- Email: [email protected]
Should we catheterize all patients with unstable angina? No—only the ones with coronary artery disease∗
Journal of the American College of Cardiology © 2001 by the American College of Cardiology Published by Elsevier Science Inc.
EDITORIAL COMMENT
Should We Catheterize All Patients With Unstable Angina? No—Only the Ones With Coronary Artery Disease* William G. Kussmaul III, MD, FACC Philadelphia, Pennsylvania In this issue of the Journal, Solomon et al. (1) have afforded us another look at the venerable Thrombolysis In Myocardial Infarction trial (TIMI)-IIIB dataset. The results cast useful light on an ongoing debate concerning how best to treat patients who present with unstable angina or non–Qwave myocardial infarction (MI)— conditions now recognized to represent a spectrum, and combined under the rubric “acute coronary syndromes” (ACS). The Solomon et al. (1) study is an analysis of patient subsets from TIMI-IIIB, originally published in 1994 (2). See page 969 The TIMI-IIIB trial recruited patients from 1989 to 1992, before the era of stents or platelet IIB/IIIA receptor blockers. Patients were required to have experienced chest pain at rest within 24 h prior to enrollment. That the chest pain represented myocardial ischemia was attested by ischemic electrocardiographic (ECG) changes, history of prior infarction, previously documented coronary stenosis or an abnormal stress thallium scan result. Eligible, consenting patients were randomized to intravenous tissue-type plasminogen activator or placebo, and also to a conservative versus an early invasive management strategy. Some 98% of patients assigned to the invasive arm underwent coronary angiography, and 63% underwent subsequent coronary revascularization (25% coronary artery bypass graft surgery; 38% percutaneous transluminal coronary intervention [PTCI]). Of the conservative group, 64% underwent catheterization for clinical indications; 50% also had coronary revascularization. The combined end points included death, MI, or a stress test showing ischemia at six weeks’ followup. The overall trial results were negative both for fibrinolytic therapy and for the early invasive strategy, although the patients in the latter group did experience shorter hospital stay, fewer episodes of rehospitalization and required less antianginal drug therapy. These results were interpreted to indicate that routine *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Cardiology Consultants of Philadelphia, Hahnemann University Hospital, Philadelphia, Pennsylvania.
Vol. 38, No. 4, 2001 ISSN 0735-1097/01/$20.00 PII S0735-1097(01)01498-X
catheterization was not indicated in patients presenting with ACS. However, although TIMI-IIIB was a model clinical trial in many ways, a plausible criticism is that the somewhat loose definition of “myocardial ischemia” may have allowed for the inclusion of patients at very low risk, and even some who did not have coronary artery disease (e.g., a patient with rest pain and an abnormal thallium result, who was subsequently shown to have normal coronary arteries). In such patients, the procedural risk of catheterization might outweigh the potential for benefit. The current report (1) reanalyzes TIMI-IIIB from this viewpoint, taking into account certain clinical factors that are readily available upon presentation to the hospital. Multivariate analysis yields four independent prognostic factors: older age, ST-segment depression at presentation, “complicated angina” and elevated baseline creatine kinase-MB fraction. A schema is derived that separates the patients into five tiers of risk, of which the top two appear to have significantly benefited from routine catheterization and intervention, whereas the lower three were not helped (or possibly may have been harmed) by catheterization and intervention as practiced in the late 1980s. Another way to state their findings would be: Among patients presenting with chest pain, those who have unstable coronary artery disease are most likely to benefit from invasive management. The concept of multivariate risk stratification is hardly new (3–11). Examination of the results of these earlier studies shows that ischemic ECG changes at presentation, advanced age and elevated cardiac enzyme markers have been repeatedly identified as significant negative prognostic factors in patients with ACS. The Solomon et al. study (1) goes further, offering treatment and outcome data showing the utility of risk stratification. Why were C-reactive protein levels not predictive of short-term prognosis? Other studies have shown the contrary (12,13). Surprisingly also, smoking status and diabetes did not enter into this multivariate predictive model. What makes multivariate risk stratification more than a dry intellectual exercise? The answer depends entirely on whether we have any effective means of