DANAMI-2

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Henning, R.A., et al. "A Comparison of Coronary Angioplasty with Fibrinolytic Therapy in Acute Myocardial Infarction". The New England Journal of Medicine. 2003. 349(8):733-42.
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Clinical Question

In patients with ST-segment elevation MI (STEMI) who present to a hospital where invasive treatment is unavailable is inter-hospital transfer for primary PCI superior to on-site thrombolysis?

Bottom Line

In patients with STEMI who present to centers where PCI is unavailable, inter-hospital transfer for primary PCI is superior to on-site thrombolysis provided the transfer time is less than 2 hours.

Major Points

Multiple large RCTs and meta-analyses have shown the superiority of primary PCI vs thrombolysis in acute MI [1][2][3]. However, at the time of this trial, the vast majority of patients with acute MI were presenting to hospitals without catheterization labs. In these cases, based on numerous studies including the GISSI and ISIS-2 trials, the standard of care was to immediately administer an intravenous thrombolytic agent versus delaying treatment for transfer to a PCI-capable center. Given the known benefit of PCI over thrombolysis in acute MI, the DANAMI-2 trial investigated if hospital transfer for PCI would be superior to on-site thrombolysis in patients presenting to centers without a catheterization lab.

Published in 2003, the DANish trial in Acute Myocardial Infarction 2 (DANAMI-2) randomized a total of 1,572 patients with acute STEMI to receive post-transfer PCI or on-site thrombolysis with tPA. Per study protocol, transfer to the nearest catheterization lab had to be completed within 3 hours; post-hoc analysis showed that 96% of patients completed transfer within a 120 minutes. At 30 days the composite primary end-point of death, disabling stroke or reinfarction was reduced in the PCI arm compared with those receiving tPA (8% vs 13.7%, P=<0.001), yielding a relative risk reduction of 40% (NNT = 18). The trial was stopped early due to the superiority seen with PCI. This superiority was largely driven by a 75% relative risk reduction in clinical reinfarction (P=<0.001). In contrast, the relative risk reduction in death and disabling stroke with PCI did not reach statistical significance. Short and long-term follow-up studies of the same 1,572 patients have shown sustained superiority with PCI[4][5].

Based primarily on the results of the DANAMI-2 and PRAGUE-2 trials, current STEMI guidelines recommend immediate transfer to a PCI-capable hospital for primary PCI if it is feasible within 120 minutes or less versus administering on-site tPA.

Guidelines

ACCF/AHA STEMI (2013, adapted)

  • Primary PCI is the recommended method of reperfusion when it can be performed in a timely fashion by experienced operators (Class I, level A)
  • EMS transport directly to a PCI-capable hospital for primary PCI is the recommended triage strategy for patients with STEMI, with an ideal FMC-to-device time system goal of 90 minutes or less (Class I, level B)
  • Immediate transfer to a PCI-capable hospital for primary PCI is the recommended triage strategy for patients with STEMI who initially arrive at or are transported to a non–PCI-capable hospital, with an FMC-to-device time system goal of 120 minutes or less (Class I, level B)
  • In the absence of contraindications, fibrinolytic therapy should be administered to patients with STEMI at non–PCI-capable hospitals when the anticipated FMC-to-device time at a PCI-capable hospital exceeds 120 minutes because of unavoidable delays (Class I, level B)
  • When fibrinolytic therapy is indicated or chosen as the primary reperfusion strategy, it should be administered within 30 minutes of hospital arrival (Class I, level B)

Design

  • Multicenter, randomized controlled trial
  • N = 1572
    • 1129 enrolled at 24 referral hospitals
    • 443 patients at 5 invasive-treatment centers
    • 782 to fibrinolysis
    • 790 to PCI
  • Setting: 24 referral and 5 invasive-treatment hospitals in Denmark
  • Enrollment: 1997-2001
  • Mean follow-up: 30 days
  • Analysis: Intention-to-treat
  • Primary outcome: Composite of death from any cause, clinical reinfarction, or disabling stroke at 30 days of follow-up

Population

Inclusion Criteria

  • Age ≥18 years
  • Anginal symptoms for ≥30 minutes but <12 hours
  • Cumulative ST-segment elevation of at least 4 mm in ≥2 contiguous leads

