EDITORIAL COMMENT
Expanding the reach of primary percutaneous coronary intervention for the treatment of acute myocardial infarction*
Christopher P. Cannon, MD, FACC , and
Donald S. Baim, MD, FACC,,*
Cardiovascular Division, Brigham and Women’s Hospital, Boston MA, USA, and the
Center for Integrating Medicine and Innovative Technology, Boston, Massachusetts, USA
* Reprint requests and correspondence: Dr. Donald S. Baim, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
dbaim{at}partners.org
One of the biggest debates in modern cardiology regards the relative merit of primary angioplasty versus pharmacologic thrombolysis for the treatment of acute myocardial infarction (MI). Following a number of encouraging pilot studies, the Primary Angioplasty in Myocardial Infarction (PAMI-1) study in 1993 showed a clear benefit of primary angioplasty over tissue plasminogen activator in reducing death or MI (1). Simultaneously, the Zwolle and Mayo Clinic groups published similar trials demonstrating a benefit of primary angioplasty (2,3). A meta-analysis of the 10 such randomized trials through 1997 demonstrated a clear and dramatic reduction in all cardiovascular end points including death, MI, stroke and intracranial hemorrhage (4). The relative reduction in mortality alone was 34% (from 6.5% for thrombolysis to 4.4% for primary angioplasty), indicating the potential of saving 2 lives for every 100 patients treated with primary angioplasty instead of thrombolysis. There was an even more dramatic in intracranial hemorrhage, which was reduced from 1.1% for patients treated with thrombolytic therapy to 0.1% for patients treated with primary angioplasty. Based on these data, primary angioplasty emerged as a superior therapy, at least in the hospitals participating in these trials.
The next question was whether such excellent results could be duplicated under "real world" conditions, given concerns regarding more delayed time to treatment and lack of operator experience in the "real world" as compared with the selected hospitals that participated in the pivotal randomized trials. Although initial comparisons in registry data failed to show a benefit in patients treated with primary angioplasty versus thrombolysis (5,6), the most recent comparisons within the large National Registry of Myocardial Infarction (NRMI) show a clear benefit of primary percutaneous coronary intervention (PCI) (7). When results were stratified based on the number of primary PCI procedures performed per year at each participating hospital, patients treated at the highest volume hospitals had the same degree of mortality benefit (3.4% vs. 5.4%, p < 0.001) seen in the randomized trials. Even at intermediate volume hospitals—two middle quartiles of volume defined as 17 to 48 primary PCI procedures per year—showed a significant benefit of primary angioplasty (4.5% mortality vs. 5.9% for thrombolysis, p < 0.001). While the lowest volume centers (performing 16 or fewer primary PCI procedures per year) showed no mortality benefit, the total stroke rate was significantly lower (0.4% vs. 1.1% for thrombolytic therapy). Preliminary data now suggest that this benefit may also extend to community hospitals that have initiated primary PCI programs despite not offering elective PCI. The Cardiovascular Patient Outcome Research Team (C-PORT) study evaluated 433 patients presenting to such community hospitals who were randomized to on-site primary angioplasty versus thrombolysis, demonstrating a lower rate of the primary end point of death, MI or stroke for primary angioplasty at both six weeks and six months (8). Thus, at hospitals that offer both primary PCI and thrombolysis, primary PCI can be accomplished with superior results to thrombolysis, and is generally the treatment of choice for patients presenting there with ST-segment elevation MI.
Although this addresses the issue of real world expertise, the issue of prolonged time to reperfusion remains. In an analysis of over 27,000 patients in NRMI Registry, an increased door-to-balloon time was found to be significantly associated with increased mortality (9). In this study, mortality was between 40% and 60% higher for patients with door-to-balloon times (between hospital arrival and the first inflation of the angioplasty balloon) >2 h, even after adjustment for differences in baseline characteristics. Thus, a major emphasis has been placed on trying to increase triage and execution efficiency and thereby reduce overall door-to-balloon times at all hospitals performing primary PCI. It also raises the real question of how to treat the patient with an acute MI who presents to a hospital without on-site primary PCI capabilities, since transfer to another facility offering primary PCI would clearly introduce additional delay.
