- Email: [email protected]
Use of coronary revascularization in patients with unstable and non-ST- segment elevation acute myocardial infarction
Use of Coronary Revascularization in Patients with Unstable and Non–STSegment Elevation Acute Myocardial Infarction Jeffrey J. Popma,
MD,
and Jacqueline Suk,
MD
Percutaneous coronary intervention can be safely performed in patients with acute coronary syndromes (ACS), including those with non–ST-segment elevation myocardial infarction (MI), and unstable angina. Although there remains debate about whether an aggressive strategy involving early coronary arteriography and revascularization should be routinely performed in patients who present with non–ST-segment elevation MI and unstable angina, recent clinical trials suggest that an aggressive approach should be taken in both intermediate- and high-risk patients with ACS. There have been 4 clinical trials that have compared the outcomes of patients presenting with non–ST-segment elevation MI or unstable angina who were assigned to invasive or conservative strategies. The Thrombolysis in Myocardial Infarction (TIMI) IIIB trial and the Veterans Affairs Non–QWave Infarction Strategies in Hospital (VANQWISH) trial failed to demonstrate a reduction in death or MI in patients assigned to an invasive approach, but it did demonstrate an important reduction in the frequency of rehospitalization. However, these studies were performed before the availability of coronary stents or the
use of glycoprotein IIb/IIIa inhibitors. In contrast, the Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease (FRISC) II and the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) trials demonstrated significant improvements in the rates of death or MI in patients with non–ST-segment elevation MI or unstable angina assigned to an invasive strategy. Event reductions were greatest in patients with non–ST-segment elevation MI or unstable angina at intermediate or high risk for an adverse outcome. Understanding that these subgroups comprise approximately 75% of patients presenting with non–ST-segment elevation MI or unstable angina, we believe that an invasive approach is indicated in most patients who develop non–ST-segment elevation MI or unstable angina. Regardless of the strategy used in ACS patients, lipid-lowering therapy is necessary to reduce recurrent ischemia events at the site of plaque instability and in atherosclerotic disease remote to the target lesion. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88:25K–29K
n the United States, ⬎750 000 percutaneous coronary intervention (PCI) procedures are performed Iannually, which exceeds the number of coronary ar-
CLASSIFICATION OF ACUTE CORONARY SYNDROMES
tery bypass graft surgeries.1 The expanded use of coronary revascularization has been a result of the favorable outcomes obtained with PCI in recent years, caused, at least in part, by the availability of glycoprotein IIb/IIIa inhibitors and stents. As the safety of coronary stenting has progressively improved, its use has broadened to include patients with acute coronary syndromes (ACS) and thrombus. Whether PCI should be routinely performed in patients with ACS has remained a controversial issue. The purpose of this review is to support the view that coronary arteriography and revascularization should be routinely performed in intermediate- and high-risk patients presenting with ACS.
From the Department of Internal Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA. Address for reprints: Jeffrey J. Popma, MD, Interventional Cardiology, Brigham and Women’s Hospital, 75 Francis Street, L-2 Cardiac Catheterization Laboratory, Boston, Massachusetts 02115. E-mail: [email protected]. ©2001 by Excerpta Medica, Inc. All rights reserved.
There will be ⬎1.4 million patients hospitalized for ACS this year in the United States.2 Under the new classification system, patients are classified as those with ST-segment elevation myocardial infarction (MI), clinically manifest as transmural myocardial ischemia and complete coronary occlusion, and those with non–ST-segment elevation MI or unstable angina, clinically manifest as nontransmural myocardial ischemia and incomplete epicardial vessel occlusion.2 Patients with non–ST-segment elevation MI have enzymatic evidence of myocardial necrosis; those with unstable angina have pain at rest, an accelerated pattern of chest pain, or new onset pain without evidence of myocardial necrosis. These classifications have been useful in planning treatment strategies in patients with ACS.2 Therapy is directed toward mechanical or pharmacologic reperfusion in patients with ST-segment elevation MI, and toward plaque stabilization using antithrombotic agents and lipid-lowering therapy in patients with non–ST-segment elevation MI and unstable angina.2 Several newer pharmacologic agents have been recently reported and are also discussed in this review. 0002-9149/01/$ – see front matter PII S0002-9149(01)02037-9
25K
TABLE 1 Clinical Outcomes in Patients Enrolled in Unstable Angina Trials TIMI IIIb3 Treatment Group
Cons
Inv
Time period Entry criteria
1989–1992 NSTEMI Unstable angina 733 740 64 98
VANQWISH4 Cons
Inv
1993–1995 NSTEMI
FRISC-II5 Cons
TACTICS6
Inv
1996–1998 NSTEMI Unstable angina 1,235 1,222 47 98
Cons
Patients (n) 458 462 Coronary arteriography 48 96 (%) Time to angiography 7.1 days 1.5 days 14 days 2 days 17 days 4 days Revascularization (%) 49 61 33 44 36.7 77.9 CABG alone (%) 24 25 20 21 18.9 35.2 Time to NR NR 24.5 days 8 days NR NR revascularization Follow-up period 6 wk 12 mo 6 mo Composite outcome 18.1 16.2 18.6 24.0* 12.1 9.4† Death 2.5 2.4 7.9 12.6† 2.9 1.9 MI 5.7 5.1 NR NR 10.1 7.8† Absolute/relative 21.9/210.5 15.4/122.5 22.7/222.3 % change in death/MI Angina at follow-up 28.6 24 NR NR 39 22‡ Repeat hospitalization 14.1 7.8‡ NR NR 24 14‡ for recurrent ischemia
Inv
1997–1999 NSTEMI Unstable angina 1,106 1,114 51 97 79 hr 37 16 93 hr
22 hr 61 22 25 hr
6 mo 19.4 15.9† 3.5 3.3 6.9 4.8† 22.2/223.1 NR 13.7
NR 11.0
PURSUIT9 Pl
Eptifib
1995–1997 NSTEMI Unstable angina 4,739 4,722 NR NR NR NR NR NR
NR NR NR NR
MIRACL7 Pl
Atorv
1997–1999 NSTEMI Unstable angina 1,548 1,538 NR NR NR 16.1 NR NR
NR 16.5 NR NR
30 days 15.7 14.2† 3.7 3.5 13.5 12.6 21.5/210
4 mo 17.4 14.8† 4.4 4.2 7.3 6.6 20.8/27.3
NR NR
NR 8.4
NR NR
NR 6.2†
Atorv ⫽ atorvastatin; CABG ⫽ coronary artery bypass graft surgery; Cons ⫽ conservative approach; Eptifib ⫽ eptifibatide; Inv ⫽ invasive approach; MI ⫽ myocardial infarction; NR ⫽ not reported; NSTEMI ⫽ non–ST-segment elevation myocardial infarction; Pl ⫽ placebo. *p ⫽ 0.05. † p ⬍0.05. ‡ p ⬍0.001.
