During the first hour of evaluation and management, the clinician forms an initial assessment of the patient's problem, institutes initial therapeutic steps, and formulates a triage plan, as described in Chapter 2. High-risk and some intermediate-risk patients with unstable angina, including those with ongoing ischemia refractory to initial medical therapy and those with evidence of hemodynamic instability, should be admitted to an ICU environment with ready access to invasive cardiovascular diagnosis and therapy. This patient group will include some patients with undiagnosed acute MI, but patients with acute MI manifesting ST-segment elevation will have been excluded during initial evaluation. Details of ICU management, early laboratory testing, and risk stratification for these patients are discussed in this chapter (see Figure 7).
Two of the major goals of this phase are to relieve pain and ischemia and to plan a definitive treatment strategy for the underlying disease process. A few patients will require prompt triage to emergency or urgent cardiac catheterization and/or placement of an IABP. However, most patients usually stabilize after a brief period of intensive pharmacologic management and, after appropriate counseling, will choose an approach for definitive therapy. Some patients will choose a more invasive strategy that may involve cardiac catheterization, PTCA, or CABG. Other patients will prefer continuation or initiation of an integrated medical regimen. These patients require careful monitoring of the response to initial therapy with surveillance for ischemia or other complications of unstable angina that may require a change in approach to treatment.
NTG has both peripheral and coronary vascular effects. It increases venous pooling, thereby decreasing myocardial preload and LV-end diastolic volume. The more modest effects on the arterial circulation are not believed to be a major contributor to the therapeutic effect of NTG. NTG vasodilates normal and atherosclerotic coronary arteries and promotes coronary collateral flow. In severe coronary obstruction, physiologic responses to decreased myocardial blood flow promote maximal vasodilatation in the absence of drug therapy. Thus, the primary benefit of NTG in unstable angina is believed to be due to decreased preload with consequent reduction in myocardial oxygen demand. Recently, an inhibition of platelet aggregation effect has been reported, but it is uncertain if this contributes to clinical benefits.
Most studies of IV NTG in unstable angina have been small and uncontrolled ( Depace, Herling, Kotler et al., 1982; Distante, Maseri, Severi et al., 1979; Kaplan, Davison, Parker et al., 1983; Roubin, Harris, Eckhardt et al., 1982). There are no randomized placebo controlled trials in unstable angina that address either the efficacy of the drug in symptom relief or reduction of cardiac events. One small randomized trial compared IV NTG with buccal NTG and found no significant difference ( Dellborg, Gustafsson, and Swedberg, 1991). Pooled analysis of studies of NTG in patients with acute MI from the prethrombolytic era suggest a 35 percent reduction in mortality ( Yusuf, Collins, MacMahon et al., 1988). However, the recently completed, but unpublished, ISIS-4 and GISSI-3 trials in acute MI patients receiving thrombolytic therapy failed to confirm this benefit. Abrupt cessation of IV NTG has been associated with exacerbation of ischemic changes on ECG ( Figueras, Lidon, and Cortadellas, 1991).
Thus, the rationale for the use of this agent in unstable angina is extrapolated from pathophysiologic principles, uncontrolled studies of efficacy, beneficial effects on mortality in acute MI, and clinical experience. There are no data that define the proper timing of initiation of therapy or its useful duration. Considerable evidence has now accumulated that continuous administration of nitrates can lead to attenuation or even elimination of therapeutic effect in as few as 24 hours ( May, Popma, and Black, 1987; Reichek, Priest, Zimrin et al., 1984; Thadani, Hamilton, Olsen et al., 1986). Consequently, nitrates should be given with a nitrate-free period when topical, buccal, or oral nitrates are administered. In addition, in stabilized patients, IV NTG should generally be converted within 72 hours to a nonparenteral alternative to avoid attenuation of effects and potential reactivation of symptoms. Patients who require continued IV NTG beyond 24 hours may require periodic increases in infusion rate to maintain efficacy.
Morphine sulfate has potent analgesic and anxiolytic effects, as well as hemodynamic effects, that are potentially beneficial in unstable angina. Meperidine hydrochloride can be substituted for morphine in patients who are allergic to morphine. No randomized trials have defined the unique contribution of morphine to the initial therapeutic regimen or its optimal administration schedule. However, morphine has many beneficial properties in unstable angina, including relief of pain and anxiety and decreases in cardiac work and oxygen consumption. In particular, morphine causes significant venodilation. In addition, it may produce modest reductions in heart rate (through increased vagal tone) and SBP. The major adverse reaction to morphine in unstable angina is an exaggeration of its therapeutic effect causing significant hypotension, especially in the presence of concomitant vasodilator therapy. This problem usually responds to IV saline boluses; rarely, pressors or naloxone may be required to restore an adequate blood pressure. The other frequent adverse reactions are nausea and vomiting, which occur in 20 percent or more of patients. Respiratory depression is the most serious complication of morphine; severe respiratory hypoventilation requiring intubation occurs in only about 1 percent of acute IHD patients treated with this agent.
