Background: In patients with ST elevation myocardial infarction, treatment with balloon angioplasty improved outcomes compared to fibrinolysis, as seen in the Primary Angioplasty in Myocardial Infarction Study Group trial. Other trials showed similar findings. However, these trials were relatively small in size and mainly conducted at hospitals with high experience in angioplasty.
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At the time this trial was conducted, limited number of hospitals offered angioplasty. Transporting patients with ST-elevation myocardial infarction to these centers posed a significant challenge, and sometimes resulting in delays in treatment.
The DANAMI-2 investigators sought to conduct a community-wide trial comparing on-site fibrinolysis vs transferring the patients for primary angioplasty.
Patients: Eligible patients had ST-segment elevation myocardial infarction with symptoms lasting for at least 30 minutes but less than 12 hours. The EKG criteria were cumulative ST-segment elevation of at least 4 mm in at least two contiguous leads.
Exclusion criteria were many and included contraindication to fibrinolysis, left bundle branch block, acute myocardial infarction and fibrinolytic treatment within the previous 30 days, pulseless femoral arteries, renal failure defined as creatinine > 2.83 mg/dL, life expectancy less than 12 months due to non-cardiac disease, and more. Patients were also excluded if they were high risk for transportation because of cardiogenic shock, persistent life-threatening arrhythmias, or a need for mechanical ventilation.
Baseline characteristics: The trial randomized 1,572 patients – 790 randomized to angioplasty and 782 to fibrinolysis. A total of 1129 patients were randomized at referral hospitals, and 443 patients were randomized at invasive-treatment centers.
The average age of patients was 63 years and 73% were men. Approximately 20% had hypertension, 7% had diabetes, 11% had prior myocardial infarction, and 58% were current smokers.
Among patients who underwent angiography and data were available, 53% had single vessel disease, 25% had two vessel disease and 14% had three vessel disease. Approximately 3% had left main involvement.
Procedures: Patients were randomly assigned in a 1:1 ratio to undergo fibrinolysis or angioplasty. Patients were recruited from 24 referral hospitals without angioplasty facilities and 5 invasive-treatment hospitals with angioplasty facilities. For patients recruited from referral hospitals, transfer to angioplasty center had to be completed within 3 hours. A physician accompanied the patient. The participating hospitals served 62% of the Danish population
Patients assigned to fibrinolysis received 300 mg of aspirin orally, beta-blocker intravenously, tissue plasminogen activator (alteplase, given as a 15-mg bolus and an infusion of 0.75 mg/kg over 30 minutes, followed by an infusion of 0.5 mg/kg for 60 minutes), and an intravenous bolus of unfractionated heparin (5000 U), followed by a 48-hour infusion of unfractionated heparin.
Patients assigned to angioplasty received 300 mg of aspirin intravenously, beta-blocker intravenously, and 10,000 U of unfractionated heparin bolus, with additional heparin during the angioplasty procedure to achieve an activated clotting time of 350 to 450 seconds.
Angioplasty was only performed for target-vessel related infarct.
Endpoints: The primary end point was a composite of death from any cause, clinical reinfarction or disabling stroke, at 30 days. Procedure-related reinfarction was not counted in the primary end point.
The trial was designed with two parallel sub-studies: One involving patients randomized at referral hospitals and the other involving patients randomized at invasive-treatment centers.
Analysis was performed based on the intention-to-treat principle. Sample size calculations assumed that the combined primary endpoint would occur within 30 days in 16% of patients assigned to fibrinolysis, 10% of those assigned to angioplasty at referral hospitals, and 9% of those assigned to angioplasty at invasive-treatment centers. Based on these assumptions, 1100 patients were needed to be enrolled at referral hospitals and 800 patients at invasive-treatment centers.
Results: Among the 4,278 patients screened for inclusion, 1,572 (36.7%) were randomized. The study was stopped early after the third interim analysis demonstrated superiority of angioplasty in the referral-hospital sub-study. The median time from the onset of symptoms to randomization was 135 minutes. The median distance patients were transported from a referral hospital to an invasive-treatment center was 50 km. The time from randomization at the referral hospital to arrival in the catheterization laboratory was under 2 hours in 96% of the patients. There were no deaths during transportation.
Among the patients randomized to fibrinolysis, 99% received the assigned treatment. Among the patients randomized to angioplasty, 98% underwent angiography. Angioplasty was attempted in 89.4% of the patients, and among them, stents were implanted in 90.4%.
Angioplasty reduced the primary composite endpoint among all patients (8.0% vs 13.7%; p <0.001). This difference was mainly driven by reduction in reinfarction (1.6% vs 6.3%; p< 0.001). There were no significant differences in death (6.6% with angioplasty vs. 7.8% with fibrinolysis; p= 0.35) or stroke (1.1% with angioplasty vs. 2.0% with fibrinolysis; p= 0.15).
The reduction in the primary endpoint with angioplasty was seen in patients randomized in referral hospitals (8.5% vs 14.2%; p= 0.002) as well as patients randomized in invasive-treatment centers (6.7% vs 12.3%; p= 0.05).
Procedure-related reinfarctions occurred in 10 patients assigned to fibrinolysis and 5 patients assigned to angioplasty. The inclusion of these events in the primary outcome did not significantly change the results.
Repeated fibrinolysis within 12 hours after randomization was performed in 26 patients in the fibrinolysis group. A total of 15 patients in the fibrinolysis group underwent rescue angioplasty.
No data provided on bleeding complications.
There were no significant subgroup interactions.
Conclusion: In patients with ST elevation myocardial infarction, angioplasty as compared to fibrinolysis reduced the composite endpoint of death from any cause, clinical reinfarction or disabling stroke, at 30 days with a number needed to treat of approximately 18 patients. This benefit was driven by reduction in reinfarction without a significant effect on death or stroke. The benefit was observed regardless whether patients were randomized at centers capable of performing angioplasty or at non-angioplasty centers, provided they were transferred to an angioplasty center within 2 hours.
This study established that transferring a patient with ST elevation myocardial infarction to centers equipped for angioplasty leads to better outcomes compared to on-site thrombolysis, provided the patient can be at the catheterization lab within two hours. These findings have been incorporated into clinical guidelines and medical practice.
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