angiography), and to treat unstable patients. A critical care or telemetry unit specialist is helpful for acute care and monitoring. A cardiothoracic surgeon should be consulted when CABG is indicated.

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Contributor Information and Disclosures
Author

Walter Tan, MD, MS Associate Professor of Medicine, Wake Forest University School of Medicine; Director of Cardiac Cath Labs, Wake Forest Baptist Medical Center

Walter Tan, MD, MS is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American Heart Association, American Stroke Association, National Stroke Association, Society for Vascular Medicine, Society of Interventional Radiology

Disclosure: Nothing to disclose.

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

David J Moliterno, MD is a member of the following medical societies: American College of Cardiology, European Society of Cardiology, Association of Professors of Cardiology, American College of Physicians, American Heart Association, American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Eric H Yang, MD Associate Professor of Medicine, Director of Cardiac Catherization Laboratory and Interventional Cardiology, Mayo Clinic Arizona

Eric H Yang, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

Acknowledgements

Steven James Filby, MD Fellow in Interventional Cardiology, The Cleveland Clinic Foundation

Disclosure: Nothing to disclose.

Justin D Pearlman, MD, ME, PhD, FACC, MA Chief, Division of Cardiology, Director of Cardiology Consultative Service, Director of Cardiology Clinic Service, Director of Cardiology Non-Invasive Laboratory, Director of Cardiology Quality Program KMC, Dartmouth-Hitchcock Medical Center, Dartmouth Medical School

Justin D Pearlman, MD, ME, PhD, FACC, MA is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Federation for Medical Research, International Society for Magnetic Resonance in Medicine, and Radiological Society of North America