Beta-blocking agents are competitive antagonists to catecholamines which exert their effects at cell membrane beta receptors. Beta1 receptors are located primarily in the myocardium; inhibition of catecholamine action at these sites reduces cardiac contractility, sinus node rate, and AV node conduction velocity. Beta2 receptors are located primarily in vascular and bronchial smooth muscle; inhibition of catecholamine action at these sites produces arterial vasoconstriction and bronchoconstriction. In unstable angina, the primary benefits of beta-blocker therapy are due to its effects on beta1 receptors that decrease cardiac work and myocardial oxygen demand.
Initial studies of beta-blocker benefits in acute IHD were small and uncontrolled. Three double blind randomized trials have compared beta blockers to placebo in unstable angina ( Gottlieb, Weisfeldt, Ouyang et al., 1986; Lubsen and Tijssen, 1987; Telford and Wilson, 1981). Meta-analysis of the available trials indicates a 13 percent reduction in risk of progression to acute MI ( Yusuf, Wittes, and Friedman, 1988). No clear effect on mortality in unstable angina has been shown to date. However, randomized trials in acute MI, recent MI, and stable angina with silent ischemia have all shown a mortality benefit for beta blockers. Thus, the overall rationale for the use of beta blockers is compelling and sufficient to make them a routine part of care for patients with unstable angina in the absence of contraindications.
Choice of beta blocker for an individual patient is based primarily on pharmacokinetic and side-effect criteria. There is no evidence that any member of this class of agents is more effective in producing beneficial effects in unstable angina than any other. The specific benefits and disadvantages of using an agent with intrinsic sympathomimetic activity remain unsettled. On the basis of side-effect profiles, initial choice of agents favors metoprolol or atenolol, and esmolol can be used if a continuous infusion is required (e.g., patient is unable to take oral medication).
Patients with marked 1 degrees atrioventricular (AV) block (i.e., ECG PR segment [PR] >0.24 seconds), any form of 2 degrees or 3 degrees AV block, a history of asthma, or severe LV dysfunction with CHF or cardiogenic shock should not receive beta blockers. Patients with significant sinus bradycardia (heart rate <60 beats/min) or hypotension (SBP <90 mmHg) generally should not receive beta blockers until these conditions have resolved. Patients with significant COPD that may have a component of reactive airway disease should be given beta blockers cautiously; initially, low doses of a beta1 selective agent should be used.
In summary, evidence for the beneficial effects of beta blockers in unstable angina are based on limited randomized trial data, along with pathophysiologic considerations and extrapolation from experience with stable angina and acute MI. The recommendation for IV beta blockers in high-risk patients is based on the demonstrated benefit in acute MI patients, as well as the hemodynamic objectives of therapy to reduce cardiac work and myocardial oxygen demand. The duration of benefit with long-term oral therapy is uncertain but appears in the acute MI literature to extend out for at least 5 years.
Calcium channel blockers reduce the myocardial cell transmembrane inward flux of calcium which in turn affects myocardial and vascular smooth muscle contraction, as well as AV conduction. The agents in this class vary in the degree to which they produce clinically important vasodilation, decreased myocardial contractility, and increased AV block. Nifedipine and amlodipine have the largest peripheral arterial vasodilatory effect, verapamil is intermediate, and diltiazem has the least effect. All four agents appear to have coronary vasodilatory properties that are equivalent. Although the different members of this class of agents are structurally diverse and may have somewhat different mechanisms of action, no reliable data demonstrate superiority of one agent over another in unstable angina. Beneficial effects in unstable angina are believed due to variable combinations of decreased myocardial oxygen demand relating to decreased afterload, contractility, and heart rate. Major side effects relate to exaggeration of these three therapeutic effects: hypotension, worsening CHF, AV block. These agents may also have a beneficial effect on LV diastolic relaxation and compliance.
There are several small randomized trials involving use of a calcium channel blocker in unstable angina. Generally, they show efficacy in relieving symptoms that appears equivalent to beta blockers ( Theroux, Taeymans, Morissette et al., 1985). The largest randomized trial, the Holland Interuniversity Trial, tested nifedipine and metoprolol in a 2x2 factorial design ( Lubsen and Tijssen, 1987). Nifedipine alone increased the risk of MI or recurrent angina relative to placebo by 16 percent, metoprolol decreased it by 24 percent, and the combination of metoprolol and nifedipine was associated with a 20 percent reduction in these events. None of these effects, however, were statistically significant. A meta-analysis of the effects of calcium channel blockers on death or nonfatal MI in unstable angina showed no effect ( Held, Yusuf, and Furberg, 1989; Yusuf, Wittes, and Friedman, 1988).