altering the shortterm prognosis of ACS patients for the better. Clearly, we do. The effectiveness of antithrombotic agents has been repeatedly shown, including aspirin, heparin, lowmolecular-weight heparins, platelet IIB/IIIA receptor antagonists and, most recently, thienopyridines, although the optimum combination of these agents has not yet been determined. Fibrinolytic agents do not confer benefit in non–ST-elevation ACS. Invasive management would certainly make sense. After all, the reason an ACS is an acute syndrome is that a pre-existent atherosclerotic plaque has become associated with fresh thrombus. Removing this complex blockage and restoring nutritive blood flow is logical, and arguing against it would appear counterintuitive. The feasibility of acute
978
Kussmaul Editorial Comment
angioplasty for ACS was shown more than 15 years ago (14 –18). The question is: To which patients is an aggressive approach best applied? The American College of Cardiology/ American Heart Association guidelines for management of ACS (19) suggest very wide latitude in determining who is an appropriate candidate for an early invasive strategy. A debate continues on this point in the literature. Recent studies (VANQWISH [20], FRISC-II [21] and now TACTICS/ TIMI-18 [22]) sound apparently contradictory notes. The overall results of Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital (VANQWISH) suggested that an early invasive approach would be harmful. Both Fragmin and Fast Revascularization during Instability in Coronary Artery Disease (FRISC-II) and TACTICS/TIMI-18 came to opposite conclusions. It makes sense that the differences among these trials may be explained by the inclusion of higher-risk patients in the latter two trials, a concept that is supported by the present reanalysis of TIMI-IIIB. If the higher-risk ACS patients are good candidates for invasive management, what about the others? The possible harm resulting from an invasive strategy in low-risk TIMIIIIB patients may be explained in part by the simultaneous administration of fibrinolytic therapy to some of these patients. Coronary intervention after full-dose lytic therapy is now recognized as a “salvage” procedure in acute MI, a situation associated with higher procedural risk than PTCI without prior fibrinolysis. Yet perhaps not coincidentally, the lowest-risk patients in VANQWISH, FRISC-II and TACTICS may also have done worse with an early invasive strategy. Many of these patients were troponin-negative. An open-season catheterization approach to patients with ACS who lack high-risk features is probably inappropriate. The limitations of the Solomon et al. study (1) are several, and they are well outlined in the report. The post hoc nature of the analysis and the decade-old vintage of the data urge caution in the interpretation of the results; yet their concordance with the outcome of recent randomized prospective trials is striking. What seems clear, based on the present study as well as the results of FRISC-II and TACTICS, is that a nihilistic approach with regard to early invasive study in patients with ACS is not warranted. The evidence presented in the current study supports the concept that higher-risk patients, at least those with clear-cut ECG changes of ischemia or elevated cardiac enzyme markers, should undergo early angiography and revascularization. Thus, the subtitle of this editorial is only slightly tongue-in-cheek. Reprint requests and correspondence: Dr. William G. Kussmaul III, Mail Stop 108, Broad and Vine Streets, Philadelphia, Pennsylvania 19102. E-mail: [email protected].
REFERENCES 1. Solomon DH, Stone PH, Glynn RJ, et al. Use of risk stratification to identify patients with unstable angina likeliest to benefit from an invasive versus conservative management strategy. J Am Coll Cardiol 2001;38:969 –76.
JACC Vol. 38, No. 4, 2001 October 2001:977–8 2. The TIMI-IIIB 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;89:1545–56. 3. Ouyang P, Brinker JA, Mellits ED, Weisfeldt ML, Gerstenblith G. Variables predictive of successful medical therapy in patients with unstable angina: selection by multivariate analysis from clinical, electrocardiographic, and angiographic evaluations. Circulation 1984;70:367–76. 4. Calvin JE, Klein LW, VandenBerg BJ, et al. Risk stratification in unstable angina: prospective validation of the Braunwald classification. JAMA 1995;273:136 – 41. 5. Cannon CP, McCabe CH, Stone PH, et al. The electrocardiogram predicts one-year outcome of patients with unstable angina and non–Q-wave myocardial infarction: results of the TIMI-III registry ECG ancillary study. J Am Coll Cardiol 1997;30:133– 40. 6. Holmvang L, Lu¨chser MS, Clemmensen P, Thygesen K, Grande P. TRIM Study Group. Very early risk stratification using combined ECG and biochemical assessment in patients with unstable coronary artery disease. Circulation 1998;98:2004 –9. 