Unstable Angina Treatment & Management

Management is directed toward (1) reducing myocardial oxygen demands; (2) improving myocardial oxygen supply; and (3) assessing the patient's risk of progression to myocardial infarction or having a complication related to treatment.

Patients with unstable angina require admission to the hospital for bed rest with continuous telemetry monitoring. One should obtain intravenous (IV) access, and provide supplemental oxygen if evidence of desaturation is noted. Because the course of unstable angina is highly variable and potentially life-threatening, the aggressiveness of the therapeutic approach must be established expeditiously.

An invasive strategy refers to the routine use of cardiac catheterization with possible revascularization, and a ischemia-guided 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. In the After Eighty trial, in which investigators evaluated the health-related quality of life (HRQOL) in patients with ACS (NSTEMI, unstable angina) aged 80 years or more who were randomized to either invasive (n = 208) or conservative (n = 216) management, there were only minor differences in HRQOL from baseline to 1-year follow-up between these interventions, as measured by the Short Form 36 health survey (SF-36). ^[41]

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.

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 (eg, nitroglycerin IV), calcium channel blockers (eg, diltiazem, verapamil), and heparin. Medications that have been convincingly shown to be capable of reducing short- or long-term adverse events are as follows:

• Aspirin

• Clopidogrel

• Beta-adrenergic blocking agents

• Lipid-lowering agents (statins)

• Angiotensin-converting enzyme (ACE) inhibitors

• 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.

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. ^[42]

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

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). ^{[42, 43]}

The Food and Drug Administration approved clopidogrel for the medical management of unstable angina/NSTEMI, STEMI in those receiving fibronolytic therapy, and for secondary prevention in recent MI, recent stroke, and peripheral artery disease. ^[44]

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. ^[45] 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 ^[45] and the CREDO (Clopidogrel for the Reduction of Events During Observation) ^[46] 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. ^{[47, 48]}

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. ^{[47, 48]}

Studies have been conducted to ascertain viable strategies for overcoming the variability in the metabolism and efficacy of clopidogrel. ^[49] 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. ^{[49, 50, 51]} However, Rudolph et al reported that compared to clopidogrel, prasugrel improves endothelial nitric oxide bioavailability and reduces platelet-leukocyte interaction and levels of inflammatory markers in patients with unstable angina undergoing PCI. ^[52]

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

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 potentially harmful as part of a dual-platelet regimen in patients with a stroke history for whom PCI is planned. ^[42] Owing to excess bleeding without clinical benefit, the US Food and Drug Administration lists a Black Box warning that does not recommend administration of prasugrel to patients 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. ^[42]

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).

Prasugrel should not be used prior to coronary angiography. Thus, based on current guidelines, patients with unstable angina being treated with upfront dual antiplatelet therapy should be given either clopidogrel or ticagrelor.

Findings from a 1-year clinical effectiveness retrospective observational comparison of prasugrel with ticagrelor using data from an integrated claims database from 15,788 patients with ACS managed with PCI revealed noninferiority of prasugrel for rates of postdischarge net adverse clinical events (NACEs), major adverse cardiovascular events (MACEs), and rehospitalization for bleeding. ^[53] However, prasugrel use was associated with a significantly lower NACEs and MACEs, mostly driven by heart failure, but with no significant difference in all-cause death, MI, unstable angina, stroke/transient ischemic attack, or bleeding. The investigators noted that physicians preferentially used prasugrel rather than ticagrelor in younger ACS-PCI patients with lower risk of bleeding or comorbidities. ^[53]

Nonthienopyridine P2Y12 inhibitor

Ticagrelor

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). ^[54]

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%. ^[21] 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. ^[55] 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. ^[55]

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). ^[42] 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. ^{[56, 57]} In fact, longer duration of abciximab use was associated with a negative trend in event rates.

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. ^[58] Whether this small benefit offsets the risk of bleeding events is a matter for the physician’s clinical judgment.

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. ^[59]

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%). ^[60] 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. ^[60] 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%). ^[61] 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. ^[61] 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. ^[62] Fondaparinux yielded a lower major bleeding rate at 9 days, as well as significant reductions in MI, stroke, and mortality at 180 days. ^[62] 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.

Reactivation of unstable angina after discontinuance of heparin has been documented among subjects not receiving concomitant aspirin therapy. ^[63]

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%). ^[64] 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. ^[64]

GUSTO IIB investigators compared recombinant hirudin with heparin in 12,142 patients, a third of whom had STEMI. ^[65] 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%). ^[65]

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. ^[66]

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. ^{[66, 67]} 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.

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. ^{[68, 69]}

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. ^[68] The benefit was mostly for recurrent symptomatic ischemia with objective evidence and requiring emergency rehospitalization (from 8.4% to 6.2%). ^[68]

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. ^[69]

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. ^[70]

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. ^[71]

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. ^[72]

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. ^[73]

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. ^{[74, 75]}

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. ^[32] 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. ^[76]

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. ^[76]

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. ^[77]

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. ^[77]

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. ^[78] 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. ^[79] 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%). ^[79]

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. 

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%. ^[32]

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. ^[76] 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).

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. ^[80] 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.

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.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (eg, evolocumab, alirocumab) are indicated to not only lower LDL-C but also to reduce the risk of unstable angina requiring hospitalization in adults with established CV disease. ^{[81, 82]}

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

Diet modification, exercise, pharmacotherapy (including ACE inhibitor therapy), preventive counseling regarding foot care, and ophthalmic examinations are indicated. ^[83]

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).

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.