In summary, evidence for the beneficial effects of calcium channel blockers in unstable angina is predominantly limited to control of symptoms ( Gerstenblith, Ouyang, Achuff et al., 1982; Muller, Turi, Pearle et al., 1984). The limited randomized trial data available are not consistent with a beneficial effect on mortality or recurrent infarction. In addition, results from randomized trials involving the use of these agents in acute MI patients suggest an overall detrimental effect on mortality, with patients with LV dysfunction being particularly at risk. Thus, this guideline recommends reserving these drugs as second- or third-line therapy following initiation of nitrates and beta blockers. When required for refractory symptom control, these agents can be used during the early in-hospital phase even in patients with LV dysfunction. However, it should be a goal, particularly in the latter group, to replace this therapy with alternatives as promptly as possible. The risks and benefits of amlodipine relative to other agents in this class remain undefined.
ASA therapy will have been initiated in all patients without contraindications at the time of initial evaluation (see Chapter 2). These patients should be carefully followed for adverse reactions (gastrointestinal upset and bleeding for ASA, thrombocytopenia and bleeding for heparin). The benefit of ASA appears to be sustained when therapy is continued for 1 to 2 years following the initial presentation. Longer term followup data in this particular population are lacking, but given the relatively short-term prognostic impact of unstable angina in coronary disease patients, long-term efficacy can be extrapolated from other studies of ASA therapy in coronary disease. Patients should be informed of the strength of evidence supporting ASA use in unstable angina and CAD. Otherwise, this simple but effective treatment may be discounted by patients because of its low cost and common use for other reasons (e.g., headache, fever).
A small percentage of the unstable angina population is unable to tolerate ASA therapy due to either hypersensitivity (primarily manifesting as life-threatening asthma) or major GI contraindications, principally a recent significant bleed from a peptic ulcer. For these patients, ticlopidine represents a reasonable alternative form of antiplatelet therapy. The mechanism of the antiplatelet effects of ticlopidine remains incompletely defined, is clearly different from ASA, and may include inhibition of mobilization of the fibrinogen receptor in activated platelets.
A multicenter randomized trial of 625 patients in Italy reported a 47 percent reduction in cardiovascular death and a 46 percent reduction in nonfatal MI at 6 months with the use of ticlopidine in unstable angina ( Balsano, Rizzon, Violi et al., 1990). This trial did not employ either heparin or ASA, and no comparison of these agents and ticlopidine was performed. For this reason, ticlopidine cannot be recommended as first-line therapy in unstable angina.
Since it takes up to 3 days for the maximal antiplatelet effect of ticlopidine to be achieved, there is no rationale for acute ED administration, as with ASA. Initial treatment with heparin is especially important in these patients with delayed onset of antiplatelet activity. Adverse effects of ticlopidine include GI problems (diarrhea, abdominal pain, nausea, vomiting) and neutropenia (<1,200 neutrophils/mm3, prevalence approximately 2.4%; severe neutropenia in 0.8%). The latter problem usually resolves within 1 to 3 weeks of discontinuing therapy. Monitoring of ticlopidine therapy includes a complete blood count and differential counts every 2 weeks for the first 3 months of therapy.
A number of other antiplatelet drugs are currently available, and still others are under active investigation. None of the currently available agents, including sulfinpyrazone and dipyridamole, have demonstrated efficacy in unstable angina; for this reason, they cannot be recommended at this time. Current investigational agents that may eventually prove to be more efficacious than ASA include drugs that reversibly block the platelet IIb IIIa receptor.
Recommendation: Heparin infusion should be continued for 2 to 5 days or until revascularization is performed (strength of evidence = C).Initial heparin dosage is 80 units/kg bolus and IV infusion of 18 units/kg/hour. An aPTT is obtained 6 hours after beginning infusion with the goal of keeping the aPTT between 46 and 70 seconds ( Raschke, Reilly, Guidry et al., 1993) or approximately 1.5 to 2.5 times control.
For hospitals with a mean control aPTT value of about 30 seconds, heparin dosage can be adjusted in the following manner:
An aPTT should be obtained 6 hours after any dosage change and used to adjust heparin infusion until aPTT is therapeutic (1.5 to 2.5 times control). When two consecutive aPTTs are therapeutic, an aPTT may be ordered and heparin adjusted every 24 hours. In addition, a significant change in the patient's clinical condition (e.g., recurrent definite ischemia, bleeding, hypotension) should prompt an immediate aPTT determination.