7. Jacobs DR, Kroenke C, Crow R, et al. PREDICT: a simple risk score for clinical severity and long-term prognosis after hospitalization for acute myocardial infarction or unstable angina. Circulation 1999;100: 599 – 607. 8. Calvin JE, Klein LW, VandenBerg EJ, Meyer P, Parrillo JE. Validated risk stratification model accurately predicts low risk in patients with unstable angina. J Am Coll Cardiol 2000;36:1803– 8. 9. Antman EM, Cohen M, Bernink PJLM, et al. The TIMI risk score for unstable angina/non-ST elevation myocardial infarction. JAMA 2000;284:835– 42. 10. Cohen M, Stinnett S, Weatherly BD, et al. Predictors of recurrent ischemic events and death in unstable coronary artery disease after treatment with combination antithrombotic therapy. Am Heart J 2000;139:962–70. 11. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent STsegment elevation. Circulation 2000;101:2557– 67. 12. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid-A protein in severe unstable angina. N Engl J Med 1994;331:417–24. 13. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. The FRISC Study Group. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. N Engl J Med 2000;343:1139 – 47. 14. Hartzler GO, Rutherford BD, McConahay DR, et al. Percutaneous transluminal coronary angioplasty with and without thrombolytic therapy for treatment of acute myocardial infarction. Am Heart J 1983;106:965–73. 15. Meyer J, Schmitz HJ, Kiesslich T, et al. Percutaneous transluminal coronary angioplasty in patients with stable and unstable angina pectoris: analysis of early and late results. Am Heart J 1983;106:973– 80. 16. Faxon DP, Detre KM, McCabe CH, et al. Role of percutaneous transluminal coronary angioplasty in the treatment of unstable angina. Am J Cardiol 1983;53:131C–5C. 17. Hartzler GO, Rutherford BD, McConahay DR. Percutaneous transluminal coronary angioplasty: application for acute myocardial infarction. Am J Cardiol 1984;53:117C–21C. 18. de Feyter PJ, Serruys PW, van den Brand M, et al. Emergency coronary angioplasty in refractory unstable angina. N Engl J Med 1985;313:342– 6. 19. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non–STsegment elevation myocardial infarction. Circulation 2000;102:1193– 209. 20. Boden WE, O’Rourke RA, Crawford MH, et al. 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;338:1785–92. 21. The FRISC Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC-II prospective randomised multicentre study. Lancet 1999;354:708 –15. 22. Cannon CP, for the TACTICS-TIMI 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 – 87.
EDITORIAL COMMENT
Should We Catheterize All Patients With Unstable Angina? No—Only the Ones With Coronary Artery Disease* William G. Kussmaul III, MD, FACC Philadelphia, Pennsylvania In this issue of the Journal, Solomon et al. (1) have afforded us another look at the venerable Thrombolysis In Myocardial Infarction trial (TIMI)-IIIB dataset. The results cast useful light on an ongoing debate concerning how best to treat patients who present with unstable angina or non–Qwave myocardial infarction (MI)— conditions now recognized to represent a spectrum, and combined under the rubric “acute coronary syndromes” (ACS). The Solomon et al. (1) study is an analysis of patient subsets from TIMI-IIIB, originally published in 1994 (2). See page 969 The TIMI-IIIB trial recruited patients from 1989 to 1992, before the era of stents or platelet IIB/IIIA receptor blockers. Patients were required to have experienced chest pain at rest within 24 h prior to enrollment. That the chest pain represented myocardial ischemia was attested by ischemic electrocardiographic (ECG) changes, history of prior infarction, previously documented coronary stenosis or an abnormal stress thallium scan result. Eligible, consenting patients were randomized to intravenous tissue-type plasminogen activator or placebo, and also to a conservative versus an early invasive management strategy. Some 98% of patients assigned to the invasive arm underwent coronary angiography, and 63% underwent subsequent coronary revascularization (25% coronary artery bypass graft surgery; 38% percutaneous transluminal coronary intervention [PTCI]). Of the conservative group, 64% underwent catheterization for clinical indications; 50% also had coronary revascularization. The combined end points included death, MI, or a stress test showing ischemia at six weeks’ followup. The overall trial results were negative both for fibrinolytic therapy and for the early invasive strategy, although the patients in the latter group did experience shorter hospital stay, fewer episodes of rehospitalization and required less antianginal drug therapy. These results were interpreted to indicate that routine *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Cardiology Consultants of Philadelphia, Hahnemann University Hospital, Philadelphia, Pennsylvania.
