Andersen HR, Nielsen TT, Rasmussen K, et al. The DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med. 2003 Aug 21;349(8):733-42. doi: 10.1056/NEJMoa025142. PMID: 12930925.
Introduction
In September 1977, a 38-year-old man presented to the University Hospital in Zurich, Switzerland, with myocardial infarction. The likely culprit was a discrete occlusion of the left anterior descending coronary artery. By then, coronary artery bypass surgery had already been established as one of the treatment modalities available for atherosclerotic occlusion. Considering the patient’s reluctance to undergo an operative procedure that cut through the middle of the chest, Andreas Grüntzig, his physician, offered him the option of opening the blocked vessel using a balloon catheter. Grüntzig had previously demonstrated the efficacy of this technique in peripheral arterial occlusions; the atheroma could be compressed, leaving behind a smooth lumen. As his patient lay awake, Grüntzig passed the balloon catheter into the stenotic segment and inflated it with consummate ease. The results were spectacular as evident on follow-up angiography. Subsequently, he performed the procedure on four more patients with equally good results. He predicted that this new technique may offer a viable therapeutic modality for patients with angina pectoris in the years to come (1).
By the 1980s, severe studies were published demonstrating the efficacy of intravenous fibrinolysis, an alternative therapy. Most coronary care units adopted this treatment modality, allowing for a time window of 6 hours after the onset of symptoms (2,3). The GUSTO IIb randomized controlled trial (RCT) compared primary angioplasty with fibrinolytic therapy using recombinant tissue plasminogen activator in patients who presented within 12 hours of ST-segment elevation myocardial infarction (STEMI). Primary angioplasty was superior, with a significantly lower incidence of the composite outcome of death, nonfatal reinfarction, and disabling stroke at 30 days (4).
At the time of conduct of the DANAMI-2 trial, most patients with acute myocardial infarction presented to hospitals that did not have the facility for angioplasty. The standard practice was expeditious intravenous fibrinolysis or transfer to a center with the facility to perform primary angioplasty. Although primary angioplasty had been shown to be superior, the requirement for transfer from the local hospital to an angioplasty center presented a significant bottleneck on its widespread
implementation. The DANAMI-2 trial investigated outcomes with on-site fibrinolysis compared to transfer to an invasive-treatment center for primary angioplasty in patients with STEMI.
Population and design
The DANAMI-2 randomized controlled trial (RCT) was conducted between 1997–2001 in patients with ST-elevation myocardial infarction. Adult patients, 18 years or older, who experienced symptoms for ≥30 minutes and <12 hours with a cumulative ST-segment elevation of ≥4 mm in two contiguous leads were included. Patients were initially evaluated at 24 referral hospitals or at five invasive-treatment centers in Denmark. They were randomized to undergo fibrinolytic therapy or primary angioplasty. Patients who were initially evaluated at the referral center and randomized to primary angioplasty were transferred to one of five invasive treatment centers. Patients were taken directly to the coronary care unit of the referral hospital by ambulance personnel (not via the emergency department); transfer to the invasive-treatment center was carried out by the same ambulance staff, thus avoiding delays.
Exclusion
Patients with contraindications to fibrinolysis, left bundle branch block, those who had sustained acute myocardial infarction and underwent fibrinolysis in the previous 30 days, those with pulseless femoral arteries, previous coronary artery bypass surgery, renal dysfunction with creatinine level >2.83 mg/dl, diabetes on metformin, non-ischemic heart disease, and a life expectancy of <12 months were excluded. Patients deemed to be at high risk for transfer due to cardiogenic shock, severe heart failure, persistent life-threatening arrhythmias, and those on mechanical ventilation were also excluded.
The fibrinolysis group
Patients randomized to the fibrinolysis group received aspirin 300 mg and intravenous beta-blocker equivalent to 20 mg of metoprolol. They received tissue plasminogen activator (alteplase) as the fibrinolytic agent – an initial bolus dose of 15 mg was followed by an infusion of 0.75 mg/kg over 30 minutes, and 0.5 mg/kg over 60 minutes. Unfractionated heparin was administered as a bolus dose of 5000 units, followed by a continuous infusion for 48 hours, aiming to maintain an activated partial thromboplastin time (APTT) between 70–90 seconds. Repeat fibrinolysis or rescue angioplasty was considered if failed reperfusion was suspected, or reinfarction or recurrent ischemia occurred.
The angioplasty group
The management protocol in the angioplasty group consisted of aspirin 300 mg, a similar dose of beta-blocker, and 10,000 U of unfractionated heparin, with further doses aiming for an APTT level of 350–450 seconds during the procedure. Platelet glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors were administered at clinician discretion. Angioplasty was performed on the infarct-related artery if it was totally occluded, >30% of the lumen was occluded, or if the flow grade was <3 based on the Thrombolysis in Myocardial Infarction (TIMI) classification. Stenting was attempted unless the arterial diameter was <2.0 mm. Patients were given ticlopidine, 500 mg, or clopidogrel, 75 mg daily for a month after the procedure. Repeat angioplasty was performed if reinfarction or recurrent ischemia occurred.
