Dual Therapy for Acute STEMI: Has The Time Arrived?

Abstract & Commentary

By Jonathan Abrams, MD Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.

Synopsis: In patients presenting with high-risk STEMI, TNK plus immediate angioplasty reduced the risk of recurrent ischemic events compared with TNK alone and was not associated with an increase in major bleeding complications.

Source: Le May MR, et al. Combined Angioplasty and Pharmacological Intervention Versus Thrombolysis Alone in Acute Myocardial Infarction (CAPITAL AMI Study). J Am Coll Cardiol. 2005;46:417-424.

Capital AMI is a Canadian multicentered, randomized controlled trial of tenecteplase (TNK) in high-risk acute ST-elevation myocardial infarction (STEMI) vs the combination of TNK and direct or primary angioplasty (PCI). The results are favorable for the combined therapy group, thus continuing an, as yet, unresolved dialogue as to whether the utilization of a fibrinolytic drug with PCI provides significant benefit over lytic therapy or PCI alone. This study was carried out in 4 Ottawa hospitals; catherizations were performed at the University of Ottawa Heart Institute. Criteria for enrollment were standard, including STEMI with high risk criteria, such as anterior infarction, extensive non anterior infarction, Killip class 3, or systolic blood pressure < 100mm/Hg.

There were many exclusions, including CABG or PCI within 6 months and recent anti-coagulation and/or glycoprotein IIb/IIIa inhibitors. Randomization was to a weight adjusted bolus of TNK with immediate transfer for PCI in the invasive group. TNK/PCI patients underwent angioplasty unless the coronary disease was not amenable to revascularization or there was TIMI grade 3 flow and a < 70% stenosis at the culprit site. PCI included stenting if the artery was large enough. IIb/IIIa inhibitors were not routinely used, but all received weight-adjusted unfractionated heparin. All subjects underwent radionuclide ventriculography at 1 week and 30 days, as well as exercise testing at 1 month.

The primary end point was a composite of death, recurrent MI, recurrent unstable ischemia, or stroke at 6 months. One hundred seventy patients were enrolled between 2001-2004. The 2 cohorts were well matched; half had anterior wall MI, 63% were smokers, 44% had hypertension, and the mean age was 58. Eighty percent of both groups were Killip class I. Time from symptom onset to TNK was 120 minutes in both groups. Stenting was successful in 90% of PCI patients. A patent infarct related artery (IRA) was present is 84%, and 52% had TIMI grade 3 flow on the initial angiogram. Angiographic success was achieved in 92% (stenosis less than 50%, TIMI grade 3). Clopidogrel was given to 90 % of the TNK-facilitated group and 57% to the TNK-alone patients (P = <0.001.) Post discharge therapy met ACC guidelines and was over 85% for all appropriate drugs.

Results: The dual therapy group had fewer primary end points at 1 month and 6 months; (21.7% vs 9.3% at 30 days, P = 0.03; 24.4% vs 11.6% at 6 months, P = 0.04). Most events were reinfarction or recurrent unstable ischemia. There were no differences in stroke or death. The majority of the benefit occurred within the first week of randomization, with parallel event curves after 7 days. There was no difference between groups in left ventricular function, CHF, or cardiogenic shock. Two thirds of the TNK-only group ultimately underwent cardiac catheterization; of these, half underwent non-protocol PCI (42 patients vs 12 patients in the TNK- facilitated group). Thus, by 6 months, 54% of the TNK- alone subjects vs 15% TNK-facilitated PCI patients required an unscheduled revascularization. Le May and colleagues conclude that compared with TNK-alone, TNK/PCI was associated with a significant reduction in the combined end point at 6 months without an increased risk of major bleeding.

Le May et al state "These results suggest that a strategy of full dose thrombolysis followed by immediate transfer of patients for PCI might be safe and might be superior to thrombolysis alone." They believe that lytic therapy allows for improved technical performance of PCI. Furthermore, they suggest that TNK, a highly fibrin-specific, weight-adjusted, single-bolus tissue plasminogen activator, may be a real advantage in STEMI. Le May et al point out that many other studies have investigated direct PCI with thrombolytics. Some of this data is favorable. In CAPITAL AMI, there were significant delays related to transfer of patients to the core hospital; they argue that prompt PCI results in better outcomes than delayed angiography, and also suggest that TNK by itself may provide earlier reperfusion and benefit in patients with a prolonged time before going to the catheterization laboratory. Le May et al state that their results are similar to the SIAM III and GRACIA-I trials, indicating that dual therapy was associated with improved 6 and 12 month results. They call for larger randomized trials, including "comparison with primary PCI" and cost effectiveness analyses.

Commentary

This study is intriguing, demonstrating a reduction of morbidity in the dual therapy group. Particularly striking, is the very low mortality at 30 days and 6 months in both groups, with no difference between the cohorts. Cardiogenic shock occurred in 3.6% and 4.7% of patients in the TNK-alone group vs TNK-facilitated patients; exercise test results were identical; hospitalizations were almost identical. Mortality was 3.6% and 2.3%, respectively at 30 days (NS) and 3.7% and 3.5% at 6 months (NS). Ischemic events were considerably less in the facilitated angioplasty group in hospital, at 30 days and at 6 months. However, although these patients were believed to be high risk, half with anterior wall STEMI, 80% Killip class 1, overall mortality was very low, perhaps due to excellent initial treatment in both cohorts, careful exclusion of patients with potential complications, and high rates of post-MI cardioprotective therapy. The lytic agent presumably resulted in some decrease in thrombus burden prior to the onset of angioplasty and stenting. Furthermore, use of clopidogrel was much greater in the PCI patients.

Large cohorts of STEMI have 30-day mortality rates of approximately 6-7%, which have not decreased appreciably over the past few years. However, this study was quite small, with only 84 patients in each group. There was no improvement in ejection fraction or exercise time, but there was more chest pain requiring re-hospitalization, and more PCI in the TNK-alone patients. In that so many major end points were comparable between the 2 strategies, it remains uncertain as to whether TNK is a superior lytic agent on its own, not necessarily requiring facilitated angioplasty. The latter decreased subsequent ischemic events, perhaps because thrombus burden would be cleaned up a bit following the lytic therapy, and the interventional cardiologist may have had better angiographic visualization in patients who had received lytic therapy. It is impressive that there was no excessive bleeding in the angioplasty patients.

I do not think that the data is convincing enough to recommend a dual approach, particularly in that LV function and mortality were not different between the 2 cohorts. The increased need for repeat catheterization could be, in part, related to failure to use clopidogrel in many non-PCI patients. The recent Chinese COMMIT/CCS-2 trial showed a benefit from clopidogrel 75mg for one month as a primary treatment in myocardial infarction in subjects given streptokinase.

Furthermore, results from ASSENT-4 were presented at the ESC meeting in early September, which did not confirm the CAPTIAL AMI results. The major outcomes were actually worse (including mortality) in the dual therapy cohort. Thus, at the present time, it appears reasonable to administer TNK in the field, if it appears that transport time will be prolonged. The interventional cardiologists in the CAPITAL trial are to be congratulated for their outstanding results, and particularly the low mortality. As many have noted, there has virtually been no decrease in STEMI mortality over the past 5-10 years. This small study optimistically suggests that the 6% barrier may be broken in the near future. Alas, ASSENT-4 does not confirm role for dual therapy with STEMI.