Vol. 38, No. 4, 2001 ISSN 0735-1097/01/$20.00 PII S0735-1097(01)01498-X
catheterization was not indicated in patients presenting with ACS. However, although TIMI-IIIB was a model clinical trial in many ways, a plausible criticism is that the somewhat loose definition of “myocardial ischemia” may have allowed for the inclusion of patients at very low risk, and even some who did not have coronary artery disease (e.g., a patient with rest pain and an abnormal thallium result, who was subsequently shown to have normal coronary arteries). In such patients, the procedural risk of catheterization might outweigh the potential for benefit. The current report (1) reanalyzes TIMI-IIIB from this viewpoint, taking into account certain clinical factors that are readily available upon presentation to the hospital. Multivariate analysis yields four independent prognostic factors: older age, ST-segment depression at presentation, “complicated angina” and elevated baseline creatine kinase-MB fraction. A schema is derived that separates the patients into five tiers of risk, of which the top two appear to have significantly benefited from routine catheterization and intervention, whereas the lower three were not helped (or possibly may have been harmed) by catheterization and intervention as practiced in the late 1980s. Another way to state their findings would be: Among patients presenting with chest pain, those who have unstable coronary artery disease are most likely to benefit from invasive management. The concept of multivariate risk stratification is hardly new (3–11). Examination of the results of these earlier studies shows that ischemic ECG changes at presentation, advanced age and elevated cardiac enzyme markers have been repeatedly identified as significant negative prognostic factors in patients with ACS. The Solomon et al. study (1) goes further, offering treatment and outcome data showing the utility of risk stratification. Why were C-reactive protein levels not predictive of short-term prognosis? Other studies have shown the contrary (12,13). Surprisingly also, smoking status and diabetes did not enter into this multivariate predictive model. What makes multivariate risk stratification more than a dry intellectual exercise? The answer depends entirely on whether we have any effective means of altering the shortterm prognosis of ACS patients for the better. Clearly, we do. The effectiveness of antithrombotic agents has been repeatedly shown, including aspirin, heparin, lowmolecular-weight heparins, platelet IIB/IIIA receptor antagonists and, most recently, thienopyridines, although the optimum combination of these agents has not yet been determined. Fibrinolytic agents do not confer benefit in non–ST-elevation ACS. Invasive management would certainly make sense. After all, the reason an ACS is an acute syndrome is that a pre-existent atherosclerotic plaque has become associated with fresh thrombus. Removing this complex blockage and restoring nutritive blood flow is logical, and arguing against it would appear counterintuitive. The feasibility of acute
978
Kussmaul Editorial Comment
angioplasty for ACS was shown more than 15 years ago (14 –18). The question is: To which patients is an aggressive approach best applied? The American College of Cardiology/ American Heart Association guidelines for management of ACS (19) suggest very wide latitude in determining who is an appropriate candidate for an early invasive strategy. A debate continues on this point in the literature. Recent studies (VANQWISH [20], FRISC-II [21] and now TACTICS/ TIMI-18 [22]) sound apparently contradictory notes. The overall results of Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital (VANQWISH) suggested that an early invasive approach would be harmful. Both Fragmin and Fast Revascularization during Instability in Coronary Artery Disease (FRISC-II) and TACTICS/TIMI-18 came to opposite conclusions. It makes sense that the differences among these trials may be explained by the inclusion of higher-risk patients in the latter two trials, a concept that is supported by the present reanalysis of TIMI-IIIB. If the higher-risk ACS patients are good candidates for invasive management, what about the others? The possible harm resulting from an invasive strategy in low-risk TIMIIIIB patients may be explained in part by the simultaneous administration of fibrinolytic therapy to some of these patients. Coronary intervention after full-dose lytic therapy is now recognized as a “salvage” procedure in acute MI, a situation associated with higher procedural risk than PTCI without prior fibrinolysis. Yet perhaps not coincidentally, the lowest-risk patients in VANQWISH, FRISC-II and TACTICS may also have done worse with an early invasive strategy. Many of these patients were troponin-negative. An open-season catheterization approach to patients with ACS who lack high-risk features is probably inappropriate. The limitations of the Solomon et al. study (1) are several, and they are well outlined in the report. The post hoc nature of the analysis and the decade-old vintage of the data urge caution in the interpretation of the results; yet their concordance with the outcome of recent randomized prospective trials is striking. What seems clear, based on the present study as well as the results of FRISC-II and TACTICS, is that a nihilistic approach with regard to early invasive study in patients with ACS is not warranted. The evidence presented in the current study supports the concept that higher-risk patients, at least those with clear-cut ECG changes of ischemia or elevated cardiac enzyme markers, should undergo early angiography and revascularization. Thus, the subtitle of this editorial is only slightly tongue-in-cheek. Reprint requests and correspondence: Dr. William G. Kussmaul III, Mail Stop 108, Broad and Vine Streets, Philadelphia, Pennsylvania 19102. E-mail: [email protected].