Serial hemoglobin/hematocrit and platelet measurements are recommended at least daily for the first 3 days of heparin therapy. In addition, any clinically significant bleeding, recurrent symptoms, or hemodynamic instability should prompt an immediate determination. Serial platelet counts are necessary to monitor for heparin-induced thrombocytopenia. Mild thrombocytopenia may occur in 10 to 20 percent of patients receiving heparin and usually appears in the first 1 to 3 days of therapy, while severe thrombocytopenia (platelet count <100,000) occurs in 1 to 2 percent of patients and typically appears after 3 to 5 days of therapy. Thrombocytopenia appears to be less frequent with bovine heparin than with porcine heparin. A rare complication (probably <0.2% incidence) is heparin-induced thrombocytopenia with thrombosis. This catastrophic complication is believed to be immunologically mediated and occurs equally with bovine and porcine heparin. A high clinical suspicion mandates immediate cessation of all heparin therapy (including that used to flush IV lines) pending further evaluation of this syndrome.
Most of the trials evaluating the use of heparin in unstable angina have continued therapy for >e;5 days. The efficacy of shorter infusion regimens thus remains undefined. Evaluation of data from the Montreal Heart Institute randomized trial of heparin and ASA showed a significantly increased reactivation rate after withdrawal of study drug with heparin alone compared with the other three regimens ( Theroux, Waters, Lam et al., 1992). The combination of heparin and ASA appears to mitigate this increase although even with ASA, there is hematologic evidence of increased thrombin activity after cessation of IV heparin. Recent uncontrolled observations suggest a reduction in heparin rebound from switching from IV to subcutaneous heparin for several days before stopping the drug.
Standard criteria for diagnosis of acute MI are based on demonstrating elevation and subsequent decline of CK levels along with evolutionary changes on serial 12-lead ECGs. CK is a nonstructural muscle enzyme that catalyzes the transfer of high energy phosphate from creatinine phosphate to adenosine diphosphate (ADP). CK occurs in three isoenzyme forms: skeletal muscle (MM), brain (BB), and MB (predominantly cardiac). CK-MB, the most sensitive and specific diagnostic test for acute MI, begins to rise within 6 hours of myocardial injury and peaks at 10 to 18 hours ( Botker, Ravkilde, Sogaard et al., 1991). Total CK begins to rise at about 12 hours after symptom onset and peaks at 12 to 24 hours. Because of the rapid rise and clearance of CK-MB and total CK, timing of blood sampling is crucial in achieving maximal detection of acute MI. The literature is mixed, however, on the optimal sampling interval ( Lee and Goldman, 1986). Rapid reporting of results of serial CK-MB measurements obtained hourly for 3 hours after presentation to the ED was found to aid early decision in 376 patients evaluated for chest pain ( Young, Hedges, Gibler et al., 1991). After the admission sample, recommendations range from every 6 to every 12 hours for the first 24 hours. A sampling interval of every 6 to 8 hours is recommended to maximize sensitivity ( Brush, Brand, Acampora et al., 1988).
Patients with severe renal insufficiency have a marked reduction in the clearance of CK from the blood. Diagnosis of acute MI in these patients is based not only on finding elevated CK and CK-MB levels but also demonstrating the rise and subsequent fall in these levels in relation to an appropriate clinical event. Patients presenting more than 24 hours after symptom onset who have negative serial CK-MBs should have serial LDH isoenzyme determinations. LDH is a widely distributed cellular enzyme that catalyzes the transformation of pyruvate to lactate. It has five isoenzymes identified on electrophoresis. LDH1 is most common in myocardium, red blood cells, and the kidney. Elevation of LDH1 is usually seen within 12 to 24 hours of myocardial necrosis and may fall to nondiagnostic levels by 72 hours.
Recently, several new laboratory tests for myocardial injury have been proposed with the goal of improving on the sensitivity and specificity of CK-MB. One such group of tests involves measuring the levels of CK-MM and -MB isoforms. Another group of tests concentrates on measuring serum levels of myocardial structural proteins, particularly troponin T, troponin I, myoglobin, and myosin light chain ( Hamm, Ravkilde, Gerhardt et al., 1992; Katus, Yasuda, Gold et al., 1984). At present, none of these approaches has been established as providing more accurate diagnostic information than CK-MB. Thus, these tests are not currently recommended as part of standard practice.
