Medical Care: Because the course of unstable angina is highly variable and potentially life threatening, the aggressiveness of the course of unstable angina is highly variable and potentially life threatening, the aggressiveness of approach or level of care needs to be established expeditiously. The obvious goal of therapy is to reverse the oxygen supply-demand mismatch by minimizing requirements and maximizing delivery of tissue nutrients. Secondary or precipitating factors, such as anemia, hypoxemia, thyroid dysfunction, or febrile illness, should be sought and corrected.
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.
Patients with unstable angina require admission to the hospital. IV access should be obtained and supplemental oxygen started. Initial management involves antiplatelet therapy (aspirin, clopidogrel, glycoprotein IIb/IIIa antagonists), anticoagulation (heparin), beta-blockade, nitrates, and consideration for cardiac catheterization. Further medical management includes lipid-lowering therapy (statins) and use of angiotensin-converting enzyme (ACE) inhibitors
Medications that provide symptomatic relief but have not been found to have an effect on long-term major events include nitrates, diltiazem or verapamil, other medications used to treat unstable angina, and heparin. Medications that have compelling evidence for reducing short- or long-term adverse events are aspirin, beta-adrenergic blocking agents, lipid-lowering agents (statins), ACE inhibitors, clopidogrel, and glycoprotein IIb/IIIa antagonists. (These are discussed below.)
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 ACS unless they have a valid contraindication.
Aspirin
Administer chewable aspirin 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 ACS, 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 MI with aspirin at 30-day follow-up and at up to 1-year follow-up in this patient population.
After initial dose, a decreased dose of 75-150 mg may be continued indefinitely.
Beta-blockers
Several controlled trials have demonstrated the benefits of beta-blockers in the treatment of MI.
Early use of IV beta-blockers (e.g., metoprolol) is preferred as it is associated with a lower rate of recurrent MI or death when compared to later therapy.
After initial treatment, patient may be switched to oral regimen for chronic therapy.
HMG coenzyme A reductase inhibitors
Multiple large, randomized, secondary prevention trials including the Heart Protection Study have demonstrated significant mortality benefit from statin therapy.
Recent results from the MIRACL 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.
The PROVE IT-TIMI 22 trial demonstrated a benefit from statin therapy even in ACS patients 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 and clinical benefit may be gained by starting 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 ST-elevation MI). The benefit in patients with unstable angina is less clear.
Currently, ACE inhibitors are recommended in patients with left ventricular dysfunction or CHF, diabetes, and hypertension.
ACE-Inhibitor therapy may be started within 24 hours of admission and titrated for BP 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 CURE trial showed that clopidogrel in addition to aspirin (vs aspirin alone) significantly reduced the composite primary end point of cardiovascular death, MI, or stroke with early benefit shown at 24 hours.
PCI CURE and CREDO trials have shown significant benefit in those patients with unstable angina who undergo coronary intervention and pretreatment 6 hours before intervention was associated with improved outcomes. However, patients who later undergo CABG (eg, those with multivessel disease) while receiving clopidogrel have an increased risk of major bleeding and requirement for surgery for bleeding.
Some experts still advocate loading patients with clopidogrel 300 mg in addition to aspirin on presentation since the benefit obtained from clopidogrel pretreatment in CREDO was greater than the added risk in the minority of patients who go on to require CABG.
Glycoprotein IIb/IIIa antagonists
In patients who are undergoing PCI (ie, those with high-risk characteristics), therapy should be started with a small-molecule IV glycoprotein IIb/IIIa inhibitor for medical stabilization.
If the patient can be catheterized within first few hours of presentation and is pain free, it is acceptable alternative to simply commence abciximab in the catheterization laboratory in conjunction with percutaneous revascularization. This is based on the findings of the Do Tirofiban and ReoPro Give Similar Efficacy Trial (TARGET) trial which confirmed the superiority of abciximab over tirofiban in an interventional setting; though a slight excess of about 2% minor bleeding (<5 g/dL) and about 2% thrombocytopenia is documented with abciximab use.
All of the currently available glycoprotein IIb/IIIa inhibitors, namely, abciximab, eptifibatide, and tirofiban, have been shown to increase the safety of acute percutaneous revascularization, with relative risk reductions in adverse events (including 30-day mortality and infarction) of approximately 30-50%.
Glycoprotein IIb/IIIa antagonists have also shown to be of benefit in high-risk patients (troponin positive, ongoing ischemia, or other high-risk features) treated with medical management alone. The relative reduction in adverse events observed in this setting is on the order of 5-7%, and only with tirofiban, eptifibatide, and lamifiban. 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 PCI. Judgment is required to decide whether this small benefit offsets the risk of bleeding events.
Heparin
Low-molecular-weight heparin and IV unfractionated heparin are 2 comparable anticoagulation strategies in the treatment of unstable angina.
The ESSENCE investigators compared low-molecular-weight heparin (enoxaparin) with unfractionated heparin. The revascularization rate in this study was intermediate at about 30%. The 30-day composite rates of death, MI, or recurrent angina were significantly reduced for subjects taking low-molecular-weight heparin (19.8% vs 23.3%, relative risk reduction of 15%). However, excess minor bleeding occurred in 11.9% vs 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 nonβST-segment elevation MI (including those with unstable angina) to unfractionated heparin or enoxaparin. All enrolled patients were treated with an early invasive strategy. No difference in composite endpoint (death or MI by 30 days) 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 initial dose of enoxaparin.
Enoxaparin and unfractionated heparin are safe alternative agents used in the treatment of unstable angina, though enoxaparin is associated with a modest increased risk of major bleeding. Switching agents is associated with increased bleeding and reduced clinical benefit.
Nitrates
IV 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 are associated with higher rates of bleeding.
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.
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, MI, 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 days, 71% revascularization rate vs 9% in the conservative arm) coupled with low-molecular-weight heparin (dalteparin) therapy provides durable benefit for individual hard endpoints. At 1 year, the invasive group had statistically significant reductions in death (2.2% vs 3.9%, relative risk reduction, 43%) and MI (8.6% vs 11.6%, relative risk reduction, 26%).
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 PCI or 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 PCI or CABG. 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 (see Image 3).
The cost-benefit ratio of an initial invasive approach based on the FRISC II trial has been estimated. At the cost of 15 extra CABG and 21 PCI procedures, the benefit per 100 patients per year is as follows:
1.7 lives saved
2 MIs prevented
20 readmissions prevented
Earlier and better symptom relief
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 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 one hour of silent ischemia during initial admission
Diet: This condition 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.
DRUG TREATMENT :
1. ANTIPLATELET AGENTS
- ASPIRIN
- CLOPIDOGREL
2. HMG-COA REDUCTASE INHIBITORS :
- ATORVASTATIN
- SIMVASTATIN
3. 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
- EPTIFIBATIDE
4. PLATELET AGGREGATION INHIBITORS :
- ABCIXIMAB
5. BETA BLOCKERS : Limit heart rate and reduce blood pressure to decrease myocardial oxygen demand, oppose effects of elevated catecholamines, and produce antiarrhythmic properties.
- METOPROLOL
- ESMOLOL
- PROPRANOLOL
- NADOLOL
6. ANTITHROMBOTIC AGENTS :
- HEPARIN
- ENOXAPARIN
7. 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. 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
- LEPIRUDIN
8. VASODILATORS :
- NITROGLYCERIN