INVASIVE OR CONSERVATIVE STRATEGIES IN PATIENTS WITH NON–ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION AND UNSTABLE ANGINA It is well recognized that coronary revascularization improves clinical outcomes in selected patients with non–ST-segment elevation MI or unstable angina, particularly those with evidence of ongoing myocardial ischemia. From 10% to 15% of patients with nonobstructive coronary artery disease and 20% of patients with triple-vessel disease with reduced left ventricular function or left main coronary artery disease may benefit from surgery.2 Early coronary arteriography identifies these patients. Yet debate still continues over whether this approach, routinely applied, will result in clinical benefits in all patients presenting with non–ST-segment elevation MI or unstable angina.2 There are 4 randomized clinical trials comparing the invasive and conservative strategies in patients with non–ST-segment elevation MI or unstable angina that have been performed to date.3– 6 These studies have differed in (1) inclusion criteria, (2) availability and use of coronary stents and glycoprotein IIb/IIIa inhibitors, (3) frequency of revascularization in invasive arms, and (4) clinical outcomes (Table 1). In aggregate, we believe that the results from these trials support an aggressive approach toward coronary revascularization in patients who present with non– ST-segment elevation MI or unstable angina. Thrombolysis in Myocardial Infarction IIIB trial: The Thrombolysis in Myocardial Infarction (TIMI) IIIB 26K THE AMERICAN JOURNAL OF CARDIOLOGY姞
trial enrolled 1,473 patients within 24 hours of ischemic discomfort because of non–ST-segment elevation MI or unstable angina and randomly assigned them in a 2 ⫻ 2 factorial design to (1) treatment with tissue plasminogen activator or placebo, and (2) an invasive or conservative strategy.3 Patients assigned to the conservative strategy were referred for cardiac catheterization and revascularization only for the occurrence of chest pain associated with ST-segment elevation or depression, ST-segment depression on Holter monitoring, or an unsatisfactory “low-level” exercise tolerance test. The primary outcome for the comparison of the invasive and conservative strategies was the occurrence of death, MI, or an unsatisfactory symptomlimited exercise tolerance test at 6 weeks. Although there were no significant differences in occurrence of the primary outcome in the 2 groups, a number of secondary outcomes demonstrated the clinical benefit of the invasive approach. Specifically, the average length of the initial hospitalization (10.2 days vs 10.9 days, p ⫽ 0.01), the frequency of rehospitalization at 6 weeks (7.8% vs 14.1%, p ⬍0.001), and the number of antianginal medications were significantly reduced in patients assigned to an invasive strategy compared with those assigned to a conservative approach. It is important to emphasize that this study was completed before the availability of coronary stents or widespread use of glycoprotein IIb/IIIa inhibitors. It is also notable that ⬎60% of patients assigned to the conservative limb ultimately underwent coronary angiography and 49% of patients underwent revascular-
VOL. 88 (8A)
OCTOBER 18, 2001
ization, suggesting that most patients with non–STsegment elevation MI and unstable angina ultimately develop ⱖ1 indications for cardiac catheterization and revascularization. These trial results showed that although death or MI were not reduced with an approach involving early coronary arteriography and revascularization, there were substantial benefits that may occur in patients who undergo early revascularization for non–ST-segment elevation MI or unstable angina, similar to those seen with early and aggressive lipid-lowering therapy.7 The Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital trial: The Veterans Affairs Non–Q-
Wave Infarction Strategies in Hospital (VANQWISH) trial assessed late clinical outcomes in 920 patients with non–ST-segment elevation MI assigned to an early aggressive or conservative strategy.4 Patients assigned to the conservative group underwent coronary arteriography and revascularization only for recurrent postinfarction angina, ⱖ2 mm ST-segment depression on exercise stress testing, or a thallium scintigraphic evidence of ⱖ2 regions of myocardial ischemia. The occurrence of death or MI 1 year after presentation was higher in patients assigned to the invasive group compared with the conservative group (24.0% vs 18.6%, respectively; p ⫽ 0.05). In patients treated with the invasive approach, 1-year mortality was also higher compared with the conservative group (12.6% vs 7.9%, respectively; p ⫽ 0.025). Event-free survival was not different between the 2 groups during the extended 12- to 44-month period of follow-up study. Interestingly, there were no deaths in patients in the invasive limb assigned to percutaneous transluminal coronary angioplasty, but the mortality rate was 11.6% in patients who underwent coronary artery bypass graft surgery in the invasive arm. There are several other notable features of the VANQWISH trial. First, although the frequency of multivessel coronary artery disease was high (74% of patients in the invasive group had multivessel disease), only 44% of patients assigned to invasive therapy actually underwent coronary revascularization, suggesting that the potential benefits of coronary revascularization were not completely realized. Second, although this study was also performed before the widespread availability of coronary stents and glycoprotein IIb/IIIa inhibitors, the clinical outcomes associated with PCI were quite favorable.4 Finally, coronary artery bypass graft surgery was performed in nearly 50% of the patients who underwent revascularization in the invasive arm. The 11.6% mortality rate in these patients exceeds the clinical experience in this subgroup of patients in other series,3,5,6 and is not fully explainable from the baseline clinical features. Thus, it is quite likely that the very high perioperative surgical mortality rate influenced the overall results of the trial. Fragmin and Fast Revascularization During Instability in Coronary Artery Disease study: In the Fragmin