REFERENCES 1. Solomon DH, Stone PH, Glynn RJ, et al. Use of risk stratification to identify patients with unstable angina likeliest to benefit from an invasive versus conservative management strategy. J Am Coll Cardiol 2001;38:969 –76.
JACC Vol. 38, No. 4, 2001 October 2001:977–8 2. The TIMI-IIIB 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;89:1545–56. 3. Ouyang P, Brinker JA, Mellits ED, Weisfeldt ML, Gerstenblith G. Variables predictive of successful medical therapy in patients with unstable angina: selection by multivariate analysis from clinical, electrocardiographic, and angiographic evaluations. Circulation 1984;70:367–76. 4. Calvin JE, Klein LW, VandenBerg BJ, et al. Risk stratification in unstable angina: prospective validation of the Braunwald classification. JAMA 1995;273:136 – 41. 5. Cannon CP, McCabe CH, Stone PH, et al. The electrocardiogram predicts one-year outcome of patients with unstable angina and non–Q-wave myocardial infarction: results of the TIMI-III registry ECG ancillary study. J Am Coll Cardiol 1997;30:133– 40. 6. Holmvang L, Lu¨chser MS, Clemmensen P, Thygesen K, Grande P. TRIM Study Group. Very early risk stratification using combined ECG and biochemical assessment in patients with unstable coronary artery disease. Circulation 1998;98:2004 –9. 7. Jacobs DR, Kroenke C, Crow R, et al. PREDICT: a simple risk score for clinical severity and long-term prognosis after hospitalization for acute myocardial infarction or unstable angina. Circulation 1999;100: 599 – 607. 8. Calvin JE, Klein LW, VandenBerg EJ, Meyer P, Parrillo JE. Validated risk stratification model accurately predicts low risk in patients with unstable angina. J Am Coll Cardiol 2000;36:1803– 8. 9. Antman EM, Cohen M, Bernink PJLM, et al. The TIMI risk score for unstable angina/non-ST elevation myocardial infarction. JAMA 2000;284:835– 42. 10. Cohen M, Stinnett S, Weatherly BD, et al. Predictors of recurrent ischemic events and death in unstable coronary artery disease after treatment with combination antithrombotic therapy. Am Heart J 2000;139:962–70. 11. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent STsegment elevation. Circulation 2000;101:2557– 67. 12. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid-A protein in severe unstable angina. N Engl J Med 1994;331:417–24. 13. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. The FRISC Study Group. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. N Engl J Med 2000;343:1139 – 47. 14. Hartzler GO, Rutherford BD, McConahay DR, et al. Percutaneous transluminal coronary angioplasty with and without thrombolytic therapy for treatment of acute myocardial infarction. Am Heart J 1983;106:965–73. 15. Meyer J, Schmitz HJ, Kiesslich T, et al. Percutaneous transluminal coronary angioplasty in patients with stable and unstable angina pectoris: analysis of early and late results. Am Heart J 1983;106:973– 80. 16. Faxon DP, Detre KM, McCabe CH, et al. Role of percutaneous transluminal coronary angioplasty in the treatment of unstable angina. Am J Cardiol 1983;53:131C–5C. 17. Hartzler GO, Rutherford BD, McConahay DR. Percutaneous transluminal coronary angioplasty: application for acute myocardial infarction. Am J Cardiol 1984;53:117C–21C. 18. de Feyter PJ, Serruys PW, van den Brand M, et al. Emergency coronary angioplasty in refractory unstable angina. N Engl J Med 1985;313:342– 6. 19. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non–STsegment elevation myocardial infarction. Circulation 2000;102:1193– 209. 20. Boden WE, O’Rourke RA, Crawford MH, et al. 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;338:1785–92. 21. The FRISC Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC-II prospective randomised multicentre study. Lancet 1999;354:708 –15. 22. Cannon CP, for the TACTICS-TIMI 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 – 87.