ATYPICAL CHEST PAIN WITH NORMAL CORONARY ARTERIES

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1 30 Profiles in Coronary Artery Disease C. Michael Gibson University of California San Francisco, School of Medicine, San Francisco, California Today's cardiologist is faced with a rapidly expanding selection of diagnostic and therapeutic modalities in the management of coronary artery disease. The purpose of this chapter is to place these evolving diagnostic and therapeutic strategies into a clinical context through the use of case histories. The discussion of the cases is largely evidence-based and draws on data from randomized, prospective trials. ATYPICAL CHEST PAIN WITH NORMAL CORONARY ARTERIES The most common clinical manifestation of coronary artery disease is chest pain, but this symptom is nonspecific and there is a broad differential diagnosis of the noncardiac causes of chest pain. An abbreviated list of the most common causes of noncardiac chest pain includes musculoskeletal disorders (costochondritis), neurologic disorders (cervical disc disease, thoracic outlet syndrome, zoster), mediastinal disorders (neoplastic and inflammatory), pulmonary disorders (pneumonia, pleuritic processes, pulmonary embolism, neoplasia, and other parenchymal processes), and gastrointestinal disorders (esophageal spasm, esophagitis, peptic ulcer disease, cholecystitis, and pancreatitis). The fairly common condition of esophageal spasm presents a particular diagnostic dilemma because both ischemic coronary artery disease and esophageal spasm may respond to nitrates. Esophageal spasm may even result in radiation of the discomfort into the left arm. A variety of cardiac conditions may also mimic the symptoms of obstructive coronary artery disease, including myocarditis, pericarditis, aortic and subaortic valvular disease, aortic dissection, thoracic aortic aneurysm, intramyocardial compression ( bridging ) of a coronary artery segment, primary pulmonary hypertension, cardiomyopathies, mitral valve prolapse, and a ruptured sinus of Valsalva aneurysm. The frequency of finding normal or nonobstructive coronary anatomy at the time of cardiac catheterization is approximately 20%, according to registry data from the Society of Cardiac Angiography (1). This frequency varies depending on local practice patterns, including the use of noninvasive tests. Female gender is associated with a more than four-fold higher incidence of false-positive exercise tolerance tests (2). The cause of atypical chest pain with documented ischemia, but in the absence of obstructive epicardial disease, is not clear. One potential cause is impaired coronary vasodilator reserve. Data suggest that 50 mg of imipramine daily may reduce the frequency of these patients' symptoms by 52%, possibly through a visceral analgesic effect (3). The prognosis of patients with chest pain and angiographically normal coronary arteries is quite good (4). Another cause of ischemic chest pain in the presence of coronary arteries that appear normal or near-normal is epicardial coronary spasm. Although Prinzmetal originally described a syndrome of focal coronary spasm that occurred at the site of fixed atherosclerotic narrowing (5), it has become appreciated that spasm can also occur at sites that are minimally diseased or are angiographically completely free of obstructive disease. Case 1 A 45-year-old man presented with chest discomfort. He had a 30 pack-year history of cigarette smoking and mild systolic hypertension treated with an angiotensin-converting enzyme inhibitor. The chest discomfort occurred predominantly at rest, often during emotional upset, but also on occasion with exertion. He exercised for 9 minutes on a standard Bruce protocol and had neither chest pain nor diagnostic electrocardiographic (ECG) changes. He was compliant with a smoking cessation program and was prescribed aspirin. However, he continued to experience substernal chest pain for the next 6 months, which prompted a diagnostic cardiac catheterization. Page 1 of 8

2 On cardiac catheterization, coronary angiography initially showed a mild lesion in the proximal circumflex artery (Fig A). The left anterior descending (LAD) and the right coronary arteries were free of disease. However, after the initial injections contrast agent, the patient developed chest pain and a very brief episode of total occlusion of the circumflex artery, which was followed by a marked and sustained reduction in the caliber of the circumflex artery (Fig B). His pulmonary capillary wedge (PCW) pressure rose to 30 mm Hg. He was treated with 10 mg of sublingual nifedipine, with resolution of the chest pain and relief of coronary spasm on angiography. He was prescribed a calcium channel blocker and experienced resolution of both his rest and exertional symptoms. FIG Example of coronary spasm. A: A diffuse mild lesion is present in the proximal circumflex on initial angiography. B: After