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Pathogenesis of acute coronary syndromes.
Thrombolysis in Myocardial Infarction (TIMI) Risk Score correlates with major adverse outcome and effect of therapy with low-molecular-weight heparin. ARD = absolute risk difference; ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; No. = number; NNT = number needed to treat.
Algorithm for initial invasive strategy. ASA = acetylsalicylic acid (aspirin); GP IIb/IIIa= glycoprotein IIb/IIIa; IV = intravenous; LOE = level of evidence; UA/NSTEMI = unstable angina/non–ST-segment elevation myocardial infarction; UFH = unfractionated heparin. (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines.)
Algorithm for initial conservative strategy. ASA = acetylsalicylic acid (aspirin); EF = ejection fraction; GP IIb/IIIa= glycoprotein IIb/IIIa; IV = intravenous; LOE = level of evidence; LVEF = left ventricular ejection fraction; UA/NSTEMI = unstable angina/non–ST-segment elevation myocardial infarction. (Adapted from 2007 ACC/AHA UA/NSTEMI Guidelines.)
Rate and timing of revascularization for patients with unstable angina using invasive versus conservative approach (FRagmin during InStability in Coronary artery disease [FRISC] II).
Time course of elevations of serum markers after acute myocardial infarction. CK = creatine kinase; CK-MB = creatine kinase MB fraction; LDH = lactate dehydrogenase.
Table 1. Patient Characteristics, GUARANTEE Versus CRUSADE Trials
Characteristics GUARANTEE, 1995-96 [11] CRUSADE, 2001-06 [12]
Mean age (y) 62 69
Patients >65 y (%) 44
Female (%) 39 40
Hypertension (%) 60 73
Diabetes mellitus (%) 26 33
Current smoker (%) 25
Hypercholesterolemia (%) 43 50
Previous stroke (%) 9
Previous MI (%) 36 30
Previous angina (%) 66
CHF (%) 14 18
Previous coronary intervention (%) 23 21
Previous coronary bypass surgery (%) 25 19
CHF = congestive heart failure; CRUSADE = Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines; GUARANTEE = Global Unstable Angina Registry and Treatment Evaluation; MI = myocardial infarction.
Table 2. Demographic Characteristics of Patients in International OASIS-2 Registry
Characteristics [14] Australia Brazil Canada Hungary Poland United States
General Number of patients 1899 1478 1626 931 1135 918
Mean age (y) 65 62 66 65 63 66
Women (%) 37 42 37 45 40 37
Clinical NQMI presentation (%) 7 7 14 22 17 16
Abnormal ECG (%) 74 91 82 95 97 87
Select treatments Beta blocker (%) 67 53 73 67 59 57
Calcium blocker (%) 59 51 53 52 43 59
Invasive procedures (index hospitalization) Cardiac catheterization (%) 24 69 43 20 7 58
PCI (%) 7 19 16 5 0.4 24
CABG (%) 4 20 10 7 0.4 17
CABG = coronary artery bypass grafting; ECG = electrocardiographic; NQMI = non-Q wave myocardial infarction; OASIS = Organization to Assess Strategies for Ischemic Syndromes; PCI = percutaneous coronary intervention.
Table 3. Thirty-Day Clinical Outcome in Patients With Acute Coronary Syndromes in Clinical Trials
Study Year Number of Patients Death (%) Myocardial Infarction (%) Major Bleed (%)
TIMI-3 1994 1,473 2.5 9.0 0.3
GUSTO-IIb 1997 8,011 3.8 6.0 1.0
ESSENCE 1998 3,171 3.3 4.5 1.1
PARAGON-A 1998 2,282 3.2 10.3 4.0
PRISM 1998 3,232 3.0 4.2 0.4
PRISM-PLUS 1998 1,915 4.4 8.1 1.1
PURSUIT 1998 10,948 3.6 12.9 2.1
TIMI-11B 1999 3,910 3.9 6.0 1.3
PARAGON-B 2000 5,225 3.1 9.3 1.1
Pooled 40,167 3.5 8.5 1.5
ESSENCE = Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; GUSTO-IIb = Global Utilization of Streptokinase and TPA (tissue plasminogen activator) for Occluded Coronary Arteries; PARAGON-A = Platelet IIb/IIIa Antagonism (lamifiban) for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PARAGON-B = Platelet IIb/IIIa Antagonism (lamifiban) for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PRISM = Platelet Receptor Inhibition in Ischemic Syndrome Management; PRISM-PLUS = Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Angina Signs and Symptoms; PURSUIT = Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; TIMI-11B = Thrombolysis in Myocardial Infarction Clinical Trial 11B; TIMI-3 = Thrombolysis in Myocardial Infarction Clinical Trial 3.
Table 4. Braunwald Classification of Unstable Angina
Characteristic Class/Category Details
Severity I Symptoms with exertion
II Subacute symptoms at rest (2-30 days prior)
III Acute symptoms at rest (within prior 48 hr)
Clinical precipitating factor A Secondary
B Primary
C Postinfarction
Therapy during symptoms 1 No treatment
2 Usual angina therapy
3 Maximal therapy
Table 5. ACC/AHA Recommendations for Preferred Invasive Strategy
Preferred Strategy [39] Patient Characteristics
Invasive Recurrent angina/ischemia at rest or with low-level activities despite intensive medical therapy
Elevated cardiac biomarkers (TnT or TnI)
New or presumably new ST-segment depression
Signs or symptoms of heart failure or new or worsening mitral regurgitation
High-risk findings on noninvasive stress testing
High-risk score (eg, TIMI, GRACE)
Reduced LV systolic function (LVEF < 40%)
Hemodynamic instability
Sustained ventricular tachycardia
PCI within 6 months
Previous CABG
Conservative Low-risk score (eg, TIMI, GRACE)
Patient or physician preference in the absence of high-risk features
ACC/AHA = American College of Cardiology/American Heart Association; CABG = coronary artery bypass grafting; GRACE = Global Registry of Acute Coronary Events; LV = left ventricle; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TIMI = Thrombolysis in Myocardial Infarction Clinical Trial; TnI = troponin I; TnT = troponin T.
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