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Optimizing outcomes in patients with STEMI: mortality, bleeding, door-to-balloon times, and guidelines: the approach to regional systems for STEMI care: defining the ideal approach to reperfusion therapy based on recent trials

Nicolas Danchin , Rocio Carda , Aurès Chaib , Antoine Lepillier , Eric Durand
DOI: http://dx.doi.org/10.1093/eurheartj/sup007 C25-C30 First published online: 22 May 2009

Abstract

Achieving rapid reperfusion is an essential step in the management of ST-elevation myocardial infarction (STEMI). Although primary percutaneous coronary intervention (PCI) is the preferred option, alternative strategies, and in particular intravenous fibrinolysis, especially as part of a pharmaco-invasive approach (i.e. followed by rapid coronary angiography with PCI when necessary) offer a reasonable alternative, when practical considerations make the performance of timely primary PCI impossible. Concomitant antithrombotic treatment is essential to grant optimal clinical results. This includes both antiplatelet and anticoagulant medications, with the aim to improve efficacy, without notably increasing bleeding complications, which are strong predictors of poor immediate and long-term outcomes. From a practical standpoint, network organization is central for optimizing patient care at the acute stage of MI. This review describes current approaches used to optimize outcomes in STEMI patients and their results in different systems of care.

KEYWORDS
  • Myocardial infarction
  • Reperfusion therapy
  • Antithrombotic treatment
  • Bleeding
  • Outcomes

Background

Reperfusion methods for the treatment of patients with ST-segment elevation myocardial infarction (STEMI) have evolved over the past three decades. The first methods of reperfusion were based on an invasive approach and in the late 1970s, K.P. Rentrop performed the first invasive reperfusion therapy using mechanical racanalization during coronary angiography; he subsequently added intracoronary fibrinolysis, forming the basis for intracoronary thrombolytic treatment.1 The first trials of intracoronary streptokinase use in the 1980s showed a reduction in infarct size as well as decreased mortality.25 However, because of practical considerations, the primary mode of reperfusion switched back to the use of intravenous thrombolytic treatment. Later on, an attempt to combine both intravenous lytics with coronary angioplasty failed because of high rates of mortality, and in the 1990s there was a return to primary angioplasty. Nonetheless, selection of an ideal reperfusion therapy, whether it be primary percutaneous coronary intervention (PCI), fibrinolysis, or a pharmacoinvasive approach incorporating both, is of paramount importance in the successful management of patients with STEMI.

Reperfusion strategies: a brief summary of randomized controlled trials

Thrombolytic therapy vs. primary percutaneous coronary intervention

The results from randomized clinical trials have formed the basis of the current reperfusion practices. Keeley et al.6 performed a quantitative analysis of 23 trials and demonstrated that primary PCI compared with thrombolytic therapy in STEMI patients resulted in reduced mortality (7 vs. 9%, P = 0.0002), reinfarction (3 vs. 7%, P < 0.0001), stroke (1 vs. 2%, P = 0.0004), and the combined endpoint of death, reinfarction, and stroke (8 vs. 14%, P < 0.0001). The CAPTIM trial was the only trial to compare primary PCI and pre-hospital thrombolytic therapy; it was the only one that found a trend towards reduced mortality at 30 days and 1 year with pre-hospital thrombolysis compared with primary PCI.7

The DANAMI-2 trial indicated that even in patients admitted to a non-PCI hospital, it was beneficial, particularly in terms of reinfarction, to transfer the patient to a hospital for primary PCI rather than treating with intravenous thrombolytic therapy in the primary hospital provided that the transfer takes <2 h.8 It is important to note that there was a huge difference between the CAPTIM and DANAMI trials regarding subsequent PCI, with rescue PCI performed in 26 vs. 1.9% of patients, and any subsequent PCI in 34.5 vs. 16.4% of patients, respectively.7,8

However, it is difficult to quickly bring patients to a catheterization lab with PCI capability, and data from the NRMI Registry indicate that as door-to-balloon and door-to-needle times increase, the mortality advantage of primary PCI over fibrinolysis declines, and varies considerably depending on patient characteristics.9 Unfortunately, despite this knowledge, there has been little progress in the time delays. An analysis of the GRACE registry, indicated that there was no improvement in the pre-hospital delay time from 1999 to 2006, and actually it was slightly longer in the latest time period (133 min during July 2005 to June 2006) compared with the earliest one (120 min during April 1999 to June 2000).10 Furthermore, the time from symptom onset to PCI has only slightly improved. These results have formed the basis for guideline recommendations for the management of patients with STEMI both in the US, where the ACC/AHA guidelines recommend a delay from first medical contact to PCI of not more than 90 min, and also in Europe, with the ESC guidelines recommending a delay of <2 h, except in patients presenting early, in which case the delay should be <90 min.11,12 When a substantial delay (e.g. >2–3 h) to primary PCI is likely, reperfusion therapy with fibrinolytic agents should be considered (Figure 1).12