and Fast Revascularization During Instability in Coronary Artery Disease (FRISC) II trial, 2,457 patients
with non–ST-segment elevation MI or unstable angina were randomized in a 2 ⫻ 2 factorial design to (1) dalteparin or placebo for 3 months, and (2) an invasive strategy or a conservative strategy.5 Patients assigned to the invasive arm underwent cardiac catheterization within a few days of symptom onset, and coronary revascularization was performed within 7 days of presentation. PCI was recommended if there were 1 or 2 epicardial stenoses approachable with PCI; coronary artery bypass graft surgery was undertaken in the event of triple-vessel or left main coronary artery disease. Patients assigned to the conservative strategy underwent cardiac catheterization for refractory or recurrent ischemia, despite maximal medical therapy, or had an exercise stress test before hospital discharge that demonstrated ischemia. After 6 months, there was a significant decrease in the composite endpoint of death or MI in the invasive group compared with the conservative group (9.4% vs 12.1%, respectively; p ⫽ 0.031). There was a significant difference in MI alone (7.8% vs 10.1%, respectively; p ⫽ 0.045) and a nonsignificant reduction in mortality (1.9% vs 2.9%, respectively; p ⫽ 0.10). Symptoms of angina and readmission for unstable angina were halved in patients treated with the invasive strategy. The benefits were greatest in high-risk patients, particularly those with electrocardiographic changes on admission. Nearly 78% of patients in the invasive group underwent revascularization compared with 37% in those assigned to the conservative therapy. Coronary stents were used in approximately 65% of revascularization procedures, although glycoprotein IIb/IIIa inhibitors were used in only 10% of cases. It is important to note that patients generally underwent revascularization only after a period of medical stabilization. These results strongly support an aggressive strategy for revascularization in patients with non–ST-segment elevation MI or unstable angina. The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy trial: The Treat Angina with Aggrastat and Determine
Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial treated 2,200 patients with non–ST-segment elevation MI or unstable angina with aspirin, unfractionated heparin, and intravenous tirofiban (0.4 g/kg per minute loading infusion, followed by a maintenance infusion of 0.1 g/kg per minute for 48 hours or until 12 hours after PCI).6 Patients were randomly assigned to an early aggressive strategy with coronary arteriography and coronary revascularization within 4 to 48 hours after presentation, or to a conservative strategy, whereby coronary arteriography was performed only for recurrent ischemia or exercise stress testing demonstrating reversible ischemia. The rate of the 6-month primary composite endpoint of death, recurrent MI, or urgent revascularization was reduced by 18% in patients assigned to the invasive strategy compared with the conservative strategy (15.9% vs 19.4%, respectively; p ⫽ 0.025). The rate of death or MI at 6 months was reduced by
A SYMPOSIUM: LIPID MANAGEMENT IN ACUTE AND LONG-TERM SETTINGS
27K
TABLE 2 Subgroup Analysis in TACTICS Trial for 6-Month Composite Events Conservative Invasive % Patients Approach Approach with Criteria % % p-Value Cardiac markers CK-MB ⬎5 ng/mL ⱕ5 ng/mL Troponin T ⬎0.1 ng/mL ⱕ0.1 ng/mL Electrocardiogram ST-segment changes present ST-segment changes absent Composite TIMI risk score Low (0–2) Intermediate (3–4) High (5–7)
patients who present with non–ST-segment elevation MI or unstable angina, and that the benefit is most marked in patients with intermediate- or high-risk characteristics using the TIMI risk score, who composed 75% of the study population.
39 61
23.9 16.8
17.3 15.4
⬍0.05 NS
VALUE OF RISK STRATIFICATION TO GUIDE THERAPY
41 59
24.5 16.6
16.4 15.1
⬍0.05 NS
38
26.3
16.4
⬍0.05
62
15.3
15.6
NS
25 60 15
11.8 20.3 30.6
12.8 16.1 19.5
NS ⬍0.05 ⬍0.05
Results from a number of studies suggested that risk stratification is important for the determination of treatment algorithms in patients who present with non–ST-segment elevation MI and unstable angina. Early coronary arteriography and coronary revascularization is indicated in patients with ACS at high- or intermediate-risk of subsequent death or MI (Table 3).8 Coronary revascularization is not indicated in patients with unstable angina who do not have intermediate- or high-risk features, do not develop unfavorable criteria on exercise testing, do not have objective signs of coronary ischemia, or in whom revascularization will not improve the quality of life.8 The TIMI risk score proved to be an important predictor of outcome in patients enrolled in the TACTICS trial.6 The TIMI unstable angina/non–ST-segment elevation MI risk score includes patient age ⬎65 years, ⱖ3 cardiac risk factors, prior coronary stenosis ⱖ50%, prior aspirin use, multiple episodes of angina, STsegment deviation, and positive cardiac markers. Using the TIMI risk score, patients at intermediate risk (risk score of 3 to 4) or high risk (risk score of 5 to 7) were seen to have the greatest benefit with an invasive approach (25% and 45% reduction, respectively), whereas low-risk patients (risk score of 0 to 2) appeared to have no advantage with an invasive approach (Table 2).6
Adapted from N Engl J Med.6
23% (7.3% vs 9.5%, respectively; p ⬍0.05). These benefits were highest in patients presenting with unfavorable prognostic factors, such as rest pain, cardiac enzyme elevation, or electrocardiographic changes (Table 2). The TACTICS trial represents the most contemporary evidence to guide clinical practice in patients who present with non–ST-segment elevation MI and unstable angina. All patients were treated with an “upstream” glycoprotein IIb/IIIa inhibitor (tirofiban), and stents were frequently used in patients assigned to both the invasive and conservative groups (83% and 86% of PCI procedures, respectively). These results suggest that an invasive approach may be beneficial in
