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Braunwald E, Mark DB, Jones RH. Unstable Angina: Diagnosis and Management. Rockville (MD): Agency for Health Care Policy and Research (AHCPR); 1994 May. (AHCPR Clinical Practice Guidelines, No. 10.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Unstable Angina: Diagnosis and Management.

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2Guideline: Initial Evaluation and Treatment of Unstable Angina


Patients with symptoms suggestive of unstable angina present to medical attention either by a telephone call to a medical provider, by a visit to a medical facility, or by emergency transport. The medical provider must appropriately match the intensity and urgency of care with the severity of presenting symptoms. Chapter 1 described the criteria by which clinicians can judge whether a patient's presenting symptoms are consistent with unstable angina and assess the short-term risk of the condition as high, intermediate, or low risk for cardiac events. This chapter describes the initial evaluation and management of patients with unstable angina. Figure 3 depicts the decision logic used to identify patients appropriate to manage using recommendations presented in this guideline.

Figure 3: Entry of patients into the unstable angina guideline.


Figure 3: Entry of patients into the unstable angina guideline.

Objectives of Care

Stabilization of acutely ill patients is the most urgent initial objective. However, for the majority of patients presenting with symptoms suggestive of unstable angina who are obviously stable, triage to the appropriate care environment is the most important early task. A pressing question influencing early care is whether the patient is having an acute MI and has indications for thrombolytic or other reperfusion therapy. During the initial evaluation, until it is clear that high-risk characteristics are not present, it is reasonable to address stabilization and triage of all patients as if they were in a high-risk category.

For all patients, anti-ischemic therapy should be instituted promptly in the ED as soon as a working diagnosis of unstable angina is established. Therapy should be directed toward relieving symptoms and stabilizing the patient by preventing ischemic complications, particularly recurrent unstable angina or acute MI.

As the situation permits, the patient should be moved from the ED to the most appropriate environment to monitor complications and minimize psychological stress and cardiac work. However, initial medical therapy in the ED should not be delayed while triage arrangements are made. Patients initially considered to have unstable angina but subsequently found to have an alternate diagnosis should be excluded from further management by this guideline at the time the alternate diagnosis is made.

Approach to Care Objectives

Entry into Medical Care Directed by the Guideline

Telephone Presentation

Recommendation: Because both clinical examination and ECG are critical to early risk assessment, the initial evaluation of the patient with symptoms suggesting possible unstable angina should be done by a medical practitioner in a facility equipped to perform an ECG and not over the telephone (strength of evidence = B).

Health practitioners frequently receive calls from patients who are concerned that the symptoms they notice reflect heart disease. Patients with severe and increasing angina or other symptoms suggesting an impending cardiac catastrophe should be urged to seek transport to an ED. More commonly, telephone calls describe situations that are not clearly urgent, and both the patient and the practitioner often have difficulty knowing which symptoms can be ignored or explored as a nonemergent problem and which should receive more immediate attention.

Patients with known CAD-including those with a recent MI, CABG, or PTCA-who contact their physician because of exacerbation or recurrence of symptoms should, in most instances, be encouraged to seek direct medical care. Only those patients who have been recently evaluated and who are calling for advice regarding modification of medication as part of an ongoing treatment plan represent exceptions to this principle.

Most telephone calls from patients without known CAD regarding chest discomfort of possible cardiac origin do not represent an emergent situation but simply reflect the desire of the patient for reassurance about the absence of disease or the safety of the symptoms described even if coronary disease might later be found to be present. Despite this fact, nonemergent patients seeking telephone advice for possible cardiac symptoms should be advised that recognition of CAD and evaluation of its severity generally cannot be adequately done by telephone because of the need for an ECG.

The importance of an ECG in early evaluation of unstable angina was emphasized in a study of 90 patients with unstable angina that documented ST-segment deviation >1 mm in two or more leads on ECG to have a positive predictive value for adverse clinical events of 79 percent and a negative predictive value of 64 percent in early evaluation of unstable angina ( Cohen, Hawkins, Greenberg et al., 1991). In a study by the Research Group on Instability in CAD in Southeast Sweden (RISC), an abnormal initial ECG was found to be present in 55 percent of 911 men at the time of ICU admission, and ST-segment abnormality was found to be predictive of 76 percent of subsequent death or MI events observed in the population after 90-day followup ( Nyman, Areskog, Areskog et al., 1993).

Patients must retain the ultimate responsibility of deciding whether they will seek medical attention and if so in what environment. A medical practitioner cannot be expected to assume responsibility for a patient with a potentially severe cardiac condition who does not present for direct evaluation. Practitioners should be cautious not to provide inappropriate reassurance to patients inclined not to seek further medical attention. However, medical practitioners may assist by providing information patients may use to decide the degree of urgency with which to seek care. The Patient and Family Guide, Managing Unstable Angina, is a good source of this information, and this companion booklet, which was developed in conjunction with this guideline, is available free of charge from the AHCPR.

Outpatient Facility or Emergency Presentation

Recommendation: Patients with suspected unstable angina who have a symptom duration >20 minutes, hemodynamic instability, or recent loss of consciousness should generally be referred to an ED. Other patients with suspected unstable angina may be seen initially either in an ED or in an outpatient facility at the discretion of the attending physician (strength of evidence = C).