Figure 1

Reperfusion strategies (Reprinted from Van de Werf F et al.,12 with permission from the European Society of Cardiology).

Percutaneous coronary intervention after thrombolysis

There are quite a few randomized trials indicating that PCI is useful after thrombolytic treatment. The REACT trial showed that, in patients who had failed thrombolytic therapy, rescue PCI was better than a conservative approach or repeated thrombolysis.13 More recently, the CARESS-in-AMI trial demonstrated that a strategy of immediate PCI was better than the standard of rescue-only angioplasty after thrombolysis, with a reduction in the primary endpoint of death, reinfarction, or refractory ischaemia at 30 days (10.7 vs. 4.4%, P = 0.005) (Figure 2).14 The Transfer-AMI trial enrolled 1030 patients <12 h after acute myocardial infarction who were treated with the ‘standard’ therapy [tenecteplase, aspirin, clopidogrel, and unfractionated (UFH) or low-molecular-weight heparin (LMWH)].15 Patients were randomly assigned to transfer for angioplasty within 6 h or to conventional rescue angioplasty or delayed elective angiography. The preliminary results show there was no difference in mortality between the standard and pharmaco-invasive treatment (3.6 vs. 3.7%, P = 0.94), but the composite endpoint of death, MI, or recurrent ischaemia was strongly in favour of the pharmaco-invasive strategy (11.7 vs. 6.5%, P = 0.004).

Figure 2

Primary endpoint at 30 days in the CARESS trial (Reprinted from Di Mario C et al.,14 Copyright © 2008, with permission from Elsevier).

Beyond reperfusion therapy: concomitant antithrombotic treatment

Concomitant antithrombin treatment has long been considered a compromise between efficacy and safety; however, recent data indicate that the impact of bleeding on subsequent adverse outcomes is much stronger than previously believed. In the GRACE registry, in-hospital mortality rates in patients with STEMI who had major bleeding were more than three times higher than those who did not experience bleeding (22.8 vs. 7.0%, P < 0.001).16 Likewise, an analysis of the GUSTO IIb, PURSUIT, and PARAGON B trials shows the impact of transfusion on mortality, with significantly higher rates of 30 day death (8.0 vs. 3.1%, P < 0.001) in patients who did vs. did not undergo a transfusion.17

The use of glycoprotein (GP) IIb/IIIa inhibitors and thrombolytics in addition to primary PCI increases the risk of major bleeding. In the FINESSE trial, patients were randomized in a 1:1:1 fashion to primary PCI with in-lab abciximab, upfront abciximab-facilitated primary PCI, or half-dose reteplase/abciximab-facilitated PCI.18 Rates of TIMI non-intracranial major bleeding and minor bleeding were significantly higher for the abciximab/lytic facilitated PCI strategy when compared with primary PCI. Major and minor bleeding combined was statistically more common in the combination strategy when compared with primary PCI and when compared with the abciximab-only group. There was also a strong trend towards increased intracranial haemorrhage through discharge or day 7 in the combined abciximab/lytic facilitation approach.

The impact of LMWH and UFH in STEMI patients treated with thrombolytics was evaluated in a meta-analysis performed by Eikelboom et al.19 Compared with placebo, LMWH was found to have a beneficial effect on 30 day death, however, there was an increase in the risk of major and minor bleeding. When LMWH was compared with UFH, there was a non-statistically significant difference in death (4.8 vs. 5.3%) and major bleeding (3.3 vs. 2.5%), although the risk of minor bleeding was increased (22.8 vs. 19.4%). And in patients receiving fibrinolysis for STEMI in the ExTRACT-TIMI 25 trial, treatment with LMWH throughout the index hospitalization was superior to UFH for 48 h but was associated with an increase in major bleeding (2.1 vs. 1.4%, P < 0.0001).20