several injections, the patient developed chest pain and the artery narrowed. The symptoms and narrowing were relieved with sublingual nifedipine. Coronary spasm can be observed during the performance of coronary angiography and is often caused by catheterinduced spasm at the ostium of the coronary artery (particularly the right coronary artery). The narrowing observed here was not induced by the catheter tip, and the patient's presenting symptoms were reproduced. This patient most likely had Prinzmetal's variant angina. He may have also had exercise-induced coronary spasm. Although coronary spasm occurred spontaneously during the course of cardiac catheterization in this patient, provocative testing with ergonovine maleate is usually required to document this syndrome. Normal coronary arteries narrow diffusely in response to this agent, but patients with variant angina respond with focal spasm that totally occludes the coronary artery. If coronary spasm is suspected based on the clinical history (nocturnal or temporally reproducible symptoms, intermittent ST-segment elevation), then calcium channel blockers and nitrates should be discontinued for at least 24 hours before coronary angiography so that provocative maneuvers do not result in a false-negative study. The vast majority of patients respond well to nitrates plus a single calcium channel blocker, but approximately 10% require a combination of calcium channel blockers. Patients with drug-resistant coronary spasm often have multivessel coronary spasm, which can be associated with fatal arrhythmias (6). If percutaneous transluminal coronary angioplasty (PTCA) is performed in a patient with variant angina, the risk of restenosis is higher than in a patient with a fixed obstruction (35% vs. 22%) (7). STABLE ANGINA Chronic ischemic heart disease is a common disorder in developed Western countries. Conventional medical management of this syndrome consists of β-blockers, aspirin, and nitrates as needed to reduce symptoms. In patients with hypercholesterolemia, there is clear evidence that the risk of cardiac events and all-cause mortality can be reduced with aggressive lipid lowering (8 10). Furthermore, prospective randomized data from angiographic trials have shown that atherosclerotic disease progression can be halted or even reversed in patients with hyperlipidemia (11). Examples of disease regression from the Familial Atherosclerosis Treatment Study (FATS), in which patients with hyperlipoproteinemia were treated with lovastatin and cholestipol or niacin and cholestipol, are shown in Fig (11). Compared with control patients, percent stenosis in treated patients typically improved by approximately 1 percentage point for each of the 2.5 years of follow-up in regression trials (11). Of interest, each of the arterial segments has been shown to respond at an independent rate to lipid-lowering therapy (12), and it has been demonstrated that, in addition to systemic risk factors, local mechanical factors such as shear stress may play a role in mediating disease progression (13). FIG Examples of lesion regression taken from the Familial Atherosclerosis Treatment Study (FATS) study. The top row Page 2 of 8

3 of images were obtained before lipid-lowering therapy, and the bottom row were obtained 2.5 years later. The left anterior descending coronary artery (LAD) improved from 100% to 28% ( arrowheads), the left-panel obtuse marginal branch (OMB) from 39% to 18% (left-panel, lower arrows), the right coronary artery (RCA) from 48% to 30%, a second OMB from 69% to 37%, and the left circumflex (LCx) from 44% to 30%. (From Brown BG, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990;323:1289. Reprinted by permission of The New England Journal of Medicine. Copyright 1990, Massachusetts Medical Society. All rights reserved.) Despite the small numbers of patients in these trials and the minimal changes in percent diameter narrowing of the arteries, a significant reduction in clinical events has been observed (11). Although lipid-lowering may not alter or may only minimally alter the extent of fixed structural lesions, it may instead improve the dynamic function of arteries, such as stabilizing the plaque against plaque rupture (14) or improving the vasomotor responsiveness of the artery to endothelial-derived relaxing factor (15). Statins may also reduce inflammation and thereby reduce reperfusion injury (16). Despite these preventive strategies and aggressive medical management, patients sometimes have persistent and/or intolerable symptoms that require cardiac catheterization to define coronary anatomy with an eye toward possible intervention. The most appropriate intervention depends on the findings at coronary arteriography. Case 2 A 55-year-old woman complained of chest discomfort that occurred with exertion in a stable pattern over the course of 2 years. Her risk factors for coronary artery disease included a total