The decision about where to perform the initial patient evaluation must be based on the individual patient's presenting complaint and circumstances, the options for transportation, and the local facilities available. In general, patients with unremitting symptoms >20 minutes in duration, with symptoms suggesting acute or worsening congestive heart failure (CHF), such as increasing dyspnea or orthopnea, and those with syncope or near-syncope, should be encouraged to go to (or be transported to) an ED. Transport of these patients by emergency medical transport teams is preferable when readily available. Transport as a passenger in a private vehicle is an acceptable alternative if waiting for an emergency vehicle would impose a long delay. All other patients may be seen initially in an outpatient facility mutually agreeable to the patient and physician.

The first 10 to 20 minutes of the initial encounter with the patient should include a brief assessment of the urgency with which evaluation must be done and treatment started. The urgency of evaluation for patients with ongoing rest pain upon presentation is substantially greater than for patients whose symptoms have already resolved. If the patient is hemodynamically stable and does not appear in great distress, the initial evaluation can precede treatment decisions. Otherwise, both must be done simultaneously. Diagnosis of hemodynamic instability is based on the patient's systolic blood pressure (SBP) (i.e., <=90 mmHg), respiratory status (i.e., acutely dyspneic), mental state (i.e., confused or obtunded), and peripheral circulation (i.e., vasoconstricted, diaphoretic).

No data are available prospectively comparing outcomes of patients treated in different initial care environments and grouped by the severity of presenting cardiac symptoms. Studies of disposition of patient groups after ED presentation for complaints of possible cardiac etiology suggest practitioners must identify the minority of patients with potentially severe disease from within the much larger group of patients who either have no CAD or at least no need for urgent care. In one study of more than 12,140 patients presenting to EDs of three university and four community hospitals for evaluation requiring consideration of acute IHD, noncardiac chest pain was diagnosed in about 65 percent ( White, Lee, Cook et al., 1990).

Even in the most urgent subgroup of patients presenting with acute-onset cardiac disorders, time is usually adequate to transport patients to an environment where they can undergo evaluation and treatment ( Ghali, Cooper, Kowatly et al., 1993; Schroeder, Lamb, and Hu, 1977). A large study of consecutive patients transported to the ED by ambulance for chest pain suspected to be of cardiac etiology resulted in a final diagnosis of acute MI in about one-third, unstable angina in one-third, and noncardiac etiology in most of the remaining third of this population. Only 1.5 percent of these patients developed cardiopulmonary arrest in the prehospital or ED settings ( Hargarten, Chapman, Stueven et al., 1990). These data suggest that patients with acute chest pain are better served by transport to an adequate ED than by compromising the quality of the care environment in an attempt to shorten the initial transport time.

Stabilization and Initial Evaluation

Initial Evaluation of Low- and Intermediate-Risk Patients. Intermediate- and low-risk patients (see Table 8) who arrive at a medical facility in a pain-free state, have unchanged or normal ECGs, and are hemodynamically stable represent more of a diagnostic than an urgent therapeutic challenge. Evaluation begins in these patients by obtaining information from history, physical examination, and ECG to be used to confirm the diagnosis of unstable angina as discussed in Chapter 1. After this initial evaluation, those patients assigned to the definitely not angina category are excluded from further management by this guideline. These excluded patients should be evaluated further for another cause of their symptoms or reassured that their symptoms are likely to be self-limited if a nonthreatening cause has been identified (e.g., anxiety, musculoskeletal pain). Reassurance should be balanced with instructions to return for further evaluation if symptoms worsen or fail to respond to symptomatic medical treatment.

Patients meeting criteria for unstable angina should receive ASA therapy, 160 to 324 mg, as described below, unless contraindications are present. Patients without pain but with definite ischemic ECG changes should be treated during this initial phase as if they have ongoing pain. Patients without ongoing pain or ischemic ECG changes should be further risk-stratified. About one-half of these patients will be known to have CAD for which they have received prior treatment. Management decisions for these patients with known CAD are similar to those for patients without known CAD but with a high likelihood of having CAD.

Details of past medical care most likely to impact on current management decisions include prior assessments of LV function and coronary anatomy, prior revascularization procedures, and recent medication history. The current historic information of greatest importance in these patients is their assessment of the severity and tempo of their symptoms in the context of their prior history. Patients who feel that their symptoms are similar to those experienced during a prior major cardiac event and patients who have undergone coronary angioplasty or a bypass operation within the past year and have intermediate- or high-risk features deserve hospital admission for more thorough evaluation in most cases. Patients with known LV dysfunction or CHF represent another group that should usually be admitted to the hospital. Patients who are at or near maximal medical treatment and who have been symptomatic over the preceding 24 hours deserve hospital admission. Others who should be admitted include patients with a symptom duration >=1 hour (even without ECG changes), patients with a history of rest pain lasting >20 minutes within the past week, or patients with a two-class worsening of angina ( Goldman, Cook, Brand et al., 1988). All low-risk patients with known CAD usually can be managed as described in Chapter 3. Hospitalization may be reasonable in some low-risk patients with known CAD, such as those with other diseases that might confound outpatient management and patients who live in areas remote from an appropriate health care facility.

