EDITORIAL COMMENT
The early days after ST-segment elevation acute myocardial infarction
Reconsidering the delayed invasive approach*
Harold L. Dauerman, MD, FACC
,*
University of Vermont College of Medicine, Burlington, Vermont, USA
* Reprint requests and correspondence: Dr. Harold L. Dauerman, Cardiac Unit, McClure 1, Fletcher Allen Health Care, 111 Colchester Avenue, Burlington, Vermont 05401, USA.
harold.dauerman{at}vtmednet.org
Physicians who care for patients with ST-segment elevation acute myocardial infarction (STEMI) at noninvasive hospitals will debate the utility of primary percutaneous coronary intervention (PCI). The primary PCI approach is generally not feasible in the recommended emergency window of time (90 ± 30 min) (1). Thus, it is not surprising that three-quarters of recent STEMI patients receiving reperfusion therapy were treated preferentially with thrombolytic therapy (2). Given the predominance of STEMI patients still being treated with thrombolysis, there remains an unsettled question for the cardiology community: do stable post-thrombolytic STEMI patients need to be referred for routine coronary angiography?
It is possible that this entire question could become irrelevant if there were widespread adoption of a time-independent transfer strategy for primary PCI (3,4). The PRAGUE-2 trial is provocative in this regard. As with almost all randomized trials of primary PCI versus thrombolysis, this trial’s door to balloon time (26 min) and total transport-related reperfusion time (97 min) are vastly different from the current practice outside of randomized trials (5). It is also possible that a facilitated approach (routine PCI after thrombolysis in an expanded window of time) (6) may more practically achieve a realistic early invasive strategy for STEMI patients. Facilitated PCI trials, though, may be years away from completion. Thus, many clinicians will continue to face an ongoing fibrinolytic standard of care for the acute STEMI presentation and an unresolved question about the subsequent need for a routine, delayed invasive approach.
For many cardiologists at U.S. medical centers, the current de facto practice does involve a routine invasive approach to STEMI patients. During the period 1994 to 1998, 78% of STEMI patients who had received fibrinolytic therapy underwent coronary angiography during their index U.S. hospitalization (7). This aggressive STEMI approach was at that time rather unique to U.S. clinical practice. For example, Canadian STEMI patients in the Global Use of Streptokinase and tissue plasminogen activator for Occluded Coronary Arteries (GUSTO-I) fibrinolysis trial had a markedly lower rate (27%) of index hospitalization cardiac catheterization (8). More recent analyses suggest that the invasive approach to STEMI have been more widely adopted. In the Global Registry of Acute Coronary Events (GRACE Registry: 1999 to 2001), a majority of international STEMI patients (55%) underwent coronary angiography during their index hospitalization (2), and approximately half of the PCI was performed in STEMI patients during the delayed invasive period (not as a rescue or primary PCI within the first 12 h after STEMI presentation). Are there data to support the increasing use of a delayed invasive approach for post-thrombolytic STEMI patients?
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Randomized trials and the delayed invasive approach to the STEMI patient
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The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of acute myocardial infarction (AMI) are quite clear: "Routine use of coronary angiography and subsequent PTCA [percutaneous transluminal coronary angioplasty] of the infarct related artery within days after receiving thrombolytic therapy" is a class III (contraindicated) recommendation (1). This statement derives from the historic Thrombolysis In Myocardial Infarction (TIMI) IIB and Should We Intervene Following Thrombolysis? (SWIFT) randomized clinical trials (9,10). In these angioplasty-era trials, there was no benefit for a routine, delayed invasive approach for the stable post-thrombolytic patient. Despite the theoretical benefit that might occur with mechanical improvement of residual stenoses, there was no benefit in post-STEMI patients with respect to reinfarction, left ventricular dysfunction, anginal class, or one-year survival. Notably, there were significantly increased rates of transfusion and emergency coronary bypass surgery for patients undergoing routine non-emergent invasive strategies after thrombolytic therapy.
On the other hand, angioplasty-era randomized trial data support the use of angiography among patients who have spontaneous or inducible post-STEMI ischemia. The Danish Acute Myocardial Infarction (DANAMI) trial assigned post-thrombolytic patients with ischemia to conservative care versus angiography. This randomized trial demonstrated a marked reduction in two-year events for the delayed invasive approach in unstable post-STEMI patients (11). Thus, the ACC/AHA guidelines recommend a delayed invasive approach only if there is evidence of ischemia after successful thrombolytic therapy (1).