TABLE 3 Agency for Health Care Policy and Research Assessment of Risk in Patients with Unstable Angina
History Character of pain
Clinical findings
ECG
Cardiac markers
High Risk
Intermediate Risk
Accelerating pain pattern during preceding 48 hr Prolonged (⬎20 min) ongoing chest pain
Prior MI, PVD, CVA, or CABG prior aspirin use Prolonged (⬎20 min) pain that has resolved with moderate or high probability of CAD Age ⬎70 yr
Pulmonary edema New or worsening MR S3 or new/worsening rales Hypotension, bradycardia, or tachycardia Age ⬎75 yr Angina at rest with ST-segment changes ⬎0.05 mV New bundle branch block Sustained ventricular tachycardia Markedly elevated (TnT or TnI ⬎ 0.1 ng/mL)
Low Risk
New-onset CCS Class III-IV without prolonged chest pain but with moderate likelihood of CAD
T-wave inversion with ⬎0.2 mV Pathologic Q-waves
Normal or unchanged ECG during an episode of chest discomfort
Slightly elevated (eg, TnT ⬎ 0.01 but ⬍0.1 ng/mL)
Normal
CABG ⫽ coronary artery bypass graft surgery; CAD ⫽ coronary artery disease; CCS ⫽ Canadian Cardiovascular Society; CVA ⫽ cerebrovascular accident; ECG ⫽ electrocardiogram; MI ⫽ myocardial infarction; MR ⫽ mitral regurgitation; PVD ⫽ peripheral vascular disease. Adapted from J Am Coll Cardiol.8
28K THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 88 (8A)
OCTOBER 18, 2001
COMPARISON WITH OTHER TRIALS IN PATIENTS WITH UNSTABLE ANGINA The beneficial results of an invasive approach in patients with non–ST-segment elevation MI and unstable angina should be viewed in the context of other trials that have evaluated pharmacologic agents for the prevention of events in patients with ACS. Although the VANQWISH trial was associated with a 22.5% increased risk for death or MI in patients treated with an invasive strategy, the invasive strategies in the other 3 other studies were associated with 10.5% to 23.1% reductions in death or MI compared with patients treated with a conservative approach.3– 6 The relative reduction in clinical events with an invasive strategy compares favorably with the relative reduction in clinical events achieved with pharmacologic therapy in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial (eptifibatide, 7%)9 and in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial (atorvastatin, 16%).7 Glycoprotein IIb/IIIa inhibitors are indicated in patients with ACS, particularly in those patients with high-risk criteria.2 Patients who undergo PCI appeared to benefit the most from pretreatment with glycoprotein IIb/IIIa inhibitor therapy. In the PURSUIT trial, the primary outcome (death or MI) was reduced in patients undergoing PCI within 72 hours of randomization from 16.7% (placebo group) to 11.6% (eptifibatide group), a 31% reduction (p ⫽ 0.01).9
CONCLUSIONS AND IMPLICATIONS FOR CLINICAL PRACTICE Patients who present with ACS should have an electrocardiogram performed as soon as logistically possible after presentation. Patients with documented ST-segment elevation should be given aspirin and considered for immediate mechanical or pharmacologic reperfusion therapy. Patients with a history of ischemia who do not have ST-segment elevation are classified as non–ST-segment elevation MI or unstable angina and should be treated with the following: aspirin; unfractionated or low-molecular-weight heparin; and anti-ischemic therapy, such as nitrates and blockers. Risk stratification should be performed to stratify patients into low-, intermediate-, and high-risk groups. Those patients with electrocardiographic changes or elevated cardiac markers may benefit from glycoprotein IIb/IIIa inhibitors. Results obtained from recent randomized clinical trials suggest that an invasive strategy for coronary arteriography and revascularization is indicated in in-
termediate- and high-risk patients who present with non–ST-segment elevation MI or unstable angina. These patients may include up to 75% of patients admitted with non–ST-segment elevation MI or unstable angina. Low-risk patients may be safely observed for recurrent ischemia or evidence of residual myocardial ischemia on exercise stress testing. Patients who are to undergo revascularization may benefit from upstream use of glycoprotein IIb/IIIa inhibitors. A critical component of medical management after percutaneous or surgical revascularization is the use of aggressive risk-factor modification, including lipidlowering therapy. Prevention of recurrent events after revascularization will depend on plaque stabilization, at least for the first 4 months after presentation with unstable angina. Whether sustained reductions in levels of low-density lipoprotein cholesterol provide incremental benefit over less-pronounced reduction is the subject of ongoing clinical trials. 1. Popma JJ, Kuntz RE. Percutaneous coronary intervention and valvuloplasty.
In: Braunwald E, Zipes DP, Libby P, ed. Heart Disease. 6th ed. Philadelphia: WB Saunders, 2001:1364 –1406. 2. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36: 970 –1062. 3. The TIMI IIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI IIIB Trial. Circulation 1994;89:1545–1556. 4. Boden WE, O’Rourke RA, Crawford MH, Blaustein AS, Deedwania PC, Zoble RG, Wexler LF, Kleiger RE, Pepine CJ, Ferry DR, Chow BK, Lavori PW, for the Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. Outcomes in patients with acute non–Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. N Engl J Med 1998;338:1785–1792. 5. Fragmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicenter study. Lancet 1999;354:708 –715. 6. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, Neumann F-J, Robertson DH, DeLucca PT, DiBattiste PM, Gibson CM, Braunwald E, for the TACTICS-Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001:344:1879 –1887. 7. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285: 1711–1718. 8. Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, Legako RD, Leon DF, Murray JA, Nissen SE, et al. ACC/AHA guidelines for coronary angiography: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). J Am Coll Cardiol 1999;33:1756 –1824. 9. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436 – 443.