Patients without known CAD and a high likelihood of CAD are managed initially as if they have high-risk unstable angina. For all other patients without known CAD, the pattern of recent symptoms defines the urgency with which further evaluation should proceed to determine the likelihood of CAD as a cause of symptoms. Patients with an intermediate likelihood of CAD for whom another cause of current symptoms cannot be determined who also appear to be at intermediate risk are usually best managed by hospitalization in a standard or intermediate care bed. Patients with an intermediate likelihood of CAD but low risk deserve further evaluation for the cause of their symptoms. In some cases, it will be logistically reasonable to proceed with a more definitive evaluation in the ED. Alternatively, patients who have been asymptomatic for >24 hours can reasonably be referred to an outpatient facility for definitive workup. However, in most situations, this evaluation should be completed within 72 hours, and patients should always be advised to return to the ED immediately for reevaluation if symptoms recur, worsen, or fail to respond to prescribed symptomatic therapy. A trial of sublingual NTG may provide useful diagnostic information in some of these patients. All patients should be instructed to observe and later report the influence of medication and activity on symptoms experienced during the interval prior to more definitive evaluation.

Patients with a low likelihood of CAD, especially those with a history of intermediate-risk features who currently do not have ongoing pain, ECG change, or hemodynamic instability, should be evaluated carefully for other causes of the presentation including: musculoskeletal chest pain>= gastrointestinal (GI) disorders, such as gastritis, peptic ulcer disease, or cholecystitis; intrathoracic disease, such as esophageal spasm, pneumonia, pleurisy, pneumothorax, or pericarditis; neuropsychiatric disease, such as hyperventilation; or panic disorder. Patients who are found to have evidence of one of these alternative diagnoses should be excluded from management by this guideline and referred appropriately for followup care. Stable angina may also be diagnosed in this setting, and patients with this diagnosis are excluded from further management by this guideline. Patients for whom a specific diagnosis cannot be made on the brief initial examination should undergo a more definitive evaluation. This evaluation may proceed in the ED or outpatient facility if time permits. Occasionally, admission to a standard hospital unit is required for definitive evaluation of patients with complex presentations.

Definitive evaluation of patients with a low likelihood of CAD and low risk is less urgent than it is for patients at higher risk. If time is not adequate in the ED setting to evaluate these low-risk patients sufficiently to arrive at an alternate diagnosis or to differentiate unstable angina from stable angina, patients should be referred for outpatient evaluation, generally within 72 hours, as described in Chapter 3.

Evaluation of Unstable Angina Patients for Precipitating Noncardiac Causes of Symptoms

Recommendation: The definitive initial evaluation of the unstable angina patient should include a systematic search for precipitating noncardiac causes that might explain the new development of unstable symptoms or the conversion from a stable to an unstable course. Thus, each patient's ECG should be evaluated for arrhythmias, and patients should have a measurement of body temperature and blood pressure, a hemoglobin or hematocrit determination, and a physical examination for evidence of other cardiac diseases (particularly aortic valve disease and hypertrophic cardiomyopathy) or hyperthyroidism (exophthalmos, resting tremor, thyroid exam). Review of the history may reveal additional potential exacerbating factors such as a recent increase in physical activity level especially in combination with environmental temperature extremes, noncompliance with medical therapy, or a recent increase in psychological stress levels (strength of evidence = C).

Information from the initial history, physical examination, and ECG will enable the practitioner to recognize and exclude patients classified as "not angina." The remaining patients should undergo more complete evaluation for secondary causes of the presentation and for manifestations of coexisting diseases that might alter management. Cardiac disorders other than CAD that may present with acute ischemia, particularly in the setting of significant CAD, include aortic stenosis and hypertrophic cardiomyopathy. Factors that increase the oxygen demand or decrease myocardial oxygen delivery to the heart may provoke or exacerbate ischemia, particularly in the presence of significant CAD. Previously unrecognized gastrointestinal bleeding is one common secondary cause of exacerbated CAD symptoms due to anemia. Acute worsening of chronic obstructive lung disease (with or without superimposed infection) may lower oxygen saturation levels enough to worsen CAD symptoms. Evidence of increased cardiac oxygen demand over normal resting levels can be judged from the presence of a fever or findings of hyperthyroidism. Similarly, uncontrolled hypertension can increase oxygen demand by making the heart work harder to eject blood during each systole (increased afterload). Sustained supraventricular or ventricular tachycardias may also provoke acute ischemic symptoms.

Initial Evaluation of High-Risk Patients

Recommendation: The initial assessment of the high-risk patient with possible unstable angina must start with a rapid evaluation of the probability of immediate adverse outcomes and the need for emergency diagnostic and therapeutic interventions. Patients with ongoing symptoms, hemodynamic instability, or recent loss of consciousness should have a directed history, physical examination, and 12-lead ECG completed within 20 minutes of arrival to a medical facility (strength of evidence = B). Specific diagnoses that must be explicitly considered are acute MI meeting criteria for reperfusion therapy, aortic dissection, leaking or ruptured thoracic aneurysm, pericarditis with tamponade, pneumothorax, and pulmonary embolism. Other noncardiovascular diagnoses may need to be considered as well, depending on initial findings (strength of evidence = B).