Although it is possible that nearly 80% of U.S. STEMI patients are being referred for early angiography on the basis of class I indications, this overwhelming majority far exceeds the incidence of recurrent ischemia/infarction in thrombolytic therapy trials (1,9,10). The increasing use of a routine post-STEMI revascularization approach may relate to the improved safety of the delayed invasive approach in the stent era. This improved safety profile is supported by the low rates of transfusion and emergency bypass surgery among patients undergoing PCI after thrombolysis in the Plasminogen-activator Angioplasty Compatibility Trial (PACT), Strategies for Patency Enhancement in the Emergency Department (SPEED), and the TIMI 10B/14B thrombolytic trials (6,12,13). There are a number of possible explanations for the improved safety and efficacy of stent-era, post-thrombolytic PCI. These include decreased abrupt closure due to stenting (less residual thrombus, stenosis, and dissections) (14), improved antiplatelet therapy (15), and decreased post-PCI bleeding complications (16). Safety issues are not fully guiding referral for a routine delayed invasive approach, though; both clinical (age, gender) and non-clinical (payor status, race) factors are playing major roles in the decision to proceed with a delayed invasive approach after AMI hospitalization (17,18).
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Registry studies and the delayed invasive approach to the STEMI patient
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There is a lack of current randomized clinical trials defining invasive care for the stable post-thrombolytic patient. It is in this setting that one may look to large registry studies to help guide current clinical practice. In this issue of the Journal, Alter et al. (19) present a well-designed, population-based registry study of Canadian AMI patients (n = 15,116) in which patients admitted to hospitals with invasive capabilities had a shorter median time to revascularization (12 days) than patients admitted to noninvasive hospitals (48 days). Among those patients undergoing revascularization during their index hospitalization, there was a 66% reduction in events compared with patients undergoing very delayed post-AMI revascularization. Although the study conclusions may be limited by the inclusion of non–ST-segment elevation myocardial infarction (NSTEMI) patients, the authors have wisely excluded all patients undergoing revascularization within 24 h of their AMI admission, which makes this study more relevant to the delayed invasive approach. As with all registry studies, conclusions regarding the efficacy of a strategy must be evaluated in the context of the registry design.
The first caveat is the inherent limitation of a population-based registry design, which is defined by the inclusion of all patients in a selected region (Ontario, Canada) with a given diagnosis (AMI). This design avoids common confounders of invasive therapies (high volume operators, only academic centers) found with highly selected patients in randomized clinical trials of STEMI (20,21). The weakness of the population-based design is that, like politics, AMI care may be local. Namely, the pattern of care in one very well-studied region may not directly translate to other regions. In this study, the median time to "early" revascularization among invasive hospitals was 12 days, which is beyond even the window of "delayed" revascularization for STEMI patients in many regions and trials (2,7,9). This is due to a routine separation of the diagnostic and PCI procedures at the Canadian centers, with frequent performance of angiography after hospital discharge. The U.S. practice for post-AMI patients emphasizes routine use of ad hoc PCI at the time of initial angiography, and an inpatient transfer strategy for patients referred for cardiac catheterization (22).
A second caveat is that patients receiving invasive versus non-invasive approaches to post-AMI care may be different. In the Worcester Heart Attack Study, patients undergoing an invasive approach after non–Q-wave AMI were younger and much more likely to receive other beneficial therapies than patients managed conservatively (18). It is reassuring that the better outcomes achieved at the invasive hospitals in the Canadian study occur in the setting of having more adverse clinical variables and only minimal medication differences present as compared with those patients hospitalized at noninvasive centers. Thus, clinical or pharmacologic confounding is unlikely to explain the benefit of the earlier post-AMI revascularization strategy in this study.
The third caveat is the impossibility of answering any questions concerning the utility of routine post-AMI revascularization from this study. All patients in this study underwent revascularization after AMI, so there is no true conservative comparison group. This study thus addresses the question about when to perform post-STEMI revascularization. Other registry studies have instead focused on the utility of an invasive approach. Patients undergoing "early" AMI revascularization in a site-based Swedish registry study had a 53% adjusted relative reduction in one-year mortality compared with conservatively managed patients (23). Not surprisingly, the patients undergoing "early" revascularization (within 14 days of AMI) in the Swedish study were clinically and pharmacologically different from conservatively managed patients. Nevertheless, after adjusting for these differences, the invasively managed STEMI patients still had a 36% relative reduction in one-year mortality (p = 0.01). Thus, the Swedish study is consistent with the findings of Alter et al. (19): an earlier post-AMI revascularization strategy appears to have significant clinical benefits.