A SYMPOSIUM: LIPID MANAGEMENT IN ACUTE AND LONG-TERM SETTINGS
29K
MD,
and Jacqueline Suk,
MD
Percutaneous coronary intervention can be safely performed in patients with acute coronary syndromes (ACS), including those with non–ST-segment elevation myocardial infarction (MI), and unstable angina. Although there remains debate about whether an aggressive strategy involving early coronary arteriography and revascularization should be routinely performed in patients who present with non–ST-segment elevation MI and unstable angina, recent clinical trials suggest that an aggressive approach should be taken in both intermediate- and high-risk patients with ACS. There have been 4 clinical trials that have compared the outcomes of patients presenting with non–ST-segment elevation MI or unstable angina who were assigned to invasive or conservative strategies. The Thrombolysis in Myocardial Infarction (TIMI) IIIB trial and the Veterans Affairs Non–QWave Infarction Strategies in Hospital (VANQWISH) trial failed to demonstrate a reduction in death or MI in patients assigned to an invasive approach, but it did demonstrate an important reduction in the frequency of rehospitalization. However, these studies were performed before the availability of coronary stents or the
use of glycoprotein IIb/IIIa inhibitors. In contrast, the Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease (FRISC) II and the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) trials demonstrated significant improvements in the rates of death or MI in patients with non–ST-segment elevation MI or unstable angina assigned to an invasive strategy. Event reductions were greatest in patients with non–ST-segment elevation MI or unstable angina at intermediate or high risk for an adverse outcome. Understanding that these subgroups comprise approximately 75% of patients presenting with non–ST-segment elevation MI or unstable angina, we believe that an invasive approach is indicated in most patients who develop non–ST-segment elevation MI or unstable angina. Regardless of the strategy used in ACS patients, lipid-lowering therapy is necessary to reduce recurrent ischemia events at the site of plaque instability and in atherosclerotic disease remote to the target lesion. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88:25K–29K
n the United States, ⬎750 000 percutaneous coronary intervention (PCI) procedures are performed Iannually, which exceeds the number of coronary ar-
CLASSIFICATION OF ACUTE CORONARY SYNDROMES
tery bypass graft surgeries.1 The expanded use of coronary revascularization has been a result of the favorable outcomes obtained with PCI in recent years, caused, at least in part, by the availability of glycoprotein IIb/IIIa inhibitors and stents. As the safety of coronary stenting has progressively improved, its use has broadened to include patients with acute coronary syndromes (ACS) and thrombus. Whether PCI should be routinely performed in patients with ACS has remained a controversial issue. The purpose of this review is to support the view that coronary arteriography and revascularization should be routinely performed in intermediate- and high-risk patients presenting with ACS.
From the Department of Internal Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA. Address for reprints: Jeffrey J. Popma, MD, Interventional Cardiology, Brigham and Women’s Hospital, 75 Francis Street, L-2 Cardiac Catheterization Laboratory, Boston, Massachusetts 02115. E-mail: [email protected]. ©2001 by Excerpta Medica, Inc. All rights reserved.
There will be ⬎1.4 million patients hospitalized for ACS this year in the United States.2 Under the new classification system, patients are classified as those with ST-segment elevation myocardial infarction (MI), clinically manifest as transmural myocardial ischemia and complete coronary occlusion, and those with non–ST-segment elevation MI or unstable angina, clinically manifest as nontransmural myocardial ischemia and incomplete epicardial vessel occlusion.2 Patients with non–ST-segment elevation MI have enzymatic evidence of myocardial necrosis; those with unstable angina have pain at rest, an accelerated pattern of chest pain, or new onset pain without evidence of myocardial necrosis. These classifications have been useful in planning treatment strategies in patients with ACS.2 Therapy is directed toward mechanical or pharmacologic reperfusion in patients with ST-segment elevation MI, and toward plaque stabilization using antithrombotic agents and lipid-lowering therapy in patients with non–ST-segment elevation MI and unstable angina.2 Several newer pharmacologic agents have been recently reported and are also discussed in this review. 0002-9149/01/$ – see front matter PII S0002-9149(01)02037-9
25K
TABLE 1 Clinical Outcomes in Patients Enrolled in Unstable Angina Trials TIMI IIIb3 Treatment Group
Cons
Inv
Time period Entry criteria
1989–1992 NSTEMI Unstable angina 733 740 64 98
VANQWISH4 Cons
Inv
1993–1995 NSTEMI
FRISC-II5 Cons
TACTICS6
Inv
1996–1998 NSTEMI Unstable angina 1,235 1,222 47 98
Cons
Patients (n) 458 462 Coronary arteriography 48 96 (%) Time to angiography 7.1 days 1.5 days 14 days 2 days 17 days 4 days Revascularization (%) 49 61 33 44 36.7 77.9 CABG alone (%) 24 25 20 21 18.9 35.2 Time to NR NR 24.5 days 8 days NR NR revascularization Follow-up period 6 wk 12 mo 6 mo Composite outcome 18.1 16.2 18.6 24.0* 12.1 9.4† Death 2.5 2.4 7.9 12.6† 2.9 1.9 MI 5.7 5.1 NR NR 10.1 7.8† Absolute/relative 21.9/210.5 15.4/122.5 22.7/222.3 % change in death/MI Angina at follow-up 28.6 24 NR NR 39 22‡ Repeat hospitalization 14.1 7.8‡ NR NR 24 14‡ for recurrent ischemia
Inv
1997–1999 NSTEMI Unstable angina 1,106 1,114 51 97 79 hr 37 16 93 hr
22 hr 61 22 25 hr
6 mo 19.4 15.9† 3.5 3.3 6.9 4.8† 22.2/223.1 NR 13.7
NR 11.0
PURSUIT9 Pl
Eptifib
1995–1997 NSTEMI Unstable angina 4,739 4,722 NR NR NR NR NR NR
NR NR NR NR
MIRACL7 Pl
Atorv
1997–1999 NSTEMI Unstable angina 1,548 1,538 NR NR NR 16.1 NR NR
NR 16.5 NR NR
30 days 15.7 14.2† 3.7 3.5 13.5 12.6 21.5/210
4 mo 17.4 14.8† 4.4 4.2 7.3 6.6 20.8/27.3
NR NR
NR 8.4
NR NR
NR 6.2†
Atorv ⫽ atorvastatin; CABG ⫽ coronary artery bypass graft surgery; Cons ⫽ conservative approach; Eptifib ⫽ eptifibatide; Inv ⫽ invasive approach; MI ⫽ myocardial infarction; NR ⫽ not reported; NSTEMI ⫽ non–ST-segment elevation myocardial infarction; Pl ⫽ placebo. *p ⫽ 0.05. † p ⬍0.05. ‡ p ⬍0.001.