Patients who have ongoing symptoms of unstable angina at rest when first seen deserve more urgent evaluation than patients with prior discomfort who are asymptomatic when first seen. Intensive medical treatment, as described in Chapter 4, should begin immediately in the ED in patients with ongoing rest pain or definite ECG ischemia and should continue as the patient is transported to the definitive care environment. Ongoing rest pain with treatment should drive initial evaluation at a more urgent pace and therapy to more aggressive regimens than is required for patients with pain that resolves rapidly as treatment is begun.

Occasionally, patients with rest angina also have hemodynamic instability manifested by hypotension, dyspnea, and/or a sense of impending catastrophe. Patients who appear unstable should have simultaneous evaluation and treatment. IV access can be obtained while a brief cardiovascular history and physical examination are completed and an ECG is taken. When initial blood work is obtained, a sample should be sent for determination of creatinine kinase (CK). Medical personnel trained in cardiopulmonary resuscitation should remain in close attendance during the period of initial stabilization. Oxygen should be administered by mask or nasal cannula.

A record review of 445 patients presenting to 10 metropolitan EDs for management of acute nontraumatic chest pain found 78 percent of patients underwent physician evaluation and 60 percent had an initial ECG within 20 minutes of arrival in the ED ( Heston and Lewis, 1992). This unselected population included patients presenting with a spectrum of severity. It is, therefore, reasonable that all patients presenting with severe symptoms be evaluated for risk within 20 minutes of arrival at the ED. In ED environments without a physician continuously present, nurses or other medical providers should assess the patient, obtain an ECG, and begin treatment to support any patient with hemodynamic instability and involve the physician in important decisions using telecommunications as appropriate to the specific circumstances occurring before the arrival of the physician in the ED.

As treatment is begun in patients with the presumptive diagnosis of high-risk unstable angina, further evaluation should continue to address other possible conditions as alternate diagnoses to unstable angina. Other severe conditions to be considered include acute MI, aortic dissection, leaking or ruptured thoracic aneurysm, acute pericarditis with tamponade, pulmonary embolism, pneumothorax, esophageal rupture, or rupture or ischemia of intra-abdominal organs. Chest or abdominal images (chest radiograph, transthoracic or transesophageal echocardiogram, computed tomogram, or magnetic resonance image) may be useful for differentiating these severe conditions from unstable angina at this early stage of evaluation. However, a history and physical examination directed by suspicion of one of these conditions remains the most important diagnostic tool. In one study of 918 consecutive patients evaluated for suspicion of unstable angina, common alternate final diagnoses included unspecified chest pain, pulmonary embolism, acute abdominal disease, and other miscellaneous diseases ( Aase, Jonsbu, Liestol et al., 1993).

Initial Treatment of Patients with Unstable Angina

Initial General Care

Recommendation: Patients with unstable angina and ongoing rest pain should be placed at bed rest during the initial phase of medical stabilization (strength of evidence = C).

Recommendation: Patients with obvious cyanosis, respiratory distress, or high-risk features (see Table 8) should receive supplemental oxygen. A finger pulse oximetry or arterial blood gas determination should be used to confirm adequate arterial oxygen saturation and continued need for supplemental oxygen (strength of evidence = C).

Recommendation: As soon as the diagnosis of unstable angina is made, patients should be placed on continuous ECG monitoring for ischemia and arrhythmia detection (strength of evidence = C).

The severity of symptoms of unstable angina will dictate some of the general patient care that should be employed during initial treatment of patients with a diagnosis of unstable angina. Patients should be placed on bed rest while ischemia is ongoing but can be mobilized to a chair and bedside commode once they become symptom-free. Subsequent activity restriction should be focused on preventing recurrent symptoms and may be liberalized as judged appropriate as patients respond to treatment. Patients with cyanosis, respiratory distress, or high-risk features (see Table 8) should receive supplemental oxygen, and adequate blood arterial saturation should be confirmed by direct measurement or pulse oximetry. No evidence is available to support the common medical practice of administering oxygen to all patients with acute chest pain syndromes in the absence of signs of respiratory distress. Although routine use of oxygen during initial evaluation would not appear to cause much harm, more selective use of oxygen for patients with questionable respiratory status or those with documented hypoxemia by finger pulse oximeter is a preferable strategy. All patients with unstable angina should undergo cardiac monitoring during their ED evaluation.

Initial Pharmacologic Treatment.[1] Drugs to be considered for use at the time of initial evaluation and treatment of patients with symptoms suggestive of unstable angina include ASA, heparin, nitrates, and beta blockers. The certainty of diagnosis, severity of symptoms, hemodynamic state and medication history will determine the choice and timing of drugs used in individual patients. Treatment with an indicated drug should begin in the ED and not be delayed until hospital admission. The aggressiveness of drug dosage will depend on the severity of symptoms and, for many drugs, will require modification throughout the subsequent hospital course. Principles of drug use are not altered by the care environment in which the drug is administered.

To avoid redundancy, a detailed description of the use of each drug will be presented only once in this guideline, although modifications of drug use required during other phases of care will be mentioned when appropriate. Because ASA and heparin are the drugs that should be considered early in the treatment of unstable angina, their use is described in this chapter. Nitrates, beta blockers and narcotics are often begun in the ED, but their use at maximum dosage and the importance of response to these agents for determining the need for alternate therapies in individual patients often occurs in the intensive care environment. For this reason the use of nitrates, beta blockers, and morphine is discussed in detail in Chapter 4. Table 9summarizes indications, contraindications, and usual dosage of drugs commonly used in the ED to treat patients with unstable angina.

