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Review Article: Treatment of Unstable Angina Pectoris/Non-ST-Segment Elevation Myocardial Infarction in Elderly Patients

Divisions of Cardiology and Geriatrics, Department of Medicine, New York Medical College, Valhalla.

	Abstract

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Elderly patients with unstable angina pectoris/non-ST-segment elevation myocardial infarction should be hospitalized. Precipitating factors should be identified and corrected. Electrocardiogram monitoring is important. Aspirin should be given as soon as possible and continued indefinitely. Clopidogrel should given for up to 9 months in patients in whom an early noninterventional approach is planned or in whom a percutaneous coronary intervention (PCI) is planned. Clopidogrel should be withheld for 5–7 days in patients in whom elective coronary artery bypass graft surgery (CABGS) is planned. A platelet glycoprotein IIb/IIIa inhibitor should also be given in addition to aspirin, clopidogrel, and heparin in patients in whom cardiac catheterization and PCI are planned. Patients whose symptoms are not fully relieved with three 0.4-mg sublingual nitroglycerin tablets or spray taken 5 minutes apart and the initiation of an intravenous beta blocker should be treated with continuous intravenous nitroglycerin. Beta blockers and angiotensin-converting enzyme (ACE) inhibitors should be given and continued indefinitely. The benefit of long-acting nondihydropyridine calcium channel blockers is limited to symptom control. Intra-aortic balloon pump counterpulsation should be used for severe ischemia that is continuing or occurs frequently despite intensive medical therapy or for hemodynamic instability. Statins should be used if the serum low-density lipoprotein (LDL) cholesterol is 100 mg/dl and continued indefinitely. Enoxaparin is preferable to intravenous unfractionated heparin in the absence of renal failure and unless CABGS is planned within 24 hours. Thrombolysis is not beneficial. High-risk patients should have an early invasive strategy with CABGS or PCI performed depending on the coronary artery anatomy, left ventricular function, presence or absence of diabetes, and findings on noninvasive testing. Following hospital discharge, patients should have intensive risk factor modification with cessation of smoking, maintenance of blood pressure below 135/85 mmHg, indefinite use of statins if needed to maintain the serum LDL cholesterol <100 mg/dl, intensive control of diabetes, maintenance of optimal weight, and daily exercise. Patients should be treated indefinitely with aspirin, beta blockers, and ACE inhibitors and with clopidogrel for up to 9 months. Nitrates should be given for ischemic symptoms. Hormonal therapy should not be given to postmenopausal women.

Older patients with unstable angina pectoris should be hospitalized, and depending on their risk stratification, may need monitoring in an intensive care unit. Patients diagnosed as having class IA unstable angina pectoris have acceleration of prior exertional angina pectoris without electrocardiographic (ECG) evidence of myocardial ischemia, and are at lowest risk for developing in-hospital complications (3). Patients diagnosed as having class IB unstable angina pectoris have acceleration of prior exertional angina pectoris with ECG evidence of myocardial ischemia (3). Patients diagnosed as having class II unstable angina pectoris have new onset of exertional angina pectoris (3). Patients diagnosed as having class III unstable angina pectoris have new onset of angina pectoris occurring at rest (3). Patients diagnosed as having class IV unstable angina pectoris have a coronary insufficiency syndrome with protracted chest pain lasting longer than 20 minutes and with persistent ECG changes of myocardial ischemia (3). Patients with class IV unstable angina pectoris are at the highest risk for developing in-hospital complications (3).

A prospective study was performed in 177 consecutive unselected patients aged 70 to 94 years, hospitalized for an acute coronary syndrome (4–6). The 177 patients included 91 women, mean age 79 years, and 86 men, mean age 77 years (4). The 177 patients included 11 African Americans, mean age 77 years, 140 whites, mean age 78 years, and 26 patients of other races, mean age 77 years (5). Unstable angina pectoris was diagnosed in 95 of the 177 elderly patients (54%), NSTEMI in 61 of the 177 elderly patients (34%), and ST-segment elevation myocardial infarction (MI) in 21 of the 177 elderly patients (12%) (4–6). NSTEMI was diagnosed in elderly patients hospitalized with ischemic-type chest discomfort lasting longer than 30 minutes without ST segment elevation but with an elevated serum creatinine kinase-MB or a cardiospecific troponin I or T level (4,5).

