Primary Angioplasty vs. Lytic Therapy for Acute Infarction: Is the Balloon Half Full or Half Empty?
ABSTRACT & COMMENTARY
An important substudy of the International Gusto IIb trial of hirudin vs. heparin in acute myocardial infarction (AMI) sought to assess whether primary angioplasty or front-loaded t-PA was more effective in reducing major clinical end points. Accordingly, 1138 patients with AMI, derived from hospitals experienced in interventional procedures, were randomized to front-loaded t-PA or primary angioplasty. High-volume angioplasty at each institution was required for participation. The primary hypothesis was that immediate angioplasty would result in at least a 40% reduction in the major clinical end points of death, reinfarction, or stroke. In addition to the comparison of angioplasty to lytic treatment, a comparison of intravenous heparin vs. hirudin for 3-5 days in the angioplasty group was assessed in a 2 ´ 2 factorial design, with approximately 250 patients in each cohort. The predominantly male study population was enrolled in 1994-1995, with a median age of 62-64 years; almost two-thirds were current smokers, and 40% had hypertension. Nevertheless, 90% of the patients were in Killip class 1, and less than 15% had had a previous MI. Median time to treatment was three hours for the t-PA patients and 3.8 hours for the angioplasty group; median time from presentation to hospital to angioplasty was 1.9 hours. A core angiography lab was used. Follow-up was obtained at 30 days and six months. Angiography in the t-PA patients was discouraged; nevertheless, more than 60% had an angiogram in hospital. The pri-mary end point was a composite clinical outcome of death, non-fatal einfarction, and non-fatal disabling stroke within 30 days. A variety of secondary endpoints was analyzed.
Assignment to angioplasty resulted in a non-significant reduction in death and a 33% decrease in the composite end point (P = 0.03) at 30 days. However, by six months after randomization, the primary outcome was no longer statistically different between the t-PA group (15.7%) and angioplasty (13.3%). Most of the benefits occurred between days five and 10 after AMI. Angioplasty was associated with more bleeding events except for intracranial hemmorhage. In patients assigned to angioplasty, 83% of the infarct arteries were occluded, with TIMI 3 flow obtained in 73-88% (core lab results were consistently not as good as those reported from the clinical sites). Eighteen percent of patients assigned to angioplasty did not undergo PTCA for a variety of reasons. The 30-day mortality rate in the angioplasty group was 5.7% vs. 7.0% in the t- PA cohort (NS); however, mortality in those assigned to angioplasty who did not undergo the procedure was 14% at one month. There was a strong correlation between TIMI flow and 30-day mortality in angioplasty patients; TIMI grade 3 flow was associated with a 1.6% 30-day mortality. There was no significant difference in end points between heparin- and/or hirudin-treated patients, and bleeding complications were comparable. The heparin-hirudin outcomes are not discussed further in this report. Disabling strokes were 1% in both groups; reinfarction at 30 days was not significantly different between t-PA and angioplasty (6.5% vs 4.4%). The authors conclude that angioplasty provides a small-to-moderate, short-term advantage over thrombolytic therapy of AMI, and angioplasty is an excellent alternative therapy when it can be applied promptly by experienced personnel. (GUSTO IIb Investigators. N Engl J Med 1997;336:1621-1628.)
COMMENT BY JONATHAN ABRAMS, MD
While the GUSTO IIb investigators believed that this comparative trial would demonstrate a robust reduction in important clinical end points for the angioplasty group, this was not quite the case, although the overall results at 30 days favor direct angioplasty. A variety of smaller previous comparative trials have suggested a major advantage to direct angioplasty vs. lytic therapy, although two large registry reports were not consistent with a significant difference between these two modalities. The GUSTO IIb substudy results are intermediate, with a moderate positive effect at one month, which became attenuated by six months. The combination of death, non-fatal reinfarction, and non-fatal disabling stroke was reduced by one-third at 30 days in the angioplasty cohort. Caveats include: 1) 18% of subjects randomized to angioplasty did not receive this procedure; 2) there were no statistical differences for a variety of prespecified secondary end points, such as infarct location, prespecified high vs. low risk, hospital angioplasty caseload, time from symptom onset to arrival, or age; and 3) the core laboratory angiographic analysis demonstrated somewhat less optimal results for every angiographic parameter than the assessment provided by the participating institutions.
This raises the possibility that other published angiographic results may tend to overestimate the benefits of direct angioplasty. The authors discuss the unexpected finding that most of the clinical benefits in the angioplasty cohort occurred not in the first 24-48 hours but between days 5 and 10. This implies that immediate infarct artery opening and restoration of TIMI 3 flow may not be the primary mechinism of benefit. I would suggest that achievement of TIMI 3 flow may have increased shear stress in the dilated arteries, resulting in enhanced endothelial vasomotor function, with less propensity for coronary vasoconstriction and spasm. Increased blood flow in the artery may also have resulted in improved anti platelet-thrombotic activity and less adhesion molecule expression in the t-PA group (i.e., a generally "healthier vessel" in the early days following angioplasty). This is speculative, of course.
The authors do not discuss the six-month results in detail, other than by stating that "the attenuation of the benefit of angioplasty . . . is notable," suggesting (but not demonstrating) that this may have been due to a greater rate of coronary reocclusion in the PTCA patients. The t-PA group composite event outcome increased from 13.7% at 30 days to 15.7% at six months, whereas the angioplasty patients had a 9.6% event rate at 30 days but had a 13.3% rate at six months, demonstrating an almost 5% event rate over the next five months. Of interest, but not discussed, almost 35% of the t-PA cohort ended up with an angioplasty during the hospital admission.
For those physicians still undecided about this major controversy, the GUSTO IIb data provide support for whatever one’s bias might be. Although the composite end point was substantially improved in the angioplasty cohort at one month, the benefits were essentially lost by six months. Furthermore, high-risk patients, anterior infarction, or high volume centers did not demonstrate an improved outcome with angioplasty, in contradistinction to results of a number of earlier and smaller studies. It would appear that either strategy is effective and appropriate, and both represent major advances in the treatment of AMI. Failure to provide revascularization by either lytic drugs or angioplasty is associated with a higher mortality rate. Angioplasty is an appropriate approach when experienced interventional cardiologists are available in institutions that perform angiography and interventional procedures with a reasonable volume. On the other hand, front-loaded t-PA is also effective, and one cannot argue that patients are being deprived of a more effective therapy when a lytic drug is given instead of angioplasty. As the authors point out, one must be cautious in interpreting results from small studies or subgroup analysis. In conclusion, either revascularization strategy is appropriate, depending on the institution and the experience of the cardiologist treating the patient with acute infarction. Angioplasty does appear to have a modest advantage over t-PA if only because there is considerable crossover to an eventual angioplasty; furthermore, the benefits of TIMI 3 flow seem incontrovertable. Nevertheless, GUSTO IIb does not provide sufficient ammunition to change our current aggressive approach to early AMI therapy with either angioplasty or effective lytic therapy.
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