Table 9: Summary of drugs commonly used in the emergency department to treat patients with symptoms suggestive of unstable angina.


Table 9: Summary of drugs commonly used in the emergency department to treat patients with symptoms suggestive of unstable angina.

Recommendation: IV thrombolytic therapy is not indicated in patients who do not have evidence of acute ST-segment elevation or left bundle branch block (LBBB) on their 12-lead ECG (strength of evidence = A).

The failure of IV thrombolytic therapy to improve clinical outcomes in the absence of acute MI with ST-segment elevation or LBBB has now been clearly demonstrated ( TIMI IIIA, 1993; TIMI IIIB, in press). A meta-analysis by Duke University staff of recent studies of thrombolytic therapy in unstable angina patients shows no benefit of thrombolysis versus standard therapy for the reduction of acute MI. Thrombolytic agents had no significant effect and actually increased the risk of MI by 1.7 percent (95% confidence interval [CI] 2.4-5.8%) (Figure 4). Consequently, such therapy is not recommended for unstable angina patients managed according to this guideline.

Figure 4: Influence of thrombolysis on myocardial infarction in patients presenting with unstable angina.


Figure 4: Influence of thrombolysis on myocardial infarction in patients presenting with unstable angina. Source: Saran, Bhandari, Narain et al., 1990; Karlsson, Berglund, Bjorkholm et al., 1992; Screiber, Rizik, White et al., 1992; (more...)

The distinction between unstable angina and acute MI often cannot be definitively made during the initial evaluation. Patients with ECG changes diagnostic of epicardial injury (i.e., >=1 mm ST-elevation in two or more contiguous leads, or ST-depression in V1-V3) or LBBB with a consistent history should be managed as if they have an acute MI, including prompt administration of ASA, beta blockers, and reperfusion therapy. In most large trials of reperfusion therapy, such patients have a >=95 percent prevalence of acute MI. In the Multicenter Chest Pain Study, however, only about 80 percent of patients meeting these criteria had acute MI ( Lee, Weisberg, Brand et al., 1989).

Recommendation: All patients with the diagnosis of unstable angina should receive regular ASA 160 to 324 mg as soon as possible after presentation unless a definite contraindication is present, such as evidence of ongoing major or life-threatening hemorrhage, a significant predisposition to such hemorrhage (e.g., recent bleeding peptic ulcer disease), or a clear history of severe hypersensitivity to ASA (strength of evidence = A).

The recommendation for an initial ASA to be given in the ED is based on the efficacy of this therapy in independently reducing mortality in patients with acute MI enrolled in the second International Study of Infarct Survival (ISIS-2) trial (1988). Those data, combined with the recognition that a definitive distinction between acute MI and unstable angina is frequently not possible at the time of acute presentation, led to the recommendation to initiate ASA immediately in appropriate patients. No randomized trials or other studies compare immediate with a more delayed initiation of ASA in unstable angina.

Some of the strongest evidence available about the long-term prognostic effects of medical therapy on coronary disease outcomes pertains to ASA. ASA inhibits the formation of thromboxane A2, thereby diminishing platelet aggregation promoted by some but not all physiologic stimuli. Since platelets are one of the main participants in the thrombotic consequences of disruption of a coronary plaque, platelet inhibition is a plausible mechanism for clinical benefit. In unstable angina, ASA has been shown to have significant benefit for stabilizing an acutely unstable coronary plaque, producing reductions in mortality and MI rates of 50 percent or more.

Four randomized trials clearly demonstrated the benefit of ASA in the long-term treatment of unstable angina. The Veterans Administration (VA) Cooperative Study Group in 1983 compared the effects of 324 mg of ASA given once a day for 12 weeks with the effects of placebo in 1,266 male veterans admitted with unstable angina ( Lewis, Davis, Archibald et al., 1983). At the conclusion of the 12-week study period, there was a 51 percent reduction in the rate of nonfatal acute MI in the ASA group (3.4% vs. 6.9%, p=0.005) and a 51 percent reduction in the rate of death or acute MI in the ASA group (5% vs. 10.1%, p=0.0005). Although the difference in the mortality rates of the ASA and placebo groups was not significant at 12 weeks, there was a significant 43 percent reduction in the mortality rate of the ASA-treated group at 1-year followup (5.5% vs. 9.6%, p=0.008).

A group of Swedish investigators reported the effects of ASA (75 mg/day) compared with the effects of placebo in 796 men admitted with either unstable angina or non-Q-wave MI ( Wallentin, 1991). Study treatment had been scheduled for 1 year, but the trial was stopped after publication of the ISIS-2 trial. All patients received at least 3 months of treatment. At 12-month followup, there was a significant 48 percent reduction in the combined rate of death and MI in the ASA group (11% vs. 21%, p=<=0.0001). However, there was no significant difference in the risk of death alone (2.7% vs. 4.5%, p=NS). ASA also reduced the incidence of recurrent angina in this trial.