cholesterol level of 280 mg/dl and a highdensity lipoprotein (HDL) level of 30 mg/dl, giving a cholesterol/hdl ratio of 7.3. The family history was notable for a myocardial infarction in her father at 50 years of age. The patient had been taking a β-blocker for the past year, which helped but did not eliminate her symptoms of exertional angina. She was following an American Heart Association Diet and wanted to engage in an exercise program to improve her HDL level. An exercise tolerance test showed 2 mm of ST depression in the inferior leads after 3 minutes. She was referred for cardiac catheterization, which showed normal LAD and circumflex arteries but an 80% eccentric right coronary artery lesion (Fig A). The patient was treated with directional atherectomy with excellent angiographic results (Fig B) and resolution of exercise-induced ischemia. FIG Example of a single-vessel intervention in a patient with stable angina. An 80% eccentric right coronary artery lesion (A) was treated with directional atherectomy with an excellent angiographic result (B). This woman had single-vessel disease, a clinical syndrome for which the benefits of PTCA have been compared with those of medical therapy in a randomized, prospective fashion in the Veterans Affairs Angioplasty Compared to Medicine (ACME) trial (17). In that study of 212 patients with single-vessel disease, PTCA resulted in a reduction of anginal symptoms compared with medical therapy at 1 month (50% vs. 24% angina free, respectively). However, although the benefit of PTCA was still significant at 6 months, the magnitude of this benefit was reduced (64% vs. 45% angina free, respectively). Patients treated with PTCA also had an improvement of 2.1 ± 3.1 minutes in exercise duration, which was significantly greater than the 0.5 ± 2.2 minutes observed in the medical therapy group. The Atorvastatin Versus Revascularization Therapy (AVERT) study demonstrated that, among patients with stable angina and minimal ischemia, aggressive lipid lowering to a low-density lipoprotein (LDL) level of 78 mg/dl can be associated with a greater reduction in hospitalization for recurrent ischemia compared with PTCA (18). Despite the lower frequency of events in the medical therapy arm of AVERT, there was still a higher frequency of angina among medical therapy patients. This eccentric lesion was not treated with conventional PTCA but rather with atherectomy, which has been shown to result in a lower rate of restenosis at 6 months (19). Case 3 Page 3 of 8

4 A 63-year-old man presented with 1 year of substernal chest pain with exertion. His risk factors for coronary artery disease included a positive family history and a history of hypertension. He did not have diabetes. On exercise tolerance testing, he was found to have anterior ST-segment depression at 4 minutes on a standard Bruce protocol. His medications included a β-blocker, aspirin, and nitrates, but he continued to experience chest pain with approximately one block of exertion. His symptoms limited his lifestyle, and he elected to undergo cardiac catheterization, which showed an 80% proximal right coronary artery lesion and a 90% mid-lad artery lesion. His PCW pressure was 10 mm Hg, and his left ventricular ejection fraction (LVEF) was 55%. The patient had diffuse disease of the coronary arteries, with small vessels that were less than 3.0 mm in diameter. He was treated with a multivessel PTCA, leaving a 10% to 20% residual stenosis at both sites. His chest discomfort resolved after the procedure. The role of percutaneous strategies in the patient with multivessel disease continues to evolve. It is difficult to interpret nonrandomized data comparing the efficacy of multivessel PTCA with that of coronary artery bypass grafting (CABG) because most multivessel PTCA series involve patients, such as this one, with two-vessel disease and a preserved LVEF. In contrast, many CABG series involve patients with three-vessel disease or left main disease and a higher proportion of patients with reduced LVEF (20). A number of randomized, prospective trials have now been completed (e.g., EAST, RITA, GABI, ERACI) (21 24) comparing percutaneous and surgical approaches to multivessel disease. These studies have shown that the incidence of death and recurrent myocardial infarction is similar after these two strategies. Although CABG has been associated with a higher incidence of myocardial infarction and longer hospitalizations, patients treated with PTCA usually require more antianginal medications and require repeat revascularization more frequently (21 24). This observation may be explained by two phenomena: first, patients treated with CABG have a higher incidence of postoperative infarction, and consequently they may experience less angina postoperatively in the infarcted territory on this basis; second, patients treated with PTCA may have been less completely revascularized. In many patients, chronic