Danish Trial in Acute Myocardial Infarction-2 - DANAMI-2

Description:

The goal of the DANAMI 2 trial was to evaluate thrombolytic vs invasive therapy in patients with acute myocardial infarction.

Hypothesis:

The invasive strategy is superior to the conservative, thrombolytic strategy in treatment of ST elevation MI. The invasive strategy will be superior both in patients presenting at on-site interventional facilities (no transfer of patient required) and without (transfer of patient required).

Study Design

Study Design:

Patients Enrolled: 1572
Mean Follow Up: 30 days
Mean Patient Age: median age=63
Female: 27

Patient Populations:

ST elevation >4 mm symptom onset >=30 minutes and <=12 hours no upper age limit

Exclusions:

Age < 18 years; thrombolytic treatment within the last 30 days acute MI within the last 30 days; high risk during transportation (cardiogenic shock or severe heart failure with hypotension, persistent life threatening arrhythmias or need for mechanical ventilation); LBBB; any cardiac condition requiring immediate surgical intervention; severe valvular or pericardial disease; severe non-cardiac disease (life expectancy < 12 months); active bleeding or bleeding diathesis; history of stroke in the past 3 months; major surgery or significant trauma in the past 1 month; severe hypertension after initial treatment (systolic > 200 mmHg or diastolic > 110 mmHg); expected time between randomization and arrival in the catheterization laboratory > 3 hours for patients randomized in referral hospitals and > 2 hours for patients randomized in invasive hospitals; infection with sepsis; aortic aneurysm with thrombus diagnosed previously; no femoral pulse or known difficulty with arterial access or bilateral femoral vascular grafts; previous coronary bypass grafting; severe renal failure; NIDDM treated with Metformin (Glucophage, Orabet) within the last 48 hours; patients in whom compliance with follow-up is doubtful or unlikely; pregnancy or lactation and females of childbearing potential not using adequate birth control.

Primary Endpoints:

Composite of death from any cause, clinical reinfarction, or disabling stroke at 30 days; procedure-related reinfarction was not included in the primary end point.

Secondary Endpoints:

Composite end-point of mortality + clinical reinfarction + significant disabling stroke at end of study period. Total mortality at end of study period. Cardiac mortality at end of study period. Angina pectoris free survival without AMI at end of study period. Quality of life at follow-up after 30 days, 1 year, 3 years and 5 years. Costs analysis at follow-up after 30 days, 1 year, 3 years and 5 years.

Drug/Procedures Used:

Patients were randomized to primary PCI or front loaded tPA - 15 mg bolus over 1-3 minutes + infusion of 0.75 mg/kg over 30 minutes (not to exceed 50 mg) + 0.5 mg/kg over 60 minutes (not to exceed 35 mg) Patients randomized to PCI were transferred to referring center if catheterization lab facilities were not available on-site.

Concomitant Medications:

Aspirin (300 mg initially followed by 75-150 mg daily) Heparin (5000 U bolus + 1000 U/hr infusion for at least 48 hours in patients randomized to tPA; 10,000 U bolus + additional heparin to keep the ACT between 350-450 seconds during procedure in patients randomized to PCI)

Principal Findings:

The trial was stopped early by the Safety and Efficacy Committee after a benefit in the composite endpoint was observed in the PCI arm in the referral-hospital substudy. The composite event rate occurred in 8.0% of patients who received PCI and 13.7% of fibrinolysis patients (p=0.0003). When the analysis was stratified by type of enrolling hospital (referral vs on-site cath lab), similar results were observed: composite rate of 14.2% with fibrinolytic vs 8.5% with PCI (p=0.002, RRR 40%) at referral hospitals and 12.3% with fibrinolytic vs 6.7% with PCI at tertiary centers (p=0.05, RRR 45%). The composite endpoint was driven by a reduction in recurrent MI (6.3% vs 1.6%, p<0.0001). There was no difference in death at 30 days was 7.8% in the fibrinolysis group vs 6.6% in the PCI group (p=0.35), or disabling stroke was 2.0% vs 1.1% (p=0.15), respectively. The time from randomization to balloon inflation was 112 minutes in the referral center patients and 91 minutes in the on-site patients, a 21 minute difference. Rescue angioplasty was performed in 1.9% of patients in the thrombolysis arm (15/782).

Interpretation:

Among patients with acute MI, treatment with PCI was associated with a reduction in the primary endpoint of death, clinical reinfarction or stroke compared with thrombolytic therapy. The primary endpoint in the trial was driven primarily by a reduction in the risk of recurrent MI among patients treated by primary PCI. This study confirms that thrombolysis when accompanied by a very low rate of PCI (1.9% in this trial) is associated with a high rate of reinfarction. Recent trials such as ASSENT 3 and the TIMI 23 / ENTIRE study have demonstrated that newer antithrombotic agents such as enoxaparin may further reduce the rates of reinfarction among patients treated with thrombolysis. The present trial does not shed light on the concept of "facilitated PCI" where a drug would be given before the PCI to improve pre-PCI patency rates. Patients were brought directly to the coronary care unit by the ambulance staff and were not processed through the emergency department, and transfer patients were transported by the same ambulance staff directly to the referral center, resulting in a door to balloon time of only 91 minutes in the tertiary centers and 112 minutes in the transfer centers, much lower than 110 minutes and 185 minute times, respectively, that was reported in US patients from the recent NRMI 4 study.

References:

1. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733-42. 2. ACC 51st Scientific Session, Atlanta, GA.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Lipid Metabolism

Keywords: Thrombolytic Therapy, Stroke, Myocardial Infarction, Patient Transfer, Coronary Care Units, Referral and Consultation, Emergency Service, Hospital, Fibrinolytic Agents, Angioplasty, Enoxaparin, Fibrinolysis, Catheterization, Tissue Plasminogen Activator


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