Recommendation: It is reasonable to measure serum lipid levels within 24 hours of admission unless patients have had a recent determination or are on chronic therapy for hyperlipidemia (strength of evidence = C). After 24 hours, determination of lipid levels should be deferred to the posthospital phase (strength of evidence = C).Serum lipid levels (total cholesterol, triglycerides, high-density lipoprotein [HDL] cholesterol) provide an important part of the data base required for planning postdischarge management. Acute MI and other major physical stresses tend to falsely depress cholesterol and triglyceride levels, probably due to elevated circulating catecholamines. There are data, however, which show that cholesterol measured within the first 24 hours of an acute MI accurately reflects nonstress levels ( Gore, Goldberg, Matsumoto et al., 1984). This is the rationale for the recommendation for an admission determination. All patients should also have a followup determination no sooner than 8 weeks after their acute presentation ( National Institutes of Health, 1990).
Recommendation: A followup ECG should be obtained 24 hours after admission and whenever the patient has recurrent symptoms or a change in clinical status (strength of evidence = C).Serial ECGs are performed in unstable angina to detect the evolutionary changes of acute MI, transient and persistent ischemic complications, and disturbances of rhythm or conduction. In the absence of specific clinical indications, the optimal sampling interval for ECGs is uncertain. New data from continuous ST-segment monitoring show much more dynamic activity of the ST-segment in unstable angina patients than had been previously appreciated. Such patients may be in a tenuous equilibrium between coronary thrombus propagation and lysis with resulting intermittent transient coronary occlusion, often in the absence of symptoms. The therapeutic implication of these findings is still unclear. Also, continuous ST-segment monitoring is not widely available at present. Thus, the panel recommends that after the admission ECG, repeat ECGs should be obtained at 24 hours and then at 48 hours. In addition, a repeat ECG should be obtained whenever the patient's clinical condition changes (e.g., recurrent symptoms, hypotension, arrhythmia, pulmonary edema).
Recommendation: In patients who are hemodynamically stable, a portable chest radiograph should be obtained upon admission unless posteroanterior and lateral chest radiographs are likely to be obtained within 48 hours of admission. Chest radiographs should be obtained initially in all hemodynamically unstable patients and repeated as necessary to evaluate patients for pulmonary edema or for other specific indications (strength of evidence = C).Because of lower cost and greater diagnostic content, a posteroanterior and lateral chest radiograph is preferable to a portable radiograph in patients with unstable angina who are hemodynamically stable. In general, the chest radiograph does not contribute substantially to the initial management of these patients and, therefore, is reasonable to defer until other more pressing management concerns have been addressed. However, any suggestion of hemodynamic instability or inclusion of an alternate diagnosis of severe intrathoracic disease is reason for an early chest radiograph, even if it must be obtained by a portable technique.
Recommendation: In patients who do not undergo early cardiac catheterization but who have had evidence of ischemia, previous infarction, or conduction abnormalities on their resting ECG or have cardiomegaly by physical examination or chest radiograph, resting LV function should be assessed within 72 hours of admission using either a radionuclide ventriculogram or a two-dimensional echocardiogram (strength of evidence = C).The resting EF is one of the most potent prognostic factors in CAD. In patients who are planned for early cardiac catheterization, this measurement can be obtained by contrast ventriculography. Clinicians who opt for an early conservative strategy (defined in Chapter 7) should obtain a resting noninvasive measure of LV function within 72 hours of admission in patients with previous infarction or cardiomegaly on chest radiograph to allow for additional risk stratification and identification of high-risk patients who should be referred for early angiography. Patients with low EFs (<0.50) should receive careful consideration for revascularization therapy because of the risk with medical therapy that increases as a function of decrease in EF. Selection of the imaging mode should be based primarily on the technology and expertise available at each site. Calculation of the EF using 2-D echocardiography is technically more difficult than by radionuclide ventriculography because of the cross-sectional nature of the images and the frequency of suboptimal sound penetration of the chest wall.
An early management strategy characterized by cardiac catheterization within 48 hours of presentation for high-risk unstable angina, with consideration of subsequent revascularization by PTCA or CABG, has been shown by the TIMI IIIB trial (in press) to provide equivalent freedom from cardiac death but better pain relief than a conservative strategy that utilizes interventional approaches only with documented failure of a medical regimen (evidence cited in Chapter 7). A more complete discussion of factors likely to influence choice of these alternate approaches for an individual patient appears in Chapter 7.2
Patient counseling to provide information, discuss relative risks and benefits, and learn patient preference about further treatment with the early invasive or conservative strategies is appropriate after the patient has reached a plateau of stabilization. This important counseling period should be scheduled for a time permitting medical practitioners to completely address these serious issues with several brief intervals of group discussion separated by periods of private reflection for the patient and family and/or advocate. In this elective setting, patients should not be hurried into making this major decision. Patients who choose an early invasive strategy will be managed as described in Chapter 7. The remaining patients will continue to be treated with a medical regimen appropriate for the severity of symptoms and will retain the option for invasive therapy if medical therapy proves ineffective.