Contrary to the results seen with LMWH, the direct thrombin inhibitor bivalirudin offers ischaemic protection while significantly reducing major bleeding compared with UFH. In the HORIZONS-AMI trial, 3602 patients with STEMI undergoing primary PCI were randomized to treatment with bivalirudin plus provisional use of GP IIb/IIIa inhibitors or UFH with routine use of GP IIb/IIIa inhibitors.21 At 30 days, bivalirudin-treated patients had significantly reduced rates of net adverse clinical events (9.2 vs. 12.1%, P = 0.005) compared with those who received UFH plus GP IIb/IIIa inhibitors, driven primarily by a significant reduction in bleeding (4.9 vs. 8.3%, P < 0.001). Furthermore, treatment with bivalirudin alone resulted in significantly lower 30 day rates of cardiac-related (1.8 vs. 2.9%, P = 0.03) and all-cause death (2.1 vs. 3.1%, P = 0.047). These results demonstrate that the concomitant antithrombin treatment has an influence on bleeding and, consequently, possibly on death rates in those patients.

Real world data: regional systems of care

Regardless of the modality utilized, the common goal of the management of patients presenting with STEMI is to shorten time delays from symptom onset to effective myocardial reperfusion. There are two ways to accomplish this goal; the first involves bringing the treatment to the patient, whereby the optimal treatment including thrombolytic and antithrombin therapy is administered in the ambulance or in the emergency room (ER). The second option is to bring the patient to the treatment, where the patient is transported as soon as possible to a hospital with PCI capabilities. Real world data are available from different systems of care, and the Vienna Model in Austria and the SAMU in France provide results from two different approaches.

The Vienna experience

In March 2003, an initiative with the goal of optimizing the organization of reperfusion strategies was started in Vienna. The program also aimed to improve the utilization of STEMI therapy and to determine the effect of implementation of guidelines on therapeutic efficacy. The system created uniformity among catheterization laboratories by the implementation of a central triage network via the Viennese Ambulance System in conjunction with recommendations to initiate thrombolytic therapy, either in-hospital or before arrival at the hospital if primary PCI could not be offered in a timely fashion, particularly in the case of patients with a duration of symptoms of <2 h. Concurrently, a prospective registry was established for control and quality assurance purposes.

Results of the Vienna STEMI registry indicate that from 2002 to 2004, there has been a shift in terms of the types of reperfusion therapy utilized, such that there has been a decline in the use of thrombolysis, an increase in the use primary PCI, and importantly a decrease in the proportion of patients who receive no reperfusion therapy.22 However, even in a very well-organized network system, it remains difficult to shorten the time delays in a dramatic fashion. Patients who underwent primary PCI very rarely had the procedure within the recommended timeframe of 2 h from symptom onset (14.6%), whereas 50.5% of those treated with thrombolysis had treatment within 2 h. After thrombolytic therapy, 91% of patients overall underwent coronary angiography, 50% immediately, and 41% within 1–5 days of thrombolysis.22

Overall, mortality rates for patients who did not receive reperfusion therapy were strikingly higher than in those patients who received primary PCI or thrombolytic therapy (18.4 vs. 8.1 and 8.2%, respectively). In patients who were treated early (0–2 h from onset of pain), there was a slight advantage for thrombolytic therapy over primary PCI (5.1 vs. 7.8%), whereas the mortality advantage was for primary PCI if the delay was between 2 and 6 h (6.7 vs. 10.6%) or 6 and 12 h (12.5 vs. 28.6%).22

The French SAMU System

The French SAMU System is a nationwide system implemented slightly more than 20 years ago, with a nationwide call number. There is one SAMU medical response centre for each French administrative region, which dispatches one of several mobile intensive care units (MICU) that can provide critical care on scene and during transport. By French law, each MICU team must include a physician, usually an anaesthesiologist or emergency physician, a nurse, and a driver trained as an emergency medical technician. Management on scene by the MICU team and precise notification to the medical centre of the patient stats allow direct admission to an adequate setting, including a catheterization lab, the ICU, or cardiac care unit (CCU).

The FAST-MI registry evaluated all patients hospitalized for acute MI in an ICU in France; approximately 60% of hospitals participated.23 For patients seen within 12 h of symptom onset, first medical contact was through SAMU in only 37% of the cases, while 30% was with the patient’s general practitioner and 15% of patients went directly to the ER. A little more than half of the patients were initially admitted to the ER, 29% to a CCU, and 15% directly to the catheterization lab, and the place of admission was dependent on the initial pathway prior to admission. When SAMU was used, only 33% of patients were brought to the ER, 42% to the CCU, and 24% directly to the catheterization lab. When the SAMU was not used, 75% of patients were admitted in the ER, 12% to the CCU, and only 10% to the catheterization lab.