Sample size
The authors calculated the sample size based on the composite primary outcome of all-cause mortality, clinical reinfarction, or disabling stroke at 30 days of follow-up. The incidence of the composite primary outcome was assumed to be 16% with fibrinolysis, 10% among those randomized to angioplasty and transferred to invasive-treatment centers, and 9% among those who were initially evaluated at the invasive-treatment center and randomized to undergo angioplasty. The sample size required 1100 patients to be treated at referral hospitals and 800 at invasive treatment centers.
Results
The study was terminated after the third interim analysis that revealed superior outcomes with primary angioplasty compared to fibrinolysis in the subgroup of patients randomized at the referral hospitals. A total of 1129 patients had undergone randomization at the referral hospitals and 443 at the invasive-treatment centers at the time of termination of the study. All except eight of 567 patients (99%) who were randomized to angioplasty at the referral hospitals were transferred to invasive-treatment centers. The baseline characteristics were similar between patients assigned to fibrinolysis or primary angioplasty.
The median transfer time, defined as the time from randomization at the referral hospital to arrival in the catheterization laboratory, was 67 minutes (interquartile range, 50–85). Nearly all patients (96%) reached the catheterization laboratory at the invasive-care center within two hours of randomization at the referral hospital.
Complications during transfer were uncommon – atrial fibrillation occurred in 14, intermittent atrioventricular block 13, and ventricular fibrillation in eight patients. No deaths occurred during transfer.
Seven hundred and seventy-five of 782 (99%) patients randomized to the fibrinolysis arm received the assigned treatment. In the angioplasty group, 777/790 (98%) received the assigned treatment. The left anterior descending artery was the culprit vessel in 46% of patients; the right coronary artery was involved in 35%, and the left circumflex artery in 12% of patients.
Outcomes
The primary outcome
The composite primary outcome of all-cause mortality, reinfarction, and disabling stroke was significantly lower with primary angioplasty compared to fibrinolysis. [107/782 (13.7%) vs. 63/790 (8%); p <0.001]. The superior primary outcome was observed among patients enrolled at the referral hospitals and at invasive-treatment centers. The relative reduction in the composite outcome was 40% among patients enrolled at referral hospitals and 45% among those enrolled at invasive-treatment centers. The primary composite outcome was superior among pre-specified subgroups of patients treated with angioplasty based on age (63 years vs. older), gender, duration of symptoms, anterior vs. non-anterior myocardial infarction, and smoking status. The outcome benefit related to angioplasty over fibrinolysis was evident regardless of the duration of symptoms (less than 2 hours, between 2–4 hours, more than 4 hours).
The number needed to treat with primary angioplasty to prevent one death, reinfarction, or disabling stroke was 17.5 patients in the overall cohort.
Among the individual components of the primary outcome, the reinfarction rate was significantly lower with angioplasty compared to fibrinolysis. In fact, the beneficial effect of angioplasty over fibrinolysis was mainly due to a 75% reduction in the incidence of reinfarction (1.6% vs. 6.3%). Among patients who suffered reinfarction, the 30-day mortality was significantly higher compared to those who did not (24.2% vs. 6.5%).
The 30-day all-cause mortality was lower with angioplasty compared with fibrinolysis, although the difference was not statistically significant (6.6 vs. 7.8%, p = 0.35). The incidence of disabling stroke was also not significantly different between groups. The main outcomes are summarized in Table 1.
Table 1. Main outcomes
|
30-d outcome |
Fibrinolysis (782 patients) |
Angioplasty (790 patients) |
Significance (p-value) |
|
All-cause mortality |
61 (7.8%) |
52 (6.6%) |
NS (0.35) |
|
Reinfarction |
49 (6.3%) |
13 (1.6%) |
S (<0.001) |
|
Disabling stroke |
16 (2%) |
9 (1.1%) |
NS (0.15) |
|
The composite outcome |
107 (13.7%) |
63 (8%) |
S (<0.001) |
Abbreviations: NS, not significant; S, significant
Repeat revascularization
At 30 days of follow-up, in the fibrinolysis group, 20 patients had undergone coronary artery bypass surgery, while 129 underwent angioplasty. In the angioplasty group, 30 patients underwent coronary artery bypass surgery, while 45 underwent repeat angioplasty. Repeat revascularization was significantly lower with angioplasty compared to fibrinolysis.
Conclusions
The DANAMI II trial demonstrated that primary angioplasty is superior to fibrinolysis for patients with STEMI, even when they are initially evaluated at a community hospital and have to be transferred to an invasive-treatment center, provided the transport time is less than 2 hours. The primary study end point, a composite of death, clinical evidence of reinfarction, or disabling stroke at 30 days, was significantly lower in the angioplasty group. Among the individual components of the primary outcome, the reinfarction rate was lower with primary angioplasty; however, mortality and the incidence of disabling stroke did not differ significantly.