total occlusions limit the ability of a percutaneous procedure to provide complete revascularization; indeed, approximately half the patients screened in the EAST trial were not deemed suitable for PTCA on this basis. Although CABG surgery is a well established and characterized technique, new percutaneous techniques and adjunctive medical strategies to prevent restenosis continue to evolve. This difference renders comparisons between these two strategies very difficult. It must also be realized that restenosis occurs relatively early after PTCA, and that vein graft degeneration occurs late after CABG. Consequently, if the duration of follow-up is short, then angioplasty will appear less efficacious, whereas long-term follow-up over many years provides a more valuable comparison of these two strategies. The corollary is that PTCA patients may cross over to a strategy of CABG early on, but patients treated with CABG may crossover to PTCA later in the course of a trial. A high rate of crossover in both directions can confound the results of these trials if they are analyzed on a conventional intention-to-treat basis. UNSTABLE ANGINA The management of unstable angina continues to evolve rapidly. A variety of new adjunctive antiplatelet agents such as clopidogrel (25) and glycoprotein IIb/IIIa inhibitors (26), as well as low-molecular-weight heparin compounds (27), have been demonstrated to be efficacious. The term unstable angina actually encompasses a variety of clinical syndromes that are of differing severity and carry differing prognoses (28). Stable angina that has begun to increase in frequency or severity (Braunwald class IB [28]) has the most benign course and may respond in many cases to medical therapy alone. These patients have a complication rate after PTCA which is comparable to that of patients with stable angina, but one that is lower than that of patients with angina at rest or postinfarction unstable angina (28). Patients with angina at rest associated with T-wave inversions or ST-segment depression (Braunwald class IIB and IIIB [28]), and particularly those with chest pain that is refractory to medical therapy, have a poorer prognosis than do patients with progressive angina. Finally, patients with postinfarction angina (Braunwald class IIC and IIIC [28]) also have a poorer prognosis than patients with progressive angina. The mainstay of medical therapy at this time remains aspirin, heparin, nitrates, and β- blockers. Thrombolytic agents were not shown to offer any clinical benefit in the Thrombolysis in Myocardial Page 4 of 8

5 Infarction (TIMI III) trial, possibly because of the exposure of fibrin-bound thrombin and the procoagulant effects after thrombolysis, as well as the platelet-rich composition of thrombi in patients with unstable angina, which are more resistant to thrombolytics (29). In patients with acute coronary syndromes, glycoprotein IIb/IIIa inhibitors have been shown to reduce the composite end point of death, recurrent myocardial infarction, and urgent revascularization by approximately 30% (26). The metaanalysis of Kong and coworkers did show an early mortality benefit for this class of agents, and a mortality benefit was observed when abciximab was combined with intracoronary stenting in the EPISTENT trial (30). The subgroups of patients who derive the greatest benefits appear to be those with ST-segment depression (not just flipped T waves), those with elevated serum troponin levels, and those for whom aspirin has failed (31). The majority of the benefit occurs in the first days after the intervention. Case 4 A 72-year-old man had undergone CABG surgery 13 years previously, with saphenous vein grafts placed to the two obtuse marginals and the LAD artery. He underwent reoperation 8 years ago, with a left internal mammary artery graft being placed to the LAD artery and saphenous vein grafts being placed to the obtuse marginal and to the posterior descending artery. He now presented with chest pain at rest and associated inferolateral ST-segment depression. Myocardial infarction was ruled out by creatine kinase enzymes, but troponin was positive. His medications on admission included oral nitrates, a β-blocker, a calcium channel blocker, aspirin, and furosemide. Despite heparinization, intravenous nitroglycerin, and maximal medical therapy for 4 days, he continued to have chest pain at rest with inferolateral ST-segment depression. FIG Example of multivessel stenting in the setting of unstable angina. A 90% lesion in the midcourse of the saphenous vein graft to the posterior descending artery (A) was treated with a 3.5-mm Palmaz-Schatz stent, leaving a 0% to 10% residual stenosis (B). A 70% lesion at the origin of the saphenous vein graft to the obtuse marginal (C) was treated with a 3.0-mm Palmaz-Schatz stent, again leaving a 0% to 10% residual stenosis (D). FIG Example of primary angioplasty for acute myocardial infarction. The patient