INVASIVE OR CONSERVATIVE STRATEGIES IN PATIENTS WITH NON–ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION AND UNSTABLE ANGINA It is well recognized that coronary revascularization improves clinical outcomes in selected patients with non–ST-segment elevation MI or unstable angina, particularly those with evidence of ongoing myocardial ischemia. From 10% to 15% of patients with nonobstructive coronary artery disease and 20% of patients with triple-vessel disease with reduced left ventricular function or left main coronary artery disease may benefit from surgery.2 Early coronary arteriography identifies these patients. Yet debate still continues over whether this approach, routinely applied, will result in clinical benefits in all patients presenting with non–ST-segment elevation MI or unstable angina.2 There are 4 randomized clinical trials comparing the invasive and conservative strategies in patients with non–ST-segment elevation MI or unstable angina that have been performed to date.3– 6 These studies have differed in (1) inclusion criteria, (2) availability and use of coronary stents and glycoprotein IIb/IIIa inhibitors, (3) frequency of revascularization in invasive arms, and (4) clinical outcomes (Table 1). In aggregate, we believe that the results from these trials support an aggressive approach toward coronary revascularization in patients who present with non– ST-segment elevation MI or unstable angina. Thrombolysis in Myocardial Infarction IIIB trial: The Thrombolysis in Myocardial Infarction (TIMI) IIIB 26K THE AMERICAN JOURNAL OF CARDIOLOGY姞
trial enrolled 1,473 patients within 24 hours of ischemic discomfort because of non–ST-segment elevation MI or unstable angina and randomly assigned them in a 2 ⫻ 2 factorial design to (1) treatment with tissue plasminogen activator or placebo, and (2) an invasive or conservative strategy.3 Patients assigned to the conservative strategy were referred for cardiac catheterization and revascularization only for the occurrence of chest pain associated with ST-segment elevation or depression, ST-segment depression on Holter monitoring, or an unsatisfactory “low-level” exercise tolerance test. The primary outcome for the comparison of the invasive and conservative strategies was the occurrence of death, MI, or an unsatisfactory symptomlimited exercise tolerance test at 6 weeks. Although there were no significant differences in occurrence of the primary outcome in the 2 groups, a number of secondary outcomes demonstrated the clinical benefit of the invasive approach. Specifically, the average length of the initial hospitalization (10.2 days vs 10.9 days, p ⫽ 0.01), the frequency of rehospitalization at 6 weeks (7.8% vs 14.1%, p ⬍0.001), and the number of antianginal medications were significantly reduced in patients assigned to an invasive strategy compared with those assigned to a conservative approach. It is important to emphasize that this study was completed before the availability of coronary stents or widespread use of glycoprotein IIb/IIIa inhibitors. It is also notable that ⬎60% of patients assigned to the conservative limb ultimately underwent coronary angiography and 49% of patients underwent revascular-
VOL. 88 (8A)
OCTOBER 18, 2001
ization, suggesting that most patients with non–STsegment elevation MI and unstable angina ultimately develop ⱖ1 indications for cardiac catheterization and revascularization. These trial results showed that although death or MI were not reduced with an approach involving early coronary arteriography and revascularization, there were substantial benefits that may occur in patients who undergo early revascularization for non–ST-segment elevation MI or unstable angina, similar to those seen with early and aggressive lipid-lowering therapy.7 The Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital trial: The Veterans Affairs Non–Q-
Wave Infarction Strategies in Hospital (VANQWISH) trial assessed late clinical outcomes in 920 patients with non–ST-segment elevation MI assigned to an early aggressive or conservative strategy.4 Patients assigned to the conservative group underwent coronary arteriography and revascularization only for recurrent postinfarction angina, ⱖ2 mm ST-segment depression on exercise stress testing, or a thallium scintigraphic evidence of ⱖ2 regions of myocardial ischemia. The occurrence of death or MI 1 year after presentation was higher in patients assigned to the invasive group compared with the conservative group (24.0% vs 18.6%, respectively; p ⫽ 0.05). In patients treated with the invasive approach, 1-year mortality was also higher compared with the conservative group (12.6% vs 7.9%, respectively; p ⫽ 0.025). Event-free survival was not different between the 2 groups during the extended 12- to 44-month period of follow-up study. Interestingly, there were no deaths in patients in the invasive limb assigned to percutaneous transluminal coronary angioplasty, but the mortality rate was 11.6% in patients who underwent coronary artery bypass graft surgery in the invasive arm. There are several other notable features of the VANQWISH trial. First, although the frequency of multivessel coronary artery disease was high (74% of patients in the invasive group had multivessel disease), only 44% of patients assigned to invasive therapy actually underwent coronary revascularization, suggesting that the potential benefits of coronary revascularization were not completely realized. Second, although this study was also performed before the widespread availability of coronary stents and glycoprotein IIb/IIIa inhibitors, the clinical outcomes associated with PCI were quite favorable.4 Finally, coronary artery bypass graft surgery was performed in nearly 50% of the patients who underwent revascularization in the invasive arm. The 11.6% mortality rate in these patients exceeds the clinical experience in this subgroup of patients in other series,3,5,6 and is not fully explainable from the baseline clinical features. Thus, it is quite likely that the very high perioperative surgical mortality rate influenced the overall results of the trial. Fragmin and Fast Revascularization During Instability in Coronary Artery Disease study: In the Fragmin