A Canadian multicenter trial reported in 1985 tested the effects of 325 mg of ASA given every 6 hours with the effects of placebo in 555 patients admitted to the CCU with unstable angina ( Cairns Gent, Singer et al., 1985). At an average followup point of 18 months, there was a significant 56 percent reduction in the risk of cardiac death (5% vs. 9.4%, p=0.009), although there was no difference in the followup rate of MI. A second Canadian study reported in 1988 examined the effects of 325 mg of ASA given twice per day versus those of placebo in 479 patients admitted to the CCU with unstable angina ( Theroux, Ouimet, McCans et al., 1988). The researchers reported a 28 percent reduction in the rate of MI over the first week of therapy in the ASA group (3.3% vs. 11.9%, p=0.012). There were too few deaths to analyze the effects of the treatment on this endpoint. Meta-analysis of these four studies to assess outcomes measured at greater than 3 months suggests that ASA reduces the risk of MI by 48 percent and the risk of death by 51 percent. There was a 47 percent reduction in the combined risk of death and MI as illustrated in the likelihood function in Figure 5.

Figure 5: Relative risk of death or myocardial infarction in unstable angina patients treated with aspirin vs. placebo.


Figure 5: Relative risk of death or myocardial infarction in unstable angina patients treated with aspirin vs. placebo. Source: Carins, Gent, Singer et al., 1985; Lewis, Davis, Archibald et al., 1983; Theroux, Ouimet, McCans et al., (more...)

No data directly compare the efficacy of different doses of ASA in patients presenting with unstable angina. However, a broad review and meta-analysis of different doses of ASA in long-term treatment of patients with CAD suggest equal efficacy of daily doses of 75-324 mg per day ( Antiplatelet Trialists' Collaboration, 1994). It appears reasonable to initiate ASA treatment in patients with unstable angina with a dose of at least 160 mg as used in the ISIS-2 (1988) trial. Thereafter, an ASA dose of 80-324 mg could be used for long-term therapy.

Recommendation: IV heparin should be started as soon as a diagnosis of intermediate- or high-risk unstable angina is made (strength of evidence = A). The initial dose is 80 units/kg by IV bolus followed by a constant infusion of 18 units/kg/hr, maintaining the activated partial thromboplastin time (aPTT) at 1.5 to 2.5 times control.

There is clear and compelling evidence that IV heparin started early in the course of unstable angina reduces the risk of subsequent MI and recurrent unstable angina. Heparin exerts its anticoagulant effect by markedly accelerating the action of circulating antithrombin III, a proteolytic enzyme that inhibits thrombin and several other activated factors in the clotting cascade. Thus, heparin acts to prevent thrombus propagation but does not lyse existing thrombi (Hirsh, 1991).

Five randomized trials of heparin use in unstable angina have been reported. Two early trials showed a benefit but must be judged inconclusive due to methodologic defects ( Telford and Wilson, 1981; Williams, Kirby, McPherson et al., 1986). A group of Swedish investigators performed a double-blind placebo-controlled trial with a 2x2 factorial design in 796 men with unstable angina or non-Q-wave infarction ( RISC Group, 1990). The active drug regimens tested were ASA 75 mg daily for >=3 months and heparin 5,000 units IV bolus every 4 hours. Drug therapy was initiated 1 to 3 days after hospital admission. This investigation did not demonstrate any therapeutic benefit of heparin alone, although patients treated with heparin and ASA combined had significantly fewer (p=0.0007) deaths and MIs than those treated with heparin alone, and fewer, but not significantly fewer, cardiac events than ASA alone ( RISC Group, 1990).

Two placebo-controlled heparin and ASA trials were performed at the Montreal Heart Institute. A 479-patient study performed between 1986 and 1988 tested treatments consisting of 650 mg of ASA immediately followed by 324 mg twice per day and a 5,000-unit IV heparin bolus followed by 1,000 units per hour in a 2x2 factorial design ( Theroux, Ouimet, McCans et al., 1988). Importantly, a double-blind placebo was used for both heparin and ASA ensuring truly unbiased assessment of efficacy. Although the study was too small to detect an effect on mortality, the risk of MI was reduced by 89 percent and the risk of recurrent refractory angina by 63 percent relative to placebo. In this study, ASA also reduced the rate of MI, but the two drugs given together were not superior to heparin alone (possibly due to the relatively small sample size and inadequate statistical power) and were associated with a slightly higher risk of serious bleeding. A more recent double-blind randomized trial from this group compared ASA (325 mg twice per day) and heparin (5,000 units IV bolus followed by a constant infusion titrated to an aPTT 1.5 to 2.5 3 control) in 484 unstable angina patients. MI (fatal or nonfatal) occurred in 0.8 percent of heparin patients and 3.7 percent of ASA patients (p=0.035). This trial was the first to clearly demonstrate the superiority of IV heparin over ASA in the acute phase of unstable angina ( Theroux, Waters, Qiu et al, 1993).

Taken together, these available trials indicate a substantial reduction in acute MI incidence from early heparin, with possible reduction of death and recurrent unstable angina. No direct data exist about the relative efficacy of bolus administration versus continuous infusion of heparin, but two randomized trials from another area of medicine suggest equivalent anticoagulant results and more bleeding complications with intermittent therapy. Thus, although continuous infusion is preferred in this guideline, centers not equipped to administer heparin by continuous infusion may substitute a regimen of 5,000 units IV bolus every 4 hours.

