And fibrinolysis became pharmacoinvasive

This editorial refers to ‘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’†, by P.G. Thrane et al., on page 847. Timely reperfusion is the cornerstone of treatment for patients presenting with ST-segment elevation myocardial infarction (STEMI).1 In fact, the development of reperfusion therapy for STEMI is one of the most successful stories in the history of medicine, since it was associated with impressive mortality reductions in less than three decades.2 In the late 1980s and early 1990s, several randomized clinical trials (RCTs) demonstrated that, compared with a conservative management, pharmacological reperfusion with intravenous fibrinolysis was associated with reduced mortality in patients presenting with STEMI.3 , 4 Mechanical reperfusion with percutaneous coronary intervention (PCI), first with balloon angioplasty5–7 and then with stenting,8 , 9 was shown to be clinically superior to fibrinolysis in head to head studies. Mortality benefit of PCI over fibrinolysis was only shown in meta-analyses including all head to head studies published up to 2003.10 , 11 Most of the studies included in these meta-analyses enrolled patients being admitted to hospitals with PCI facilities; however, many times PCI is not an immediate option and requires transport to another facility. Two landmark trials published almost simultaneously in 2003, DANAMI-212 (n = 1572) and PRAGUE-213 (n = 850), studied the clinical impact of transfer to PCI vs. onsite fibrinolysis (in DANAMI-2 one-third of the population was recruited in a centre with PCI facilities). The primary outcome in PRAGUE-2 (all-cause death at 30 days) was not significantly different between groups (6.8% in PCI vs. 10% in fibrinolysis, P = 0.12), but the main secondary outcome [composite of death, re-myocardial infarction (re-MI), or stroke at 30 days] was significantly less in the PCI arm. Conversely, the primary endpoint in DANAMI-2 (composite of death, re-MI, or disabling stroke at 30 days) was significantly reduced in the PCI group.12 All individual components of the primary endpoint favoured PCI, but the statistical significance was mainly driven by the large reduction in the rates of re-MI at 30 days (1.6% vs. 6.3%, P < 0.001). As in PRAGUE-2,13 all-cause death rates in the DANAMI-2 trial were numerically lower in the PCI arm but differences did not reach statistical significance (6.6% vs. 7.8%, P = 0.35). Outcome rates in the subpopulation of patients enrolled in non-PCI centres were consistent with the entire population. The rates of 30 days repeat revascularizations were significantly less in the PCI arm (9.1% vs. 18.9%, P > 0.001).12 In the 3-year pre-specified follow-up of the DANAMI-2,14 the rates of the primary composite endpoint were still significantly lower in the PCI group, and again the differences were driven by a significant reduction in the cumulative rates of re-MI (8.3% vs. 12.3%, P = 0.007). Differences in the incidence of cumulative repeat revascularizations were even larger than in the earlier follow-up (25% vs. 46%, P < 0.001). The 5 years follow-up of the PRAGUE-2 RCT showed similar results, with significant differences favouring PCI for re-MI (12% vs. 19%, P = 0.009) and for repeat revascularizations (33% vs. 51%, P < 0.001). In DANAMI-2, cardiac death rates were non-significantly less in the PCI arm at 3 years.14 In this issue of the European Heart Journal, the very long-term follow-up of the DANAMI-2 RCT (16 years) is presented.15 The primary outcome of this not pre-specified follow-up (composite of death or re-hospitalization for MI) remained significantly less in the PCI arm, and again this was only driven by a significant reduction in the rates of re-MI (19% vs. 24.5%). The 16-year cumulative rate of repeat revascularizations was less in the PCI group (42% vs. 65.3%). Figure 1 shows the cumulative and time-period incidence of cardiovascular events in DANAMI-2 trial. Of special note, the 16-year incidence of cardiac mortality was significantly lower in the PCI group (18.3% vs. 22.7%). Conversely, the non-cardiac death rate was numerically higher in the PCI group (30.5% vs. 28%). As a result, all-cause death was very similar between groups (50.5% vs. 51.3%) at 16 years follow up. The results reported here15 are unique from several perspectives. First, this study represents the longest follow-up ever reported in an RCT comparing two reperfusion strategies for STEMI. The study demonstrates that transfer for PCI (as long as it can be done in a timely manner after STEMI diagnosis) is overtly superior to stand-alone fibrinolysis. Compared with stand-alone fibrinolysis, PCI is associated with a long-lasting benefit in terms of reduction of re-MI and repeat revascularizations. Secondly, and more importantly, this is the first time that primary PCI is shown to be associated with less cardiac mortality than stand-alone fibrinolysis in an RCT (4.4% absolute difference), and this is a major result. Thanks to the very long-term follow-up, this study is able to show differences not found by other trials. The fact that PCI was associated with numerically higher rates of non-cardiac death, and that all-cause death was virtually identical in both treatment arms does not reduce the clinical relevance of the findings of the trial. The competing risks of cardiac and non-cardiac deaths and the very long-term follow-up are probably the cause of the higher rates of non-cardiac deaths. Given that the intervention (PCI) is not expected to increase long-term