and Fast Revascularization During Instability in Coronary Artery Disease (FRISC) II trial, 2,457 patients
with non–ST-segment elevation MI or unstable angina were randomized in a 2 ⫻ 2 factorial design to (1) dalteparin or placebo for 3 months, and (2) an invasive strategy or a conservative strategy.5 Patients assigned to the invasive arm underwent cardiac catheterization within a few days of symptom onset, and coronary revascularization was performed within 7 days of presentation. PCI was recommended if there were 1 or 2 epicardial stenoses approachable with PCI; coronary artery bypass graft surgery was undertaken in the event of triple-vessel or left main coronary artery disease. Patients assigned to the conservative strategy underwent cardiac catheterization for refractory or recurrent ischemia, despite maximal medical therapy, or had an exercise stress test before hospital discharge that demonstrated ischemia. After 6 months, there was a significant decrease in the composite endpoint of death or MI in the invasive group compared with the conservative group (9.4% vs 12.1%, respectively; p ⫽ 0.031). There was a significant difference in MI alone (7.8% vs 10.1%, respectively; p ⫽ 0.045) and a nonsignificant reduction in mortality (1.9% vs 2.9%, respectively; p ⫽ 0.10). Symptoms of angina and readmission for unstable angina were halved in patients treated with the invasive strategy. The benefits were greatest in high-risk patients, particularly those with electrocardiographic changes on admission. Nearly 78% of patients in the invasive group underwent revascularization compared with 37% in those assigned to the conservative therapy. Coronary stents were used in approximately 65% of revascularization procedures, although glycoprotein IIb/IIIa inhibitors were used in only 10% of cases. It is important to note that patients generally underwent revascularization only after a period of medical stabilization. These results strongly support an aggressive strategy for revascularization in patients with non–ST-segment elevation MI or unstable angina. The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy trial: The Treat Angina with Aggrastat and Determine
Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial treated 2,200 patients with non–ST-segment elevation MI or unstable angina with aspirin, unfractionated heparin, and intravenous tirofiban (0.4 g/kg per minute loading infusion, followed by a maintenance infusion of 0.1 g/kg per minute for 48 hours or until 12 hours after PCI).6 Patients were randomly assigned to an early aggressive strategy with coronary arteriography and coronary revascularization within 4 to 48 hours after presentation, or to a conservative strategy, whereby coronary arteriography was performed only for recurrent ischemia or exercise stress testing demonstrating reversible ischemia. The rate of the 6-month primary composite endpoint of death, recurrent MI, or urgent revascularization was reduced by 18% in patients assigned to the invasive strategy compared with the conservative strategy (15.9% vs 19.4%, respectively; p ⫽ 0.025). The rate of death or MI at 6 months was reduced by
A SYMPOSIUM: LIPID MANAGEMENT IN ACUTE AND LONG-TERM SETTINGS
27K
TABLE 2 Subgroup Analysis in TACTICS Trial for 6-Month Composite Events Conservative Invasive % Patients Approach Approach with Criteria % % p-Value Cardiac markers CK-MB ⬎5 ng/mL ⱕ5 ng/mL Troponin T ⬎0.1 ng/mL ⱕ0.1 ng/mL Electrocardiogram ST-segment changes present ST-segment changes absent Composite TIMI risk score Low (0–2) Intermediate (3–4) High (5–7)
patients who present with non–ST-segment elevation MI or unstable angina, and that the benefit is most marked in patients with intermediate- or high-risk characteristics using the TIMI risk score, who composed 75% of the study population.
39 61
23.9 16.8
17.3 15.4
⬍0.05 NS
VALUE OF RISK STRATIFICATION TO GUIDE THERAPY
41 59
24.5 16.6
16.4 15.1
⬍0.05 NS
38
26.3
16.4
⬍0.05
62
15.3
15.6
NS
25 60 15
11.8 20.3 30.6
12.8 16.1 19.5
NS ⬍0.05 ⬍0.05
Results from a number of studies suggested that risk stratification is important for the determination of treatment algorithms in patients who present with non–ST-segment elevation MI and unstable angina. Early coronary arteriography and coronary revascularization is indicated in patients with ACS at high- or intermediate-risk of subsequent death or MI (Table 3).8 Coronary revascularization is not indicated in patients with unstable angina who do not have intermediate- or high-risk features, do not develop unfavorable criteria on exercise testing, do not have objective signs of coronary ischemia, or in whom revascularization will not improve the quality of life.8 The TIMI risk score proved to be an important predictor of outcome in patients enrolled in the TACTICS trial.6 The TIMI unstable angina/non–ST-segment elevation MI risk score includes patient age ⬎65 years, ⱖ3 cardiac risk factors, prior coronary stenosis ⱖ50%, prior aspirin use, multiple episodes of angina, STsegment deviation, and positive cardiac markers. Using the TIMI risk score, patients at intermediate risk (risk score of 3 to 4) or high risk (risk score of 5 to 7) were seen to have the greatest benefit with an invasive approach (25% and 45% reduction, respectively), whereas low-risk patients (risk score of 0 to 2) appeared to have no advantage with an invasive approach (Table 2).6
Adapted from N Engl J Med.6
23% (7.3% vs 9.5%, respectively; p ⬍0.05). These benefits were highest in patients presenting with unfavorable prognostic factors, such as rest pain, cardiac enzyme elevation, or electrocardiographic changes (Table 2). The TACTICS trial represents the most contemporary evidence to guide clinical practice in patients who present with non–ST-segment elevation MI and unstable angina. All patients were treated with an “upstream” glycoprotein IIb/IIIa inhibitor (tirofiban), and stents were frequently used in patients assigned to both the invasive and conservative groups (83% and 86% of PCI procedures, respectively). These results suggest that an invasive approach may be beneficial in