All 177 elderly patients underwent coronary angiography. The patients with ST-segment elevation MI or NSTEMI underwent coronary angiography within 1–12 hours of hospitalization. The patients with unstable angina pectoris had coronary angiography performed within 24–48 hours of hospitalization after optimal medical management (4–6). Nonobstructive CAD was diagnosed if there was <50% stenosis in the coronary arteries (4–6). Significant obstructive CAD was present in 154 of 177 elderly patients (87%), nonobstructive CAD in 19 of 177 elderly patients (11%), and no CAD in 4 of the 177 elderly patients (2%) (Table 1) (4,5).

Table 2 shows the clinical features of patients with unstable angina pectoris who are at high risk for death or nonfatal MI according to the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines (7). Table 3 shows the clinical features of patients with unstable angina pectoris who are at intermediate risk for short-term risk of death or nonfatal MI (7). Table 4 shows the clinical features of patients with unstable angina pectoris who are at low risk for short-term risk of death or nonfatal MI (7).

	RISK ASSESSMENT

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In 9461 patients in the Platelet IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy trial, the most important baseline features associated with mortality were age, heart rate, systolic blood pressure, ST-segment depression, signs of heart failure, and increased levels of cardiac biomarkers (8). Antman and colleagues developed a 7-point risk score (9) from the Thrombolysis In Myocardial Infarction 11B (TIMI 11B) study (10), and then validated it in 3 additional studies (11–13). The score was defined as the sum of 7 individual prognostic variables: age 75 years; more than 3 coronary risk factors; prior angiographic CAD; ST-segment deviation; more than 2 anginal episodes within 24 hours; use of aspirin within 7 days; and elevated cardiac biomarkers (9). The risk of developing death, recurrent MI, or recurrent severe myocardial ischemia that needed coronary revascularization ranged from 5% with a score of 0 or 1 to 41% with a score of 6 or 7 (9–13). A progressively greater benefit from low-molecular-weight heparin (LMWH) (10,11), platelet glycoprotein IIb/IIIa receptor inhibitors (12), and an invasive strategy (13) have been reported in patients with increasing risk score.

The Joint European Society of Cardiology/ACC Committee for the Redefinition of Myocardial Infarction emphasized the use of cardiac-specific troponins as critical markers of the presence of myocardial necrosis (14). Cardiac troponins should be used in conjunction with appropriate clinical features and ECG changes in the diagnosis of NSTEMI (14). Myocardial injury from myocarditis, trauma, or cardioversion may also cause myocardial necrosis and release of cardiac troponins.

	THERAPY

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Treatment of patients with unstable angina pectoris/NSTEMI should be initiated in the emergency department. Reversible factors precipitating unstable angina pectoris should be identified and corrected. ECG monitoring is important since arrhythmias may occur and ST–T-wave changes are a marker of increased risk of complications.

Oxygen should be administered to patients who have cyanosis, respiratory distress, congestive heart failure, or high-risk features. Oxygen therapy should be guided by arterial oxygen saturation and should not be given if the arterial oxygen saturation is more than 94%. Morphine sulfate should be administered intravenously when anginal chest pain is not immediately relieved with nitroglycerin or when acute pulmonary congestion and/or severe agitation is present.

Table 5 lists ACC/AHA class I indications for the use of drugs in the treatment of patients with unstable angina pectoris/NSTEMI (15). Aspirin should be administered to all patients with unstable angina pectoris/NSTEMI unless contraindicated, and continued indefinitely (15). The first dose of aspirin should be chewed rather than swallowed to ensure rapid absorption. Clopidogrel should be administered to patients who are unable to tolerate aspirin because of hypersensitivity or major gastrointestinal intolerance (15).