The efficacy of ASA and heparin in combination is suggested, but this benefit has not been unequivocally demonstrated relative to monotherapy by their complementary mechanisms of action and demonstrated value in different phases of the disease. ASA has been shown to provide benefits with an initial ED dose in patients who are later confirmed to have the diagnosis of acute MI. ASA may also prevent reactivation of acute IHD when heparin therapy is discontinued later in the hospital course. Finally, ASA has demonstrated efficacy in long-term secondary prevention. Heparin, on the other hand, is the most efficacious agent available to reduce early in-hospital ischemic events. Thus, the combination of the two agents for initial therapy in unstable angina is strongly recommended.

Treatment and Assessment of Relief of Symptomatic Ischemia

Treatment of Symptomatic Ischemia

Recommendation: Anti-ischemia medication should be begun and titrated to dosages that are adequate to relieve symptomatic ischemia without excessive bradycardia or hypotension. Patients should be encouraged to participate in monitoring the success of medication in relieving their pain. Use of a 10-point numerical pain rating scale, visual analog scale, or adjective rating scale is suggested to help them describe the intensity of pain (strength of evidence = C).

Relief of symptoms of unstable angina is attempted in the ED with beta blockers and nitrates. If oral and sublingual administration of these agents does not relieve ischemia, IV use is indicated. Morphine sulfate is used when these measures are ineffective and can also be helpful during the initial stages of therapy while these other agents are being titrated up to target doses. After initial symptom control is achieved, any recurrent ischemic symptoms should prompt performance of an urgent ECG with the goal of obtaining a recording during symptoms. Calcium channel blockers are reserved for patients requiring an additional agent beyond nitrates and beta blockers and for patients with variant angina. The detailed rationale and mode of use for each of these agents are presented in Chapter 4.

Patients who are counseled on the goal of relief of ischemic symptoms can assist greatly in monitoring effectiveness of therapy by accurately reporting changes in pain intensity. Patients with well-developed coping skills may underreport their pain. In addition, some patients believe that because they are ill, they should expect to feel some pain. These patients often receive less medication than they need to control their anginal symptoms. Use of an objective scale aids in assessment of efficiency of treatment to relieve pain and ischemia. The 10-point individual patient-based intensity score grades pain in severity ranging from 1 being barely perceptible to 10 being the most severe pain ever experienced ( Scott and Huskisson, 1976; Sriwatanakul, Kelvie, Lasagna et al., 1983).

Assessment of the Relief of Ischemia. A vast majority of patients who present with signs of ischemia at rest stabilize rapidly and have decreasing or absent chest pain after 30 minutes of aggressive medical management. These patients should be admitted to an ICU or intermediate care unit. Failure to respond to initial therapy should prompt reconsideration of other possible catastrophic causes of chest pain including ongoing acute MI, aortic dissection, pulmonary embolism, pneumothorax, esophageal rupture, or rupture or ischemia of intra-abdominal organs. Patients considered to have unstable angina after further evaluation who fail to respond within 30 minutes to initial treatment are at increased risk for MI or cardiac death ( Gibson, Young, Boden et al., 1987; Larsson, Jonasson, Ringqvist et al., 1992; Silva, Galli, and Campolo, 1993). These patients are best served by care in the ICU of an institution with capabilities to perform intra-aortic balloon pump (IABP) placement, cardiac catheterization, PTCA, and CABG. Transfer may be considered to another institution when ED care has begun in an institution without access to these invasive technologies.

The benefits of transfer to a facility providing these options of care must be weighed against the risks. In some cases, such as extremely elderly patients or elderly patients with advanced comorbidity, transfer may be inappropriate and/or not in accordance with the wishes of the patient and his or her family. However, in most situations, prompt transfer of severely ill patients with unstable angina to an institution offering definitive care is the most judicious choice. Where long distances are involved, helicopter transport staffed by cardiovascular specialists may benefit deteriorating patients with unstable angina, but ambulance transport is usually adequate in the absence of signs of hemodynamic instability. In remote regions of the country where transfer is not feasible, care should continue in the most satisfactory environment available. Aggressive pharmacologic treatment should continue during the time interval between the decision for transfer, and the time transfer could occur with the option to abort the transfer if the patient improves sufficiently.

Patient Counseling

Recommendation: As permitted by the level of urgency, the health care team should inform the patient and the patient's family or advocate of the probable diagnosis, most reasonable treatment strategies, and most likely outcomes at appropriate intervals during initial evaluation and treatment. At the conclusion of this phase, questions and plans for the next phase of care should be addressed (strength of evidence = C).

The symptoms of unstable angina often develop abruptly, evoking anxiety and fear in patients. Moreover, the prevalence of cardiac death in our society leads many patients to overestimate the potential threat of their cardiac symptoms, and this fear is reinforced by the obvious concern of health care providers. Many patients will be treated by health care providers they do not know, and others lack knowledge of the health care system and its procedures. Good communication between the patient and health care providers is often hindered by these factors and further reduced by the immediate need of the health care team to diagnose and stabilize the patient. Health care providers must overcome communication barriers and provide the patients timely reassurance and information relating to appropriate management of their condition.