Recommendation: The goal of medical therapy for unstable angina is to institute a regimen in which patients receive daily ASA (160 to 324 mg) and IV heparin (adjusted to maintain an aPTT value of 1.5 to 2.5 times control) plus nitrates and beta blockers (with a resting heart rate <e;60 beats/min). Calcium channel blockers may be added in the subset of patients with significant hypertension (SBP >150 mmHg), in patients who have refractory ischemia on beta blockers, and in patients with variant angina. Recurrent symptoms after the initial hemodynamic goals of therapy have been achieved may be regarded as a failure of medical therapy and should prompt consideration of urgent cardiac catheterization (strength of evidence = C).Patients who desire a noninterventional strategy of early treatment of unstable angina will be started on an initial medical regimen with serial reassessments to determine the success of therapy and the occurrence of significant complications. During the initial hours of therapy, medications are titrated up to their target doses as permitted by the patient's hemodynamic state and general medical condition. Prior to achievement of the target regimen, the patient may have recurrent symptoms requiring the physician to consider whether a change in course (such as emergency catheterization) would be appropriate. In addition, once the desired level of medical therapy has been reached, recurrent symptoms may indicate a need for a still more intensive regimen or for triage to early cardiac catheterization. Thus, clinical decisionmaking at this juncture requires criteria by which the adequacy of medical therapy can be judged and failure of such therapy defined. In addition, it is necessary to understand the prognostic importance of the different manifestations of recurrent ischemia so that changes in management can be formulated based on the patient's short-term risk of adverse events.
Criteria defining the adequacy of medical therapy in unstable angina serve two roles: first, they provide the practitioner with explicit therapeutic goals to ensure that patients receive the full benefits available from such therapies; and second, they provide guidance about the conditions under which early diagnostic catheterization and subsequent revascularization should be considered. If inadequate levels of medical therapy are employed, recurrent symptoms may precipitate an otherwise avoidable referral for invasive study. On the other hand, excessively aggressive therapeutic endpoints may provoke harmful complications or needlessly delay revascularization in patients likely to benefit from this therapy.
The optimal level of medical therapy for the unstable angina patient has not yet been established. Two general approaches have been proposed to define adequate medical therapy. The first defines adequate medical therapy as maximally tolerated doses of nitrates, beta blockers, and calcium channel blockers plus ASA and heparin. The implication of this definition is that failure of medical therapy cannot be declared until each drug has been pushed up to limiting levels so that any further increment would cause hemodynamic deterioration or toxicity. The second approach is to define adequate medical therapy by arbitrary levels of each of the key therapeutic agents. For example, in addition to heparin and ASA, this criterion might require the patient to be on IV nitrates (e.g., >e;50 micro-g/min) or nonparenteral nitrates (e.g., >e;1 inch of ointment) and a combination of beta blockers and calcium channel blockers with a heart rate <e;60 beats per minute and an SBP <e;150 mmHg. Since achievement of steady state medication effects may require 24 hours or more even with parenteral administration, some criteria for adequate medical therapy also specify a minimum duration such therapy should be continued prior to referral for invasive study. Intensive medical treatment for unstable angina is usually very effective. In one recent study, only 11 of 502 patients (2%) admitted for unstable angina were found to be truly refractory to medical therapy ( Grambow and Topol, 1992).
Based on current understanding of the most prevalent pathophysiology of unstable angina (i.e., plaque rupture with thrombus formation and propagation), it is proposed that failure of medical therapy be defined in terms of continuing angina despite having an adequate anticoagulant effect with at least moderate reductions in cardiac oxygen demand through decreases in heart rate and blood pressure. Thus, for this guideline a patient will not be said to have failed (or be "refractory" to) medical therapy until he or she is receiving ASA (>e;160 mg/day) and IV heparin with an aPTT of 1.5 to 2.5 times control. In addition, in the absence of limiting symptoms, IV NTG should be infused at >e;50 micro-g/min (or topical NTG at >e;1 inch of ointment every 6 hours for three doses followed by a 6- to 8-hour nitrate-free interval or an equivalent regimen of oral or buccal nitrates). Beta blockers should be used to keep the resting heart rate at an average of <e;60 beats/minute. Significant hypertension (i.e., resting SBP >e;150 mmHg) resistant to first-line medical therapy is an indication for addition of calcium channel blockers.
Although it is theoretically desirable to have this regimen in place for >e;24 hours before declaring any patient a failure of medical therapy, to do so in all cases may be inappropriate or even dangerous. In particular, patients who have one or more recurrent severe, prolonged (>20 minutes) ischemic episodes particularly when accompanied by pulmonary edema, a new or worsening MR murmur, hypotension, or new ST- or T-wave changes should be considered high risk, regardless of the level of medical therapy, and triaged to early cardiac catheterization. Patients with shorter, less severe ischemic episodes without accompanying hemodynamic or ECG changes are at substantially lower risk and should be continued on medical therapy to the prespecified targets.