The 2002 ACC/AHA guidelines update states that clopidogrel should be administered for up to 9 months in addition to indefinite use of aspirin in hospitalized patients with unstable angina pectoris/NSTEMI in whom an early noninterventional approach is planned or in whom a percutaneous coronary intervention (PCI) is planned (15). Clopidogrel should be withheld for 5–7 days in patients in whom elective coronary artery bypass graft surgery (CABGS) is planned (15).

Data from 12,562 patients in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial demonstrated that clopidogrel 75 mg daily combined with aspirin 75–325 mg daily administered for 3–9 months caused a 20% significant decrease in cardiovascular death, nonfatal MI, or stroke compared with patients treated with aspirin plus placebo (16). In the 2658 patients in this study who had PCI, patients treated with aspirin plus clopidogrel had a 30% significant reduction in cardiovascular death, nonfatal MI, or urgent target-vessel revascularization within 30 days of PCI compared with patients treated with aspirin plus placebo (17).

In many hospitals where patients with unstable angina pectoris/NSTEMI undergo diagnostic cardiac catheterization within 24–36 hours of hospitalization, clopidogrel is not given until it is clear that CABGS will not be scheduled within the next several days (15). A loading dose of clopidogrel can be given to a patient on the cardiac catheterization table if a PCI is to be performed immediately (15). If a PCI is not performed, clopidogrel can be administered after the cardiac catheterization (15). A platelet glycoprotein IIb/IIIa inhibitor should also be administered in addition to aspirin, clopidogrel, and heparin in patients in whom a PCI is planned (15).

Table 6 lists the ACC/AHA class IIa indications for the use of drugs in the treatment of patients with unstable angina pectoris/NSTEMI (15). Abciximab can be used for 12–24 hours in patients with unstable angina pectoris/NSTEMI in whom a PCI is planned within the next 24 hours (15). Eptifibatide or tirofiban should be administered in addition to aspirin and LMWH or unfractionated heparin to patients with continuing myocardial ischemia, an elevated cardiospecific troponin I or T, or with other high-risk features in whom an invasive management is not planned (15). A platelet glycoprotein IIb/IIIa inhibitor should also be administered to patients already receiving aspirin, clopidogrel, and heparin in whom cardiac catheterization and PCI are planned (15,18–20).

Nitrates should be administered immediately in the emergency department to patients with unstable angina pectoris/NSTEMI (7). Patients whose symptoms are not fully relieved with three 0.4-mg sublingual nitroglycerin tablets or spray taken 5 minutes apart and the initiation of an intravenous beta blocker should be treated with continuous intravenous nitroglycerin (7). Topical or oral nitrates are alternatives for patients without ongoing refractory symptoms (7).

Beta blockers should be administered intravenously in the emergency department unless there are contraindications to their use followed by oral administration and continued indefinitely (7). Metoprolol may be given intravenously in 5-mg increments over 1–2 minutes and repeated every 5 minutes until 15 mg has been given followed by oral metoprolol 100 mg twice daily. The target resting heart rate is 50–60 beats per minute.

An oral angiotensin-converting enzyme inhibitor should also be administered, unless there are contraindications to its use, and continued indefinitely, especially if diabetes mellitus, hypertension, congestive heart failure, or left ventricular systolic dysfunction is present (7). In patients with continuing or frequently recurring myocardial ischemia despite nitrates and beta blockers, verapamil or diltiazem should be added to their therapeutic regimen in the absence of left ventricular systolic dysfunction (class IIa indication) (7). The benefit of calcium channel blockers in the treatment of unstable angina pectoris is limited to symptom control (7). Intra-aortic balloon pump counterpulsation should be used for severe myocardial ischemia that is continuing or occurs frequently despite intensive medical therapy or for hemodynamic instability in patients before or after coronary angiography (7).