Limitations
Although 4278 patients were screened, following exclusions, only 1572 (37%) were randomized. Patients with diabetes on metformin, peripheral vascular disease, previous coronary artery bypass surgery, and renal dysfunction were all excluded – these represent subgroups of patients who may have poor outcomes with angioplasty. In the angioplasty group, clopidogrel was administered in >80% of patients, which may have reduced the incidence of reinfarction. The time to transfer to the invasive-treatment center appears crucial; nearly all patients arrived within 2 hours of randomization. Expeditious transfer to a center with facility for angioplasty may hold the key to improved outcomes. Among patients who underwent fibrinolysis, rescue angioplasty was performed sparingly (15 patients); this may be at variance contemporary practice.
Subsequent studies
The findings of the PRAGUE-2 RCT echoed those of the DANAMI II trial (5). The investigators randomized 850 patients with STEMI within <12 hour of symptom onset at a community hospital to undergo fibrinolysis (n=421) or transfer to a center with the facility for primary angioplasty (n=429). Thirty-day mortality, the primary endpoint, was lower among patients who underwent primary angioplasty compared with those who underwent fibrinolysis (6.0% vs 10.4%, p <0.05). The improved survival was largely confined to patients who were randomized >3 hours after onset of symptoms. The composite endpoint of death, reinfarction, and stroke at 30 days was also lower among patients who underwent primary angioplasty (8.4% vs. 15.2%, p <0.003). The European and American guidelines currently recommend primary percutaneous coronary intervention (pPCI) if the duration between STEMI diagnosis or first medical contact to reperfusion is expected to be less than 120 minutes (6,7).
Follow-up studies of the DANAMI II trial
A 3-year follow-up of the DANAMI II trial revealed sustained benefits among patients who underwent primary angioplasty (8). The composite endpoint of death, reinfarction, or disabling stroke remained significantly lower compared to fibrinolysis (19.6 vs. 25.2%, p = 0.006). The results at 16 years of follow-up was published in August 2019, including the status of all except 5 of the 1572 patients originally included (9). The primary outcome was a composite of all-cause mortality or rehospitalization for myocardial infarction. Patients who had undergone primary angioplasty revealed a lower rate of the composite endpoint compared to those who underwent fibrinolysis [58.7% vs. 62.3%; HR 0.86, 95% confidence interval (CI) 0.76–0.98]. The superiority of angioplasty was driven by lower rate of rehospitalization in patients treated with angioplasty (19.0% vs. 24.5%; HR 0.75, 95% CI 0.60–0.93). There was no significant difference in all-cause mortality between the two groups. However, the risk of cardiac death was lower with primary angioplasty (18.3% vs. 22.7%; HR 0.78, 95% CI 0.63–0.98). This study established the sustained beneficial effects of primary angioplasty compared with fibrinolytic therapy at 16 years of follow-up.
Summary
The DANAMI-2 trial established the superiority of angioplasty compared to fibrinolysis in patients with STEMI, even among those who had to be transferred to an invasive treatment center to undergo the procedure. It remains the first and largest RCT that compared transferring patients with STEMI for primary angioplasty with administration of onsite fibrinolysis. In fact, the benefit of primary angioplasty was similar for patients who were transferred from referral hospitals compared with those who were admitted directly to the invasive-treatment centers. Complications were few, with no deaths reported during the transfer. The study provided the impetus for the establishment of routine angioplasty at community hospitals for patients with STEMI. The findings of the DANAMI-2 trial and similar findings from other studies, led to the recommendation that percutaneous coronary intervention may be carried out if the duration between the diagnosis of STEMI or first medical contact to balloon time is expected to be less than 120 minutes.
References
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2. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Lancet Lond Engl. 1986 Feb 22;1(8478):397–402.
3. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet Lond Engl. 1988 Aug 13;2(8607):349–60.
4. A Clinical Trial Comparing Primary Coronary Angioplasty with Tissue Plasminogen Activator for Acute Myocardial Infarction. N Engl J Med. 1997 Jun 5;336(23):1621–8.
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6. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019 Jan 7;40(2):87–165.
7. O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Jan 29;127(4):e362-425.
8. Busk M, Maeng M, Rasmussen K, Kelbaek H, Thayssen P, Abildgaard U, 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. Eur Heart J. 2008 May 1;29(10):1259–66.
9. Thrane PG, Kristensen SD, Olesen KKW, Mortensen LS, Bøtker HE, Thuesen L, et al. 16-year follow-up of the Danish Acute Myocardial Infarction 2 (DANAMI-2) trial: primary percutaneous coronary intervention vs. fibrinolysis in ST-segment elevation myocardial infarction. Eur Heart J. 2020 Feb 14;41(7):847–54.
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