The major ischemic complications seen in unstable angina are acute MI, recurrent unstable angina, acute ischemic pulmonary edema, new or worsening MR, cardiogenic shock, malignant ventricular arrhythmias, and advanced AV block. Aside from maximizing the medical regimen described in the previous section and instituting appropriate adjunctive therapy (e.g., pulmonary artery pressure monitoring and inotropic therapy for shock, antiarrhythmic therapy for malignant ventricular arrhythmias, pacemaker for symptomatic high-grade AV block), the clinician should consider either insertion of an IABP or cardiac catheterization or both.
IABP counterpulsation is a method of providing temporary circulatory assistance in the form of reduced afterload and increased coronary perfusion pressure. The balloon catheter is placed percutaneously via the femoral artery and positioned in the descending thoracic aorta with the tip of the catheter several centimeters distal to the left subclavian artery. The device is synchronized with the ECG or arterial pulse tracing so that the balloon is rapidly inflated during diastole (after closure of the aortic valve) with an inert gas (helium) and rapidly deflated just before the onset of systole (and opening of the aortic valve). The IABP produces a significant reduction in afterload with a consequent reduction in myocardial work and oxygen demand. It also increases the cardiac output by a modest amount (usually 10 to 20%, depending on the extent of LV dysfunction). Finally, the IABP increases thoracic aortic diastolic pressure with a consequent increase in coronary perfusion pressure. Whether this latter effect increases coronary blood flow distal to a critical coronary stenosis or decreases the likelihood of early progression to complete coronary occlusion remains controversial.
Consecutive series of patients admitted to the hospital for unstable angina show the IABP to be required for symptom control in only about 1 percent of cases ( White, Lee, and Cook, 1990). Because patients entering the initial intensive management phase represent the highest risk subgroup of patients with unstable angina, the need for IABP in this subgroup is anticipated to be in the range of 3 percent. The IABP almost always stabilizes patients with severe myocardial ischemia and causes an almost immediate and dramatic relief of pain and ECG changes ( Rankin, Newton, Califf et al., 1984). Therefore, the persistence of continued symptoms after introduction of the IABP suggests that unstable angina is not the total etiology of the presenting condition, and further evaluation should be pursued as mandated by signs or symptoms of other primary or associated disorders. Reassessment should be made for other potentially devastating causes of symptoms that could be mistaken for unstable angina, such as pneumothorax, aortic dissection, dissecting aneurysm, esophageal rupture, or perforated peptic ulcer.
There are no randomized trials of IABP use in unstable angina. Uncontrolled series suggest that it is a very effective short-term method of stabilizing the unstable angina patient ( Aroesty, Weintraub, Paulin et al., 1979). In experienced centers, approximately 10 to 15 percent of patients will develop vascular complications with prolonged use of balloon pumps, often compromising distal limb blood flow ( Kantrowitz, Wasfie, Freed et al., 1986; Makhoul, Cole, and McCann, 1993). For this reason, patients receiving an IABP should be maintained on full-dose IV heparin with serial monitoring of aPTT, unless contraindications to heparin therapy exist. About half of ischemic leg complications are reversed by pump removal; many of the remainder require an embolectomy procedure.
In summary, experience shows that use of an IABP can be a very effective temporizing measure to allow stabilization of high-risk acute unstable angina patients. However, no clinical trials have established the optimal parameters for this intervention. Because of the complications associated with use of this procedure, it should be attempted only in centers that have clinicians experienced in the placement of the device and have access to emergency vascular surgery support should it be required.
In this guideline, emergency catheterization refers to a diagnostic catheterization study that is performed immediately or as soon as possible (i.e., <6 hours) after the precipitating event. Urgent catheterization is performed because of less severe precipitating events or because the patient exhibits features of high-risk unstable angina (see Table 8). Urgent catheterization is usually performed within 24 hours of presentation of the precipitating event. Elective catheterization, which is discussed in Chapter 7, is used to describe all diagnostic catheterization procedures not meeting the above criteria.
Since cardiac catheterization is a diagnostic procedure, it provides health benefits only when it yields information that can be used to plan and execute effective therapies. Thus, the utility of catheterization is tied closely to the subsequent decisions about triage for revascularization. Evidence for benefit of revascularization based on cardiac catheterization findings is discussed in Chapter 7. Unstable angina patients meeting criteria for emergency catheterization commonly have at least one of the following findings:
Because of the high-risk nature of this population, options for emergency surgical referral should be clearly defined prior to initiation of the catheterization procedure.