Exclusion Criteria

  • Contraindication to fibrinolysis
  • Left bundle branch block
  • Acute MI and fibrinolytic treatment within the previous 30 days
  • Pulseless femoral arteries
  • Previous CABG surgery
  • Renal failure (Cr >2.83 mg/dL)
  • Diabetes treated with metformin
  • Nonischemic heart disease
  • Noncardiac disease associated with a life expectancy of less than 12 months
  • Patients judged to be at high risk during transportation because of cariogenic shock or severe heart failure (systolic BP <65 mm Hg)
  • Persistent life-threatening arryhythmias
  • Need for mechanical ventilation

Baseline Characteristics

From patients in the fibrinolysis group

  • Demographics: Age 64, Male sex (73.3%)
  • Cardiac History:
    • HTN: 20.4%
    • Diabetes: 7.5%
    • Current smoking: 57.3%
    • Previous MI: 12.5%
    • Previous PCI: 2.7%
    • Previous stroke: 4.3%
    • HR: 72
    • Systolic BP: 125
    • Anterior index MI: 52%
  • Medication History:
    • Aspirin: 22.2%
    • Beta-blockers: 13.6%
    • ACE inhibitors: 10.4%
    • Calcium antagonists: 12.0%
    • Nitrate: 7.3%
    • Diuretics: 16.8%
    • Lipid-lowering drugs: 7.0%
    • Coumadin: 1.8%
  • Angiographic features (from PCI group):
    • Nonstenotic vessels: 6.1%
    • Single-vessel disease: 53.7%
    • Double-vessel disease: 24.1%
    • Triple-vessel disease: 13.1%
    • Involvement of the left main coronary artery: 3.6%

Interventions

  • Patients were randomized to receive fibrinolysis or transfer to PCI-capable center
    • Patients in fibrinolysis group received 300 mg aspirin, IV beta blocker, tPA (15-mg bolus and then tapering infusion over 60 minutes), IV bolus of unfractionated heparin
    • Patients in PCI group received 300 mg aspirin, same dose of IV beta blocker, and 10,000 U of unfractionated heparin. Platelet glycoprotein IIb/IIIa-receptor blockers were administered at the discretion of the physician. PCI was then performed.

Outcomes

Comparisons are fibrinolysis vs. PCI expressed as risk.

Primary Outcomes

Composite of death, reinfarction, or disabling stroke
13.7% vs. 8.0% (P<0.001)

Secondary Outcomes

Death
7.8% vs. 6.6% (P=0.25)
Reinfarction
6.3% vs. 1.6% (P<0.001)
Disabling Stroke
2.0 vs. 1.1% (P=0.15)

Adverse Events

  • Among patients assigned to PCI:
    • Atrial fibrillation developed in 14
    • Intermittent advanced atrioventricular block in 13
    • Ventricular fibrillation in 8
    • One patient had refractory ventricular fibrillation on arrival at the invasive-treatment center and died one hour later after an unsuccessful attempt at resuscitation.

Criticisms

  • Patients in both arms of the study were not mandated to receive clopidogrel
  • The strategy of revascularization after thrombolysis was very conservative in this trial, with only a minority of patients receiving post-thrombolysis revascularization

Funding

  • Grants from the Danish Heart Foundation, the Danish Medical Research Council, AstraZeneca, Bristol-Myers Squibb, Cordis, Pfizer, Pharmacia-Upjohn, Boehringer Ingelheim, and Guerbet (all in Denmark).
  • Authors with multiple ties to industry

Further Reading

  1. Weaver WD, et al. “Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review.” JAMA. 1997 Dec 17;278(23): 2093-8.
  2. Zijlstra F, et al. “Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction.” NEJM. 1999 Nov 4;341(19): 1413-9.
  3. GUSTO IIb Subsidy Investigators. “A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators.” NEJM. 1997 Jun 5;336(23): 1621-8.
  4. Busk M, et al. “The Danish multicentre randomized study of fibrinolytic therapy vs. primary angioplasty in acute myocardial infarction (the DANAMI-2 trial): outcome after 3 years follow-up.” Euro Heart J. 2008 May 29;29(10): 1259-66.
  5. Nielsen PH, et al. “Primary angioplasty versus fibrinolysis in acute myocardial infarction: long-term follow-up in the Danish acute myocardial infarction 2 trial.” Circulation. 202010 April 6;121(13): 1484-91.