developed chest pain and ST-segment elevation and was found to have a totally occluded obtuse marginal branch (A). The patient underwent primary percutaneous transluminal coronary angioplasty, with restoration of TIMI grade 3 flow and a minimal residual stenosis (B). He was prescribed a glycoprotein IIb/IIIa inhibitor and was later brought to the cardiac catheterization laboratory, where he was found to have total occlusion of all his native vessels proximally, a patent left internal mammary artery graft to his LAD artery, a 90% lesion in the midcourse of the saphenous vein graft to the posterior descending artery (Fig. 30.4), and a proximal 70% lesion of the saphenous vein graft to the first obtuse marginal artery. The LVEF was moderately reduced at 40%. The patient had a 3.5-mm Palmaz-Schatz stent placed in the saphenous vein graft to the posterior descending artery, leaving a 0% to 10% residual stenosis (Fig A, B). He was given a loading dose of clopidogrel. An exercise tolerance test with thallium imaging performed 10 days after the procedure showed persistent lateral wall ischemia. Therefore, a second 3.0-mm Palmaz-Schatz stent was placed in the saphenous vein graft to the obtuse marginal, again leaving a 0% to 10% residual stenosis (Fig C, D). He continued to receive clopidogrel for 1 month after the procedure and experienced full resolution of his symptoms. This patient had an uncomplicated postintervention course, as has 140,300,410]become common since the introduction of glycoprotein IIb/IIIa inhibitors, intracoronary stenting, and clopidogrel. Glycoprotein IIb/IIIa inhibitors have been shown to reduce the incidence of myocardial infarction before intervention, and this patient was given a glycoprotein IIb/IIIa inhibitor before the intervention. As discussed previously for patients with stable Page 5 of 8

6 angina, the choice of revascularization strategies in the patient with unstable angina and multivessel disease is complex. This patient would have required a third CABG operation, which carries a mortality rate two to three times greater than that of the second operation and much higher than that of the initial operation (32). Some authors have advocated dilating only the culprit lesion in the setting of unstable angina (33). However, this patient demonstrates that multiple lesions may require dilation to eliminate exercise-induced ischemia. There are conflicting results in the literature as to whether patients with unstable angina have a higher restenosis rate than those with stable angina. Although conventional angioplasty of bypass grafts has been associated with a high rate of restenosis, the results of stent placement in bypass grafts have been more favorable (34). In addition, intracoronary stenting of native coronary vessels larger than 3.0 mm has been shown to reduce restenosis rates at 6 months when compared with conventional angioplasty in randomized trials (35),(36). ACUTE MYOCARDIAL INFARCTION Although thrombolysis has been the primary mode of therapy for acute myocardial infarction, thrombolytic strategies have been limited by the fact that approximately 20% of patients fail to achieve reperfusion, 10% to 15% experience reocclusion, and approximately 1% have a risk of intracranial bleeding (37). Since the last edition of this textbook, more potent and fibrin-specific thrombolytic agents have been evaluated (38),(39), and they have now been combined with glycoprotein IIb/IIIa inhibitors to accelerate the rate of thrombolysis (40). At the same time that improvements have been developed for thrombolytic strategies, newer interventional techniques have been introduced that present a formidable challenge to thrombolytic agents because they may achieve a higher incidence of TIMI grade 3 flow and a lower rate of reocclusion and are associated with a low rate of intracranial hemorrhage (37),(41). Case 5 A 70-year-old woman was admitted to the hospital with chest pain at rest and nonspecific ECG changes. Her risk factors for coronary artery disease included hypercholesterolemia and hypertension. After admission, she was treated with aspirin and heparin, and the dosing of her β-blocker was increased. On the second day of hospitalization, she developed chest pain that was refractory to intravenous nitrates, heparin, aspirin, and β-blockers. An ECG showed 1 to 2 mm of new ST-segment elevation in leads I, L, and V6, as well as 1 to 2 mm of ST depression in leads V1-V2. She received an additional bolus of heparin for a subtherapeutic partial thromboplastin time and was given 5 mg of metoprolol intravenously. The patient developed chest pain in the afternoon, at a time when the cardiac catheterization laboratory staff was present in the hospital and a cardiac catheterization suite was immediately accessible. She was rushed to the cardiac catheterization suite, where she was found to have single-vessel disease with a totally occluded circumflex obtuse marginal