[2]Perfusion grade=0 indicates no antegrade flow beyond the occlusion. Perfusion grade=1 indicates penetration without perfusion where the contrast material passes beyond the obstruction ( TIMI Study Group, 1985).Patients found at catheterization to have an occluded culprit vessel (defined as the vessel most likely by location and angiographic appearance to be responsible for the observed ischemia) and ongoing pain/ischemia with a total symptom duration of <12 hours should in most cases undergo emergency revascularization. This may take the form of primary PTCA, intracoronary thrombolytic therapy with adjunctive PTCA as necessary, or emergency bypass surgery. Because the risks of PTCA are increased in the setting of an acutely unstable plaque relative to stable CAD, the strategy for acute intervention has often been to do only as much as necessary to restore adequate distal flow and relieve symptoms but no more. In some cases, repeat coronary contrast injections, with or without intracoronary thrombolytic therapy, may confirm improvement in distal flow so that acute revascularization is not necessary. In these patients, placement of an IABP plus continuation of IV heparin may allow further intervention to be deferred for several days when it can be performed under more controlled, more elective circumstances with lower risk of abrupt closure or other complications. However, timing of PTCA in this setting remains controversial.
Data on the effects of acute catheterization on death and nonfatal MI come from the TIMI IIIB study (in press), which showed that at 42 days early invasive and early conservative strategies were associated with equivalent "hard" outcomes of death and MI (discussed in detail in Chapter 7). In addition, the early invasive strategy showed a reduction in late recurrent ischemia, use of antianginal medication, and need for rehospitalization.
Patients with persistent ischemia who do not have adequate distal flow established after initial contrast injections and who are not candidates for PTCA, for example because of severe three-vessel or left main disease, should be considered for emergency placement of an IABP. Consultation with a cardiac surgeon about the options for triage to emergency CABG surgery for these patients should take place as soon as possible.
The large majority of unstable angina patients will stabilize and become pain free with appropriate intensive medical therapy. Transfer from intensive to nonintensive medical management is undertaken when the patient is hemodynamically stable (including no uncompensated CHF) and ischemia has been successfully suppressed for >e;24 hours. Once these criteria are satisfied, any parenteral medicines can be converted to nonparenteral regimens in preparation for this transfer. Heparin use should be reassessed after 24 hours and may be discontinued in selected patients, such as those who are found to have a clearly identified secondary cause for unstable angina (e.g., anemia). ASA is continued without interruption.
In most cases, the first option for relieving anxiety should be counseling by the health care team. Patients should be encouraged to discuss their life situation and knowledge and concerns about the import of their disease on their life. Orientation of the patient to the unit, its routines, and the type of care they are likely to receive often allays needless fears. Counseling about diagnostic and treatment alternatives should continue in as positive a tone as permitted by the severity of the situation. For some patients, speaking with a member of the clergy may provide additional reassurance. If these strategies are ineffective, judicious use of an anxiolytic agent may assist in decreasing sympathetic tone and resulting ischemia.
Recommendation: Counseling should continue in this phase regarding the significance of clinical events that have occurred and management alternatives. Where appropriate, the health care team should reassure the patient that a functional recovery is possible and indicate how soon the patient may be able to resume his or her activities (strength of evidence = C).As the health care team prepares to move the patient into the nonintensive medical management phase, it is often a good time to reiterate for the patient the significance of events that have taken place during the period of intense medical management. The slower pace of events and less intensive care at the conclusion of this phase affords the patient some time to adjust to his or her condition and hospitalization.
Patients with unstable angina whose symptoms are controlled for >e;24 hours with intensive medical therapy should be stratified according to whether the diagnosis of acute MI or no MI has been made. Patients with unstable angina, as well as those with non-Q-wave MI who remain free of symptoms or signs of ischemia, should appropriately pass to the nonintensive hospital management phase. Patients with persisting symptomatic unstable angina during the first 24 hours will be advised to undergo cardiac catheterization and myocardial revascularization if the anatomy is suitable and if they have no contraindications. Patients who prefer continued intensive medical management to cardiac catheterization and myocardial revascularization or are not candidates for these procedures will continue to receive intensive care at a level and for a duration dictated by the level of their disease activity.
The medical record should include or update the following minimal information in addition to the information available on admission:
Typically, most high-risk, unstable angina patients can be stabilized within 24 to 48 hours of admission to the ICU. Some unstable patients will progress to sustain a transmural MI and others will require urgent cardiac catheterization, PTCA, or CABG. However, the majority of patients will rapidly become asymptomatic on aggressive medical therapy. Patients who remain asymptomatic for 24 hours may be transferred to a regular hospital room for initiation of the nonintensive phase of management.
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