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J Am Coll Cardiol, 2001; 38:977-978 © 2001 by the American College of Cardiology Foundation |
a Cardiology Consultants of Philadelphia, Hahnemann University Hospital, Philadelphia, Pennsylvania. USA
Reprint requests and correspondence: Dr. William G. Kussmaul III, Mail Stop 108, Broad and Vine Streets, Philadelphia, Pennsylvania 19102
Wkussmaul{at}aol.com
The Solomon et al. (1) study is an analysis of patient subsets from TIMI-IIIB, originally published in 1994 (2).
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’ follow-up. 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 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 short-term prognosis of ACS patients for the better. Clearly, we do. The effectiveness of antithrombotic agents has been repeatedly shown, including aspirin, heparin, low-molecular-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 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 TIMI-IIIB 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.
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