In terms of reperfusion strategies, 21% of patients received pre-hospital thrombolytics, 11% received in-hospital thrombolytics, 38% underwent primary PCI, and 30% received no reperfusion therapy. Interestingly, the type of reperfusion therapy was dependent on the use of the SAMU system. When the SAMU was used, the proportion of patients receiving pre-hospital thrombolytic therapy was much higher than when it was not used (36 vs. 13%), and the reverse was found for in-hospital thrombolytics (7 vs. 14%). Importantly, only 18% of patients had no reperfusion therapy when they were taken by the SAMU, compared with 36% when other routes were used.

Among patients having called the SAMU directly, the time from the call to reperfusion varied depending on the type of reperfusion therapy. The time to pre-hospital thrombolysis was 40 min, in-hospital thrombolysis was 84 min, and primary PCI was 130 min. Furthermore, these are median times, indicating that less than half of the patients are undergoing primary PCI within 2 h of their first call to SAMU. In patients who had called the SAMU first, 80% of those with pre-hospital thrombolysis were treated within 60 min of the initial call; in contrast, only 6% of those treated with primary PCI had the procedure within 60 min and 44% within 2 h of first call. Another factor that influenced outcomes in the FAST-MI registry was the number of parties involved prior to hospital admission. When only one person was involved, the in-hospital mortality rate was 4.2%, however, this rate increased to 5.5% when two people were involved and 9.7% when there were three or more people involved. These results underscore the importance of organization of care for patients with STEMI.

When primary PCI is not used, the strategy advocated in France is a pharmaco-invasive one, with 96% of patients undergoing coronary angiography after intravenous thrombolysis.24 Approximately 85% of patients undergo subsequent PCI (87% after pre-hospital thrombolysis), and 58% of these patients undergo PCI within 24 h. In-hospital mortality was 4.3% for thrombolysis and 5.0% for primary PCI. In patients receiving thrombolysis, 30 day mortality was 9.2% when PCI was not used and 3.9% when PCI was subsequently performed. One-year survival was 94% for thrombolysis and 92% for primary PCI (P = 0.31); after propensity score matching, 1-year survival was 94% and 93%, respectively.

Management of ST-segment elevation myocardial infarction: evolution over 10 years

From 1995 to 2005, the management of STEMI in France has evolved with respect to reperfusion therapy. There has been a gradual increase in the use of primary PCI, from 12% in 1995 to 23% in 2000 and 35% in 2005, and while thrombolytic therapy has only slightly declined from 38 to 29%, the percentage of patients receiving pre-hospital thrombolysis has almost doubled from 9.6 to 18.8% (data on file). Also, the use of early/rescue PCI (PCI within 24 h of thrombolytic therapy) has increased from 9.9 to 58%, and any PCI during the hospital stay has also increased dramatically from 15% in 1995 to 84% in 2005.

Coupled with the trends in reperfusion strategies has been a strong decline in mortality, with a relative reduction of ∼45% over 10 years, regardless of the type of reperfusion therapy. Reduced mortality has been demonstrated in both those patients receiving thrombolysis and primary PCI, but also interestingly, for the patients who had no reperfusion therapy at all. There has been considerable progress in the management of STEMI such that patients receiving no reperfusion therapy in 2005 have in-hospital mortality rates that are comparable to those treated with primary PCI in 1995.

Summary and conclusions

Although primary PCI is the reference method of reperfusion, it remains difficult to apply in many circumstances and the time delays are often much longer than expected. As such, early thrombolysis is a reasonable option, but the best results are achieved when coronary angiography, with or without PCI, is performed rapidly thereafter. In order to achieve the recommended time delays, some countries have concentrated their efforts on bringing the patients to a PCI-capable institution, while others have highly developed pre-hospital emergency systems. Beyond reperfusion therapy, attention should be given to the safety of reperfusion therapy, with a specific focus on selecting antithrombotic agents known to reduce the risk of bleeding.

Conflict of interest: N.D. has received research grants from Pfizer and Servier and has received speaking and/or consulting fees from BMS, Boehringer-Ingelheim, GSK, Merck-Schering, Sanofi-aventis and Servier.

References

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