TABLE 3 Agency for Health Care Policy and Research Assessment of Risk in Patients with Unstable Angina
History Character of pain
Clinical findings
ECG
Cardiac markers
High Risk
Intermediate Risk
Accelerating pain pattern during preceding 48 hr Prolonged (⬎20 min) ongoing chest pain
Prior MI, PVD, CVA, or CABG prior aspirin use Prolonged (⬎20 min) pain that has resolved with moderate or high probability of CAD Age ⬎70 yr
Pulmonary edema New or worsening MR S3 or new/worsening rales Hypotension, bradycardia, or tachycardia Age ⬎75 yr Angina at rest with ST-segment changes ⬎0.05 mV New bundle branch block Sustained ventricular tachycardia Markedly elevated (TnT or TnI ⬎ 0.1 ng/mL)
Low Risk
New-onset CCS Class III-IV without prolonged chest pain but with moderate likelihood of CAD
T-wave inversion with ⬎0.2 mV Pathologic Q-waves
Normal or unchanged ECG during an episode of chest discomfort
Slightly elevated (eg, TnT ⬎ 0.01 but ⬍0.1 ng/mL)
Normal
CABG ⫽ coronary artery bypass graft surgery; CAD ⫽ coronary artery disease; CCS ⫽ Canadian Cardiovascular Society; CVA ⫽ cerebrovascular accident; ECG ⫽ electrocardiogram; MI ⫽ myocardial infarction; MR ⫽ mitral regurgitation; PVD ⫽ peripheral vascular disease. Adapted from J Am Coll Cardiol.8
28K THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 88 (8A)
OCTOBER 18, 2001
COMPARISON WITH OTHER TRIALS IN PATIENTS WITH UNSTABLE ANGINA The beneficial results of an invasive approach in patients with non–ST-segment elevation MI and unstable angina should be viewed in the context of other trials that have evaluated pharmacologic agents for the prevention of events in patients with ACS. Although the VANQWISH trial was associated with a 22.5% increased risk for death or MI in patients treated with an invasive strategy, the invasive strategies in the other 3 other studies were associated with 10.5% to 23.1% reductions in death or MI compared with patients treated with a conservative approach.3– 6 The relative reduction in clinical events with an invasive strategy compares favorably with the relative reduction in clinical events achieved with pharmacologic therapy in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial (eptifibatide, 7%)9 and in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial (atorvastatin, 16%).7 Glycoprotein IIb/IIIa inhibitors are indicated in patients with ACS, particularly in those patients with high-risk criteria.2 Patients who undergo PCI appeared to benefit the most from pretreatment with glycoprotein IIb/IIIa inhibitor therapy. In the PURSUIT trial, the primary outcome (death or MI) was reduced in patients undergoing PCI within 72 hours of randomization from 16.7% (placebo group) to 11.6% (eptifibatide group), a 31% reduction (p ⫽ 0.01).9
CONCLUSIONS AND IMPLICATIONS FOR CLINICAL PRACTICE Patients who present with ACS should have an electrocardiogram performed as soon as logistically possible after presentation. Patients with documented ST-segment elevation should be given aspirin and considered for immediate mechanical or pharmacologic reperfusion therapy. Patients with a history of ischemia who do not have ST-segment elevation are classified as non–ST-segment elevation MI or unstable angina and should be treated with the following: aspirin; unfractionated or low-molecular-weight heparin; and anti-ischemic therapy, such as nitrates and blockers. Risk stratification should be performed to stratify patients into low-, intermediate-, and high-risk groups. Those patients with electrocardiographic changes or elevated cardiac markers may benefit from glycoprotein IIb/IIIa inhibitors. Results obtained from recent randomized clinical trials suggest that an invasive strategy for coronary arteriography and revascularization is indicated in in-
termediate- and high-risk patients who present with non–ST-segment elevation MI or unstable angina. These patients may include up to 75% of patients admitted with non–ST-segment elevation MI or unstable angina. Low-risk patients may be safely observed for recurrent ischemia or evidence of residual myocardial ischemia on exercise stress testing. Patients who are to undergo revascularization may benefit from upstream use of glycoprotein IIb/IIIa inhibitors. A critical component of medical management after percutaneous or surgical revascularization is the use of aggressive risk-factor modification, including lipidlowering therapy. Prevention of recurrent events after revascularization will depend on plaque stabilization, at least for the first 4 months after presentation with unstable angina. Whether sustained reductions in levels of low-density lipoprotein cholesterol provide incremental benefit over less-pronounced reduction is the subject of ongoing clinical trials. 1. Popma JJ, Kuntz RE. Percutaneous coronary intervention and valvuloplasty.
In: Braunwald E, Zipes DP, Libby P, ed. Heart Disease. 6th ed. Philadelphia: WB Saunders, 2001:1364 –1406. 2. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36: 970 –1062. 3. The TIMI IIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI IIIB Trial. Circulation 1994;89:1545–1556. 4. Boden WE, O’Rourke RA, Crawford MH, Blaustein AS, Deedwania PC, Zoble RG, Wexler LF, Kleiger RE, Pepine CJ, Ferry DR, Chow BK, Lavori PW, for the Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. Outcomes in patients with acute non–Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. N Engl J Med 1998;338:1785–1792. 5. Fragmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicenter study. Lancet 1999;354:708 –715. 6. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, Neumann F-J, Robertson DH, DeLucca PT, DiBattiste PM, Gibson CM, Braunwald E, for the TACTICS-Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001:344:1879 –1887. 7. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285: 1711–1718. 8. Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, Legako RD, Leon DF, Murray JA, Nissen SE, et al. ACC/AHA guidelines for coronary angiography: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). J Am Coll Cardiol 1999;33:1756 –1824. 9. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436 – 443.
A SYMPOSIUM: LIPID MANAGEMENT IN ACUTE AND LONG-TERM SETTINGS
29K