The Lipid Coronary Artery Disease study randomized 126 patients with an acute coronary syndrome to early treatment with pravastatin, alone or in combination with cholestyramine or nicotinic acid, or to usual care (21). At 2-year follow-up, the patients who received early lipid-lowering therapy had a significantly lower incidence of clinical cardiovascular events (23%) than the usual-care group (52%) (21). In the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering trial, 3806 patients were randomized to atorvastatin 80 mg daily or to placebo 24–96 hours after an acute coronary syndrome (22,23). During the 16-week study, the primary end-point event of death, nonfatal MI, resuscitated cardiac arrest, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization was significantly reduced from 17.4% in the placebo-treated group to 14.8% in the atorvastatin-treated group (22). Fatal or nonfatal stroke was also significantly reduced 51% by atorvastatin (23).

In patients with unstable angina pectoris in the Long-Term Intervention With Pravastatin in Ischemic Disease study, compared with placebo, pravastatin significantly reduced mortality by 26% during 6-year follow-up (24). A retrospective analysis of 2 large studies showed that 18% of 20,809 patients with acute coronary syndromes were discharged from the hospital on lipid-lowering drugs (25). At 6-month follow-up, treatment with lipid-lowering drugs was associated with a significant 33% reduction in mortality and a significant 20% reduction in death or MI (25).

In the Platelet Receptor Inhibition in Ischemic Syndrome Management study of 1616 patients with acute coronary syndromes, 379 patients continued statin therapy after hospital discharge and 89 patients discontinued statin therapy after hospital discharge (26). At 30-day follow-up, patients who continued statin therapy had a 51% significant reduction in new coronary events, whereas patients who discontinued statin therapy had a 293% significant increase in new coronary events (26).

In the Lescol Intervention Prevention study, 1677 patients were randomized to receive fluvastatin 80 mg daily or placebo beginning 2 days after PCI (27). At 3.9-year median follow-up, compared with placebo, fluvastatin significantly reduced the incidence of cardiac death, nonfatal MI, or reintervention procedures 22% (27). The reduction in major adverse cardiac events by fluvastatin was independent of serum total cholesterol levels (27).

On the basis of the available data, the ACC/AHA 2002 guidelines recommend the use of statins in patients with acute coronary syndromes and a serum low-density lipoprotein cholesterol >100 mg/dl 24–96 hours after hospitalization (15). Statins should be continued indefinitely after hospital discharge (15,28,29). The ACC/AHA 2002 guidelines also recommend use of a fibrate or nicotinic acid if the serum high-density lipoprotein cholesterol is less than 40 mg/dl, occurring as an isolated finding or in combination with other lipid abnormalities (15).

Table 7 shows the ACC/AHA indications for use of anticoagulation in the treatment of patients with unstable angina pectoris/NSTEMI (15). Anticoagulation with subcutaneous LMWH or with intravenous unfractionated heparin should be added to antiplatelet therapy with aspirin and/or clopidogrel in patients with high-risk or intermediate-risk unstable angina pectoris/NSTEMI (class I indication) (10,15,30–32). Enoxaparin is preferable to intravenous unfractionated heparin in patients with unstable angina pectoris/NSTEMI in the absence of renal failure and unless CABGS is planned within 24 hours (class IIa indication) (15).

Intravenous thrombolytic therapy is not recommended for the treatment of unstable angina pectoris/NSTEMI (15). Thrombolysis is not beneficial in the absence of acute MI without ST-segment elevation, a posterior wall MI, or presumably new left-bundle branch block, and will actually increase risk of MI (33).