non-cardiac death (as compared with fibrinolysis), the most relevant outcome to be interpreted is time to event. In fact, if the follow-up of the trial were to be prolonged for long enough, one can anticipate that all-cause death would be identical (100%), with significantly lower cardiac death and significantly higher non-cardiac death in the PCI arm. These facts reinforce the concept of measuring time to event in long-term follow-ups like the one presented here. The DANAMI-2 very long-term follow-up data presented by Thrane et al.15 have been obtained thanks to fantastic Danish national registries where vital status, cause of death, re-hospitalizations for MI, and even incidence of revascularizations can be obtained in virtually the entire population. This registry has been validated before for these purposes.16 While the 30-day12 and 3-year follow-up14 were included in the study protocol as a pre-specified endpoint and adjudicated by an independent committee, the 16-year follow-up is only based on registries. While the quality of data in this very long-term follow-up is expected to be lower than in the previous cut-offs, this seems to have had little impact in the results reported. The most relevant questions to put this article into perspective are to what extent the results reported represent today’s standards and how they will change our practice. The DANAMI-2 trial enrolled patients from 1997 to 2001. Reperfusion regimes back then were significantly different from current standards.1 The primary PCI technique has been significantly improved, but the fibrinolysis strategy has changed conceptually to a greater extent. Fibrinolytic agents, their administration protocol, and the concomitant antithrombotic regime (agents and treatment maintenance) have been improved. Patients undergoing fibrinolysis in the DANAMI-2 trial received accelerated tissue plasminogen activator (t-PA; 90 min infusion) and unfractionated heparin for 48 h, while dual antiplatelet therapy was maintained for 1 month. Today’s recommended fibrinolysis regime includes tenecteplase (TNK) bolus plus enoxaparin and dual antiplatelet therapy for 1 year.1 However, the old fibrinolysis regime might have had only a small clinical impact on the differences between treatment arms only in the very short term. Something more relevant to interpret the long-term results of this study is the rate of post-fibrinolysis invasive angiography. In DANAMI-2, according to standards of the late 1990s, angiography was seldom performed. Patients with failed thrombolysis were conservatively managed, and planned angiography in patients with successful fibrinolysis was not considered. This management explains the excessive incidence of repeat revascularizations and re-MI rates, the main driver of the long-term clinical differences between treatment arms. Based on evidence from several RCTs and meta-analyses,17 , 18 current guidelines recommend an early (2–24 h) routine angiography (plus PCI if indicated) in all patients.1 The STREAM trial19 is the most recent large RCT comparing transfer to PCI vs. onsite fibrinolysis and applied current state-of-the-art management to fibrinolysis patients. In this trial, cardiac mortality at 1 year was similar for both treatment strategies (4.0% vs. 4.1%),20 showing that, today, any potential clinical benefit of timely transfer to PCI over fibrinolysis appears in the very early phase (bleeding events, microvascular obstruction, etc). Benefits of early angiography after successful fibrinolysis (pharmacoinvasive strategy) apply not only to intervention of the residual lesion in the infarct-related artery (IRA), but also to the potential intervention to the non-IRA. Current myocardial revascularization guidelines recommend preventive PCI of the non-IRA during hospital admission in STEMI patients.21 This approach has been associated with a significant reduction in the rates of re-MI and future coronary revascularizations.22 However, the benefits of angiography in identifying severe stenosis in the non-IRA probably had no impact on the long-term results of DANAMI-2 since the protocol of the study considered a conservative approach to severe non-IRA stenosis in the PCI arm. Overall, the results presented in this study only represent the differences between PCI and stand-alone fibrinolysis, a strategy no longer recommended. In summary, the 16 years follow-up of the DANAMI-2 trial represent a strong (indirect) argument to further reinforce current recommendations for performing an invasive approach early after successful fibrinolysis and to treat all severe residual stenoses.1 Cumulative and time period incidence of major endpoints in DANAMI-2. Data are calculated (not actual) from DANAMI-2 publications, thus percentages are a proxy for actual numbers to illustrate the trajectories in the incidence of endpoints. As noted in the text, primary endpoint differences are mainly driven by the excess in re-infarction rates in the fibrinolysis arm at 30 days. Conversely, the rate of revascularizations is lower in the PCI arm at every follow-up. The latter explains to a large extent the reduced incidence of cardiac death at 16 years follow-up. CUM, cumulative. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. B.I. holds grants related to this topic from the Instituto de Salud Carlos III-Fondo de Investigación Sanitaria (PI16/02110) and the Fondo Europeo de Desarrollo Regional (FEDER, RD: SAF2013-49663-EXP). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-201-0505). Conflict of interest: none declared.