branch (Fig A). The patient underwent primary PTCA with restoration of normal TIMI grade 3 flow and a minimal residual stenosis (Fig B). She was discharged to home 3 days later, after a negative submaximal exercise tolerance test. FIG Example of a lesion with a high risk of reocclusion after thrombolysis. The lesion is an ulcerated, eccentric plaque in the right coronary artery with TIMI grade 2 flow that was collateralized by the left anterior descending coronary artery. There are several prospective randomized trials comparing the efficacy of primary PTCA with that of thrombolytic therapy (41). This patient was in many ways an ideal candidate for primary PTCA, both because immediate access to cardiac catheterization was available and because she was an elderly woman, a subgroup that has been shown to derive particular benefit from primary PTCA (42). In the Primary Angioplasty in Myocardial Infarction trial (PAMI), primary PTCA was associated with a lower rate of intracranial hemorrhage and a lower rate of reinfarction or death compared with thrombolytic therapy (42). This patient is part of a small subgroup of patients with a circumflex lesion, the natural history of which is not well characterized in thrombolytic trials because such lesions represent less than 15% of lesions in these trials. Page 6 of 8

7 Case 6 A 56-year-old man presented with chest discomfort that awoke him from sleep 1 hour before admission. On presentation to the emergency room, he had a blood pressure of 92/54 mm Hg. His ECG showed sinus bradycardia at a rate of 52 beats per minute (bpm), with 2 mm of ST-segment elevation in leads II, III and avf. He was given a bolus of heparin intravenously and treated with 100 mg of tissue-type plasminogen activator (tpa) over 90 minutes. Initially, he was treated with intravenous nitroglycerin, which resulted in a further drop in blood pressure. Rightsided leads were obtained, which showed 1 mm of ST-segment elevation in the right precordial leads. He was treated aggressively with intravenous fluids, resulting in a rise in his blood pressure, but he also began to develop rales on examination. His chest pain persisted for the first 60 minutes after thrombolysis. Given the patient's hemodynamic instability and persistent chest pain, he was taken to the cardiac catheterization laboratory. Shortly after vascular access was obtained, his chest pain resolved and his ST-segment elevation improved. On angiography, he was found to have an ulcerated eccentric 90% stenosis in the mid-right coronary artery (Fig. 30.6), with TIMI grade 2 flow that was collateralized by the LAD artery. Given that the vessel was open and the patient's pain had resolved, it was elected not to intervene. However, 6 hours later the patient developed recurrent chest pain, and repeat cardiac catheterization showed a total occlusion of the right coronary artery, which was treated with PTCA, resulting in restoration of TIMI grade 3 flow and a 30% residual stenosis. This patient had several angiographic features on early catheterization that have been associated with reocclusion 1 day later (43). In descending order of importance, these angiographic features are the presence of an ulceration, the presence of TIMI grade 2 (slow) flow, the presence of thrombus, the presence of an eccentric lesion, increased lesion severity, and the presence of collaterals. The management of a patent artery with slow flow is poorly defined. Despite an intuitive belief that routine adjunctive angioplasty should improve clinical outcomes in patients with a patent (normal and slow flow combined) but narrowed artery after successful thrombolysis, several large trials have shown no benefit for PTCA in this setting (44). Currently, there is an impetus toward improving the flow in patent arteries after thrombolysis based on the finding that better TIMI flow grades and better TIMI frame counts are associated with improved outcomes (45),(46). However, it remains unclear whether TIMI grade 2 flow is just a marker of larger infarcts or a cause of more extensive necrosis. Indeed, it has been shown that the magnitude of slow flow is proportional to the extent of myocardial necrosis (47), and Kloner et al. demonstrated repeatedly that this may be mediated by the microvasculature (48). Furthermore, we showed that perfusion at the level of the myocardium (the myocardial perfusion grade or blush) is a predictor of mortality in acute myocardial infarction, independent of flow in the epicardial artery (49). It appears that flow in all three arteries (not just the culprit artery) may be abnormal, and that global flow abnormalities are related to a higher mortality rate in acute myocardial infarction (50). Therefore, there is an increased emphasis on treating the microvasculature in addition to treating the stenosis in patients with TIMI 2 flow. Treatment of the stenosis may confer benefits above and beyond those of improved flow, such