	INTERVENTION

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The 2 most recent studies comparing an early invasive strategy with an early conservative strategy in patients with unstable angina pectoris/NSTEMI showed a benefit in patients randomized to the early invasive strategy (13,34). At 1-year follow-up of 2457 patients with unstable angina pectoris/NSTEMI randomly assigned to invasive or noninvasive therapy in the Fragmin and Fast Revascularization During Instability Coronary Artery Disease II study, the invasive strategy significantly decreased the incidence of death or nonfatal MI 26% (34). At 6-month follow-up of 2220 patients with unstable angina pectoris/NSTEMI randomized to an early invasive or to a conservative strategy in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy—Thrombolysis In Myocardial Infarction 18 (TACTICS—TIMI 18) study, patients randomized to an early invasive strategy had an 18% significant decrease in death, nonfatal MI, or rehospitalization for an acute coronary syndrome compared with patients treated with a conservative strategy (13).

Table 8 shows the ACC/AHA class I indications for an early invasive strategy in patients with unstable angina pectoris/NSTEMI (15). In the absence of any of these indications, either an early invasive strategy or an early conservative strategy may be offered to hospitalized patients who do not have contraindications to coronary revascularization (15).

Table 9 shows the ACC/AHA guidelines for coronary revascularization in patients with unstable angina pectoris/NSTEMI (15). These guidelines recommend CABGS for patients who have significant left main CAD, 3-vessel CAD, or 2-vessel CAD with significant proximal left anterior descending CAD, and either a left ventricular ejection fraction less than 50% or with demonstrable myocardial ischemia on noninvasive testing (7). PCI or CABGS is recommended for patients with unstable angina pectoris/NSTEMI who have 1-vessel or 2-vessel CAD without significant proximal left anterior descending CAD, but with a large area of viable myocardium and high-risk criteria on noninvasive testing (7). PCI is recommended for patients with unstable angina pectoris/NSTEMI who have multivessel CAD with a suitable coronary anatomy and with normal left ventricular function and without diabetes mellitus (7).

	RISK STRATIFICATION

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Table 10 shows ACC/AHA class I indications for risk stratification in patients with unstable angina pectoris/NSTEMI (7). Prompt coronary angiography should be performed without noninvasive risk stratification in patients who fail to stabilize with intensive medical treatment (7).

Table 11 shows noninvasive test results that predict a high risk for adverse outcome (>3% annual mortality rate) (7). Patients with any of the noninvasive findings listed in Table 11 should have an early invasive strategy (7).

Table 12 shows noninvasive test results that predict an intermediate risk for adverse outcome (1%–3% annual mortality rate) (7). Table 13 shows noninvasive test results that predict a low risk for adverse outcome (<1% annual mortality rate) (7). These patients should not ordinarily be considered for coronary angiography unless the diagnosis is unclear (7).

	POSTDISCHARGE FOLLOW-UP

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The prevalence of CAD is very high in elderly persons (35). Elderly patients with unstable angina pectoris/NSTEMI have a very high prevalence of coronary risk factors (4–6). Following hospital discharge for unstable angina pectoris/NSTEMI, elderly patients should have intensive risk factor modification. Smoking should be stopped. Dyslipidemia should be treated as previously discussed with diet plus lipid-lowering drugs (15,28,29). Blood pressure should be lowered to <135/85 mmHg (7,36), Diabetes mellitus should be tightly controlled (7,37). Optimal weight should be maintained. Daily exercise should be performed.

Patients should be discharged on aspirin plus clopidogrel in the absence of contraindications, on beta blockers in the absence of contraindications, and on angiotensin-converting inhibitors in the absence of contraindications. Nitrates should be given for ischemic symptoms. A long-acting nondihydropyridine calcium channel blocker may be given for ischemic symptoms that occur despite treatment with nitrates plus beta blockers. Hormonal therapy should not be administered to postmenopausal women.

If angina pain becomes more frequent or severe or is precipitated by less effort or occurs at rest, the patient should contact his or her physician for additional treatment and testing. Angina pain that lasts longer than 15 to 20 minutes or persistent anginal pain despite 3 nitroglycerin doses taken at 5-minute intervals should prompt the patient to go to the nearest hospital emergency department, preferably by ambulance, or the quickest available alternative (7).

	Acknowledgments

Received December 5, 2002

Accepted December 11, 2002

	References

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