To address this matter, in this issue of the Journal, the PAMI investigator group reports results of the Air-PAMI study (10). In this trial, high risk patients with ST-segment elevation MI (anterior MI, age >70 years, heart rate >100 beats/min or blood pressure <100 mm Hg or Killip Class 2 to 3), were randomized to either on-site thrombolytic therapy (80% tissue plasminogen activator or recombinant plasminogen activator) or transfer to another facility for primary PCI. Although the study design was an excellent one to resolve this contentious issue, slow patient accrual over more than 3 years at 12 sites led to premature termination of enrollment after entry of only 138 patients— 32% of the targeted sample size. Despite this limitation, the AIR-PAMI study has several important findings. As expected, the time to treatment was quite long for patients transferred for primary angioplasty. Using a blend of ground (79%) and helicopter (21%), transport times over the 32 ± 36 mile interhospital distance took only 26 min, but delays in initiating the transfer added 43 min to the process, and contributed importantly to the mean door-to-balloon time of 155 min. No patients died or required cardiopulmonary resuscitation during transfer, but estimated time to reperfusion was nearly an hour longer than that for thrombolytic therapy (using a door-to-drug time of 51 min, and an estimated time of 45 min from thrombolytic administration to reperfusion). Despite this estimated delay to reperfusion, the composite end point—death, MI or disabling stroke—was reduced by 38% (from 13.6% for on-site thrombolysis to 8.4% for primary PCI). Although this difference did not reach statistical significance in the unadjusted analysis given the smaller-than-planned sample size, there was clear benefit when baseline differences were adjusted using a prespecified multivariate analysis which showed that the strategy of transfer for primary angioplasty was associated with reduction in the primary end point (odds ratio, 0.16; p = 0.03). Although it is not conclusive, this study provides support for the overall strategy of transfer for primary angioplasty in lieu of on-site thrombolysis.
We now have data from two related European studies. The PRAGUE (PRimary Angioplasty in patients transferred from a General community hospital to specialized PTCA Units, with or without Emergency thrombolysis) compared three strategies: 1) on-site thrombolysis (as studied in Air-PAMI); 2) immediate transfer for primary angioplasty; and 3) initial thrombolytic therapy followed by transfer for emergency angioplasty (11). The lowest rate of death, MI or stroke at 30 days was seen in the group transferred for primary angioplasty (8%), compared to 23% for on-site thrombolysis alone and 15% for patients treated with both thrombolysis and primary angioplasty. The dominant contributor to this benefit was a reduction in reinfarction in patients treated with primary angioplasty only (1%), compared to 10% in patients treated by thrombolysis only, and 7% for patients treated with both thrombolysis and primary angioplasty. A much larger study, DANAMI-2, compared transfer for primary PCI versus thrombolysis. This trial was stopped early by the Data and Safety Monitoring Committee, and results presented at the March 2002 meeting of the American College of Cardiology show a significantly reduced incidence of death, recurrent infarction or stroke at 30 days (8.5 vs. 14.26, p = 0.002) for patients transferred from a community to a tertiary hospital for primary PCI rather than receiving on-site thrombolytic therapy (12).
Even as these important studies were underway, however, important shifts have been taking place in PCI technique adjunctive pharmacology. Stenting (rather than balloon angioplasty) has become the dominant form of primary PCI, although it was used in only 34% of the Air-PAMI patients. In addition, many studies have suggested that platelet glycoprotein IIb/IIIa receptor blockade is beneficial during primary PCI. Indeed, one randomized trial of coronary stenting with IIb/IIIa inhibition compared with front-loaded tissue plasminogen activator showed a 66% reduction in death, MI or stroke with the primary PCI strategy (13), although the larger CADILLAC trial showed minimal incremental benefit from routine IIb/IIIa blocker administration at the time of primary stenting (14). Large-scale trials of routine earlier initiation of IIb/IIIa receptor blockade before primary PCI are underway.
Thus, the results of the Air-PAMI study are seen best in the context of the ongoing evolution that is taking place in primary PCI and its associated adjunctive therapies. In particular, it appears that there may be benefit in prompt and efficient transfer of patients from a community hospital that does not offer primary PCI to a nearby one that does. Conversely, an alternative model might be to regionalize acute MI care services (akin to what has been done for major trauma services). According to this model, patients found to have ST-segment elevation on field 12-lead electocardiography would not necessarily be brought to the nearest hospital. Instead had the community set up a network of "cardiac centers" offering 24 h/7 days primary PCI, such patients would have had suitable medical pretreatment (for example, administration of aspirin, clopidogrel and IIb/IIIa inhibition) initiated in the ambulance and be transferred directly to the cardiac catheterization laboratory at such a center, thereby avoiding a second ambulance trip and minimizing time-to-reperfusion. Pilot studies of this strategy, are just beginning in Florida and in Boston, but further study will be needed before its role in the continued refinement of reperfusion strategy for patients with acute MI is established.
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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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