Management of patients with unstable angina often requires a decision on the use of alternative tests and procedures with major risks and benefits to patients, and the clinical situation often imposes urgency on reaching these decisions. Obtaining appropriate informed consent is necessary medical practice and is not reiterated at every decision point in this guideline. Patients may be assisted in the difficult task of assimilating and responding appropriately to this information during periods of stress by reiteration of information. The patient may wish to designate a family member or other friend to serve as an advocate for the patient to ensure that the patient understands the information presented by the health care team and to assist in articulating the preferences of the patient. The role of the advocate should not be considered adversarial but should facilitate better communication between care providers and the patient. Communication efforts from health care providers promote a sense of teamwork with the patient and will be rewarded by less anxiety and increased compliance for the patient.

Conclusion of Initial Evaluation and Treatment Phase

At the conclusion of the initial evaluation and treatment phase, the patient presenting with symptoms suggestive of unstable angina should be assigned to one of four diagnostic categories:

  1. Alternate diagnosis, not IHD.
  2. Stable angina.
  3. Reperfusion-eligible acute MI.
  4. Unstable angina.

In assigning patients to these groups, the general approach should be to assume that the patient's symptoms are due to CAD until proven otherwise.

Patients with a diagnosis other than unstable angina and patients with known CAD who are felt to have symptoms attributable to another cause are managed as indicated by their presumptive diagnoses. Patients with suspected unstable angina, but with symptoms that are not sufficiently severe to meet definitional criteria for unstable angina, are categorized and managed as stable angina. Patients with prolonged (i.e., >20 minutes) chest discomfort and ECG evidence of epicardial injury (ST-segment elevation or ST-segment depression consistent with posterior wall injury) or LBBB are diagnosed and managed as reperfusion-eligible acute MI. All other patients (i.e., those with both unstable angina and acute non-ST-segment elevation MI) should be diagnosed as unstable angina and managed as described in Chapters 3, 4, and 5 of this guideline.

Recommendation: High-risk unstable angina patients should be admitted initially to an ICU bed whenever possible (strength of evidence = B). Intermediate-risk unstable angina patients should be admitted to an ICU or monitored cardiac bed (strength of evidence = C). Low-risk unstable angina patients may be managed as outpatients with planned early followup evaluations (strength of evidence = C).

Selection of the appropriate environment for further care of patients diagnosed as having unstable angina is determined primarily by assessment of the short-term risk of untoward events. This benefit must be balanced against the extra monetary cost and possibility of complications from needlessly intensive care ( Wears, Li, Hernandez et al., 1989). High-risk patients should be admitted to an ICU environment and ideally should be kept there until they have been stabilized and are symptom-free for at least 24 hours or additional prognostic information is obtained (e.g., resting measure of LV function, acute coronary angiography) that indicates they are not as high risk as initially believed. Patients judged intermediate risk may occasionally be managed by careful, intense outpatient care, but more commonly will be admitted to an ICU, intermediate care unit, or monitored hospital bed ( Fineberg, Scadden, and Goldman, 1984). At this transition point, intermediate- and high-risk patients should have a basic understanding of what will happen in the next 3 to 6 hours, including knowledge of the identity of the physicians and nurses with primary care responsibility. Low-risk patients who retain the working, but not definite, diagnosis of unstable angina after initial evaluation should undergo additional evaluation as soon as can be arranged but generally no later than 72 hours after initial presentation.

Medical Record

Information to be entered in the medical record summarizing initial evaluation and management for each patient includes:

  • Age and sex.
  • Duration and nature of symptoms prior to presentation.
  • Previous history of CAD; if yes, prior noninvasive test result, prior cardiac catheterization result, prior myocardial revascularization procedure (bypass or angioplasty).
  • Medication and drug use.
  • Risk factors (diabetes, smoking, hypercholesterolemia, hypertension).
  • Systemic causes for precipitating or exacerbating ischemia.
  • ECG interpretation.
  • Initial and final assignment of likelihood of CAD (high, intermediate, low) and basis.
  • Initial and final risk assignment (high, intermediate, low) and basis.
  • Summary of other pertinent positive and negative findings.
  • Major or minor complications of diagnosis or treatment.
  • Patient counseling, including assessment of patient response.
  • Disposition for further care.
  • Deaths classified as noncardiac or cardiac.
  • Cardiac deaths classified as precipitated by arrhythmia, progressive ischemia, or progressive cardiac failure.

Duration of Initial Evaluation and Treatment Phase

The initial assessment of whether a patient has unstable angina and which triage option is most suitable generally should be made within the first hour after the patient's arrival at a medical facility. Lack of appropriate hospital beds or transport facilities to move the patient to another medical facility may prevent expedient implementation of the triage decision. In such cases, stabilization and management of ischemic symptoms should continue as if the patient were admitted to the hospital. Patients judged to be low risk at initial evaluation may have completion of their definitive evaluation deferred for up to 72 hours as long as the severity and frequency of symptoms do not worsen.



Some of the recommendations in this guideline suggest the use of agents for purposes or in doses other than those specified by the Food and Drug Administration (FDA). Such recommendations are made after consideration of concerns regarding nonapproved indications. Where made, such recommendations are based on more recent clinical trials or expert consensus.


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