Fibrinolysis vs Transport-Angioplasty in Acute STEMI: The Answer is In
Abstract & Commentary
The DANAMI-2 investigators, representing 29 hospitals and a patient base reflecting 62% of the Danish population, have reported on a trial assessing whether randomization to either fibrinolytic therapy or transport to an interventional facility results in differing major cardiovascular rates following acute ST elevation myocardial infarction (STEMI). Five invasive-treatment hospitals received transfers from 24 referral hospitals without angioplasty programs, as well as direct admissions, between December 1997 and October 2001, when the study was stopped prematurely. Randomization to either fibrinolytic therapy or transfer to an invasive-treatment hospital for direct angioplasty was carried out in the emergency room. Subjects presenting directly to an angioplasty facility were randomized to lytic therapy or angioplasty. Fibrinolytic subjects received conventional alteplase, beta-blocker, and aspirin, as well as unfractionated heparin (UH) for 48 hours. Angioplasty patients received aspirin, a beta-blocker, and UH; a IIb/IIIa antagonist could be used at the discretion of the treating physician. Stenting was attempted in all patients with an infarct artery diameter > 2.0 mm. Ticlopidine or clopidogrel was given daily for 1 month. Individuals with failed reperfusion with lytic therapy underwent repeat fibrinolysis; reinfarction or recurrent ischemia in the angioplasty cohort was treated by repeat angioplasty.
The primary end point was a composite of all-cause death, clinical reinfarction, or disabling stroke at 30 days. Eligible patients had at least 30 minutes of chest pain for up to 12 hours and ST segment elevation. There were many exclusions, including LBBB or an MI within 30 days. Patients in cardiogenic shock or severe heart failure were excluded. The study analysis compared the fibrinolytic strategy to direct angioplasty, as well as an analysis of the outcomes in those who presented initially to a referral hospital vs those randomized at an invasive-treatment center. Approximately 4300 patients with STEMI were screened; the study was stopped prematurely at the third interim analysis by protocol because "angioplasty was superior to fibrinolysis in the referral hospital substudy." A total of 1029 patients were randomized at the outside referral hospitals and 443 at the invasive-treatment centers. Characteristics of both cohorts were similar. Randomization occurred rapidly; 27% within an hour of chest pain onset, 31% between 1 and 2 hours, 24% between 2 and 4 hours, 9% between 4 and 6 hours, and 9% after 6 hours. The median time from symptom onset to randomization was 135 minutes. The median distance for transported individuals was 50 km (range, 3-150 km); fully one-third came from hospitals within 25 km of the invasive facility and another third between 26 and 50 km. Median transfer time from randomization was 67 minutes; 43% were seen at the invasive hospital at under 1 hour and another 53% had a transfer time of 1-2 hours postrandomization. No deaths occurred during transfer, although atrial and ventricular fibrillation and complete AV block occurred in a total of 35 patients.
Sixty-eight percent of the entire cohort undergoing angiography had initial TIMI 0-1 coronary artery flow. The postangioplasty results were as expected, with TIMI 0-1 flow in 2%, TIMI 2 flow in 16%, and TIMI 3 flow in 82%. Stents were used in 93% of the angioplasty patients; 310 of the 790 assigned to angioplasty received a IIb/IIIa inhibitor. The LAD was the culprit vessel in 46%, RCA in 35%, and LCX in 12%.
Angioplasty was superior regarding the composite outcome compared to fibrinolysis, with a relative reduction of 40% in individuals referred from referral hospitals and 45% in those treated initially at the invasive-treatment center. Most of the benefit was related to a 75% reduction in the relative risk of clinical reinfarction; death and stroke reduction did not achieve statistical significance, although the mortality was slightly lower in the angioplasty group (6.6 vs 7.8%). Overall reinfarction rate was 6.3% in the fibrinolytic cohort and 1.6% in the angioplasty cohort; the composite end point was 13.7% with fibrinolysis vs 8.0% with angioplasty (P < .001). Of note, the relative benefit of angioplasty vis-à-vis fibrinolysis was comparable no matter the duration of time from symptom to onset of treatment, even in the 377 patients whose symptoms had begun > 4 hours before the time of treatment. Only 62 patients had a clinical reinfarction, but mortality was high, 24.2% vs 6.5% in the rest of the patients (P = .0001). Baseline and discharge medications did not vary among the groups.
Anderson and associates concluded that "primary angioplasty is superior to fibrinolysis . . . even when patients are admitted to a local hospital without angioplasty capabilities and must be transported to an invasive-treatment center." The DANAMI-2 investigators "trained" 3 institutions that were not initially performing direct angioplasty. They concluded that a transport-angioplasty approach to acute STEMI should and could become available in many more institutions. They stress that their protocol was highly tuned to maximize transfer and minimize all delays. The median time from admission to start of transportation in the referral centers was 50 minutes, better than in previous reports, such as AIR-PAMI. Furthermore, they point out that the transfer time represented only 14% of the total time from symptom onset to initiation of treatment, although 70% of the patients were transported more than 25 km. They recommend that in the future, emphasis should be placed on the logistics of transporting patients as well as adjunctive medications; they suggest initial ECG evaluation in the ambulance, with direct transfer to an invasive center even if immediate surgical backup is not available (Anderson HR, et al. N Engl J Med. 2003;349:733-742).
Comment by Jonathan Abrams, MD
It would appear that the door is finally closed on the issue as to whether individuals should receive fibrinolysis when they can be transferred within a reasonable amount of time to an invasive facility. Clearly, such patients benefited even if they were transferred between 3 and 4 hours after symptom onset, and there was even a cohort in whom the invasive therapy took place > 6 hours from onset of symptoms. Thus, physicians at outlying hospitals should not be advised to use fibrinolytic therapy when prompt transfer can be made, with a target goal of 1-2 hours until arrival in the invasive institution. It is likely that direct angioplasty does a better job than lytic therapy in "cleaning up" the disturbed vascular wall, possibly leading to less platelet aggregation and activation, with a subsequent decrease in reinfarction. The reinfarction rates in the angioplasty group are strikingly low. Long-term follow-up will hopefully become available; it will be of interest to see whether the end point difference at 30 days widens or narrows at 12 months. Cardiologists and hospitals that have been contemplating developing an immediate transfer policy for STEMI patients should move promptly to fulfill the various criteria required, and especially the availability of experienced invasive cardiologists. The majority of American hospitals do not have catheterization laboratories, but most individuals live relatively close to an invasive center.
A final note: In spite of widely disseminated guidelines for post-MI therapy, it would appear that the Danes are not much different than Americans with respect to the appropriate use of preventive medications at discharge; 96% received aspirin and 87% beta-blockers, but only 50% were given lipid-modifying agents and only 36% received ACE inhibitors. The underuse of statins, as well as ACE inhibitors, is comparable to that in the United States, and clearly there is room for improvement, as has been noted by many individuals. Finally, the DANAMI-2 investigators are to be complimented on this outstanding trial that required great organizational skills and included a very large number of patients.
Dr. Abrams, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.
The DANAMI-2 investigators, representing 29 hospitals and a patient base reflecting 62% of the Danish population, have reported on a trial assessing whether randomization to either fibrinolytic therapy or transport to an interventional facility results in differing major cardiovascular rates following acute ST elevation myocardial infarction (STEMI).
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