as potential reduction in the risk of reocclusion. Case 7 A 69-year-old woman presented to the emergency room of a local community hospital with 5 hours of substernal chest discomfort radiating to the left arm, and 2 mm of ST-segment elevation in the anterior precordial leads. She had a blood pressure of 90/60 mm Hg, a pulse rate of 90 bpm, and rales one-half way up her lung fields bilaterally. She was treated immediately with aspirin, intravenous heparin, and 1.5 million units of streptokinase. After 60 minutes of persistent chest pain and ST-segment elevation, she was transferred for cardiac catheterization. She was found to have a totally occluded LAD artery, which was treated with rescue PTCA, resulting in restoration of TIMI grade 3 flow and a minimal residual stenosis. There has been only one randomized, prospective trial assessing the efficacy of rescue angioplasty for failed Page 7 of 8

8 thrombolysis. There is an inherent belief among angioplasty operators that restoring perfusion would certainly be beneficial, and this bias is reflected by the fact that almost 80% of operators approached to participate in the Randomized Evaluation of Salvage Angioplasty with Combined Utilization of Endpoints (RESCUE) study (51) declined, because they believed that it would be unethical to withhold attempted revascularization for an occluded vessel immediately after failed thrombolysis. The RESCUE trial involved 150 patients from 20 centers with TIMI grade 0 or 1 flow 1.5 to 8 hours after myocardial infarction. Generalization of results from this trial are limited because enrollment was restricted to patients with their first myocardial infarction and to those patients with an anterior infarction. There was no difference in outcome for the prespecified primary end point of the trial, the resting LVEF at 30 days after myocardial infarction (40% with PTCA vs. 39% without PTCA). The incidence of death in patients treated with rescue angioplasty was 5.2%, which did not differ significantly from the 9.9% for those not treated with rescue angioplasty. As a secondary end point, death and congestive heart failure were analyzed together, and there was a trend for a reduced incidence in the group treated with rescue PTCA (6.5% vs. 16.4%, p =.055). The magnitude of benefit in this trial and in others may be small because thrombolysis must first fail over the course of the first 90 minutes, and time must then be taken to bring the patient to the cardiac catheterization suite. Because of the inherent time delays in performing rescue angioplasty, the benefits of early restoration of patency may not be realized. Several other trials have evaluated the strategy of rescue PTCA in a nonrandomized, retrospective fashion (52). In keeping with the fact that the early and full reperfusion paradigm of thrombolytic success is only partially fulfilled in cases of successful rescue PTCA, the delayed and often full reperfusion achieved in these patients in the TIMI 4 trial resulted in an overall rate of adverse events (death, severe congestive heart failure, cardiogenic shock, or LVEF less than 40%), 28.8%, that was intermediate between that of patients with immediate thrombolytic success (22.8%) and that of patients treated with no rescue PTCA for an occluded vessel (35.1%), who frequently achieved reperfusion even later (52). Overall success rates have varied (71% to 100%) and on the whole have been lower than those reported for primary PTCA, probably because of either a larger or a more pharmacologically resistant thrombus burden (53). Similarly, mortality rates have been high (10% to 17%), and in particular the mortality rates of patients with a failed procedure have been very high (33% to 39%) (53). Pooled data have shown no improvement in left ventricular function between the time of the rescue procedure and 7 days later and suggest that the rate of reocclusion is higher in patients treated with tpa (24%) compared with nonspecific plasminogen activators (14%) (53). A potential problem with a strategy of rescue PTCA lies in identifying patients who would be appropriate candidates for intervention, because reliable clinical and noninvasive markers of reperfusion have not been validated for widespread use. The utility of new device interventions in this setting has not been evaluated. The management of acute myocardial infarction continues to evolve rapidly. Throughout all of the clinical trial data, one paradigm that consistently emerges is the importance of early restoration of patency regardless of the thrombolytic agent or mechanical strategy used to open the artery. In keeping with the time-dependent nature of the open-vessel hypothesis, the choice of a revascularization strategy should be guided by the clinician's assessment of the most expeditious method by which patency can be achieved in a given patient, at a given time of the day, at a given institution, by a given operator (37). Page 8 of 8