Are there registry studies that contradict the notion that earlier and more frequent post-AMI revascularization are beneficial? A recent GUSTO-I analysis compared outcomes of STEMI patients hospitalized initially at invasive or non-invasive hospitals (24). The GUSTO-I analysis appears to contradict the findings of the Canadian registry study. One-year outcomes appear to be similar regardless of the initial site of hospitalization for the STEMI patients in this fibrinolysis trial. This difference may be due to the inclusion of only trial-eligible patients or the aggressive use of early transfer to invasive sites for unstable patients (20,21,24). In addition, the GUSTO-I analysis may provide an indirect correlation of the angioplasty-era trial findings of SWIFT and TIMI IIB (9,10). The GUSTO-I trial was performed between 1990 and 1993, and the advantage of the increased use of a delayed invasive approach at invasive hospitals may be very difficult to show in that earlier time period.
While the GUSTO-I trial data are relevant primarily to the angioplasty era, one can acknowledge that even the Swedish and Canadian registry studies may be outdated given the fast pace of improvements in PCI techniques. Thus, the advent of routine AMI stenting and antiplatelet therapy may diminish the applicability of these registry analyses to current outcomes (25). This concern is addressed by a GRACE registry analysis performed during the 1999 to 2001 period comparing 451 patients with thrombolytic treated STEMI undergoing late angiography (>12 h after STEMI onset) with 1,056 patients treated conservatively. There was a marked adjusted reduction in hospital mortality among the delayed invasive group compared with the thrombolytic therapy alone group (relative risk 0.30, 95% confidence interval 0.13 to 0.63) (26). This analysis includes both stable and unstable post-thrombolytic patients in the early days after STEMI, which limits any absolute conclusions regarding a routine, delayed invasive approach. The GRACE findings, though, are in general agreement with the stent-era Canadian and Swedish multicenter registry studies: STEMI patients who undergo cardiac catheterization in the early days after hospitalization appear to fare better than their conservatively treated counterparts.
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What do we do now for the stable post-thrombolytic STEMI patient?
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Taken in total, do we have an answer from the sum of these registry studies and randomized trials to the basic question: "Should all STEMI patients undergo angiography during their index hospitalization?" It is clear from both retrospective analyses (GUSTO-I trial) and randomized clinical trials (SWIFT and TIMI 2B) that the answer was clearly "no" in the balloon angioplasty era (1,9,10,24). It is equally clear from registry studies and clinical trials (PACT, SPEED, TIMI 10B/14B) that earlier timing of PCI in the current stent era does not have the same increased hazard seen in the balloon angioplasty era (6,12–14). Thus, we have a partial answer: the complete prohibition on routine, index hospitalization PCI for stable patients after thrombolytic therapy is no longer supported.
Even if we could remove the cognitive barriers to mandating transfer for index hospitalization PCI, there are non-clinical barriers of great significance. For example, only 53% of NSTEMI patients are currently receiving an early invasive approach, despite clear guidelines based upon recent clinical trials (2,27–29). Whether or not these non-clinical barriers will require reorganization of our health care systems to employ a "trauma center" concept for all STEMI patients is unclear (3,4). It may be equally important to understand geographic, payor status, gender-related, and age-related barriers that appear to play a considerable role in the current practice of transfer for a delayed invasive approach after AMI (17,18).
It is easy to conclude that we need a new randomized trial of the delayed invasive approach in the stent era to provide clarification. This conclusion does not help in the immediate period before further trial data are available. One can instead conclude that there are basic observations already available to guide clinical judgment: 1) Nearly 80% of U.S. patients with STEMI do get angiography during their index hospitalization (7). 2) Outcomes among STEMI patients in the U.S. have markedly improved during a period of increasing use of AMI revascularization (30). 3) The use of revascularization in the first 14 days after AMI has been shown in the stent era to be associated with improved outcomes, as compared with later or no-revascularization options (19,23,26). 4) The use of PCI during the early period after thrombolysis no longer confers the hazard it did in the angioplasty era (12–14). A physician who chooses to transfer only unstable or ischemic post-STEMI patients is still operating in a manner that is trial based and guideline driven (1,9–11). Based upon these stent-era registry findings, it is also reasonable to accept the change already occurring in many clinical practices—namely, a routine hospital revascularization strategy for stable patients after STEMI.
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Footnotes
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* 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. 
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References
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Randomized trials and the...
Registry studies and the...