European Heart Journal Advance Access originally published online on May 11, 2007
European Heart Journal 2007 28(12):1418-1424; doi:10.1093/eurheartj/ehm087
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Variations in the use of emergency PCI for the treatment of re-infarction following intravenous fibrinolytic therapy: impact on outcomes in HERO-2
1 Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand
2 Cardiology Department, Bristol Royal Infirmary, Bristol, UK
3 Cardiology Department, and South West Sydney Clinical School (UNSW) Liverpool Hospital, Sydney, Australia
4 Flinders Medical Centre, Adelaide, Australia
5 NHMRC Clinical Trials Centre, University of Sydney, Australia
6 Department of Cardiology, Gasthuisberg University Hospital, Leuven, Belgium
Received 15 February 2006; revised 7 March 2007; accepted 15 March 2007; online publish-ahead-of-print 11 May 2007.
* Corresponding Author. Cardiology Department, Liverpool Hospital, Elizabeth St, Liverpool NSW 2170, Australia. Tel: +61 2 9828 3069; fax: +61 2 9828 3341. E-mail address: j.french{at}unsw.edu.au
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Abstract |
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Background: Patients who suffer re-infarction during initial hospitalization for ST-elevation myocardial infarction (STEMI) have decreased survival compared to patients without re-infarction, so treatment of re-infarction may influence survival.
Methods and results: To determine whether the utilization of reperfusion therapies varied within 12 h of re-infarction and was associated with 30-day mortality, we studied 552 patients with re-infarction of 17 073 patients with STEMI enrolled in HERO-2 in five regions (Russia, Eastern Europe, Western Countries, Asia, and Latin America). Patients presenting within 6 h of symptom-onset were randomized to receive either bivalirudin or unfractionated heparin intravenously just prior to streptokinase. Re-infarction occurred in 2.8 and 3.6% of bivalirudin and heparin treated patients, respectively (P = 0.004), but treatment assignment did not influence mortality after re-infarction. Patients with re-infarction had a higher 30-day mortality than those without re-infarction (24 vs. 10%; P < 0.001 by Cox model). Within 12 h of re-infarction, fibrinolytic therapy was administered to 12.0 and 8.2% underwent percutaneous coronary intervention (PCI); these two treatments were more frequently utilized in patients from Western countries (n = 112), compared to patients from other countries (n = 440) (34.8 and 16.1% compared to 6.1 and 6.1%, respectively, P < 0.001). Mortality was 15% in patients receiving reperfusion therapy for re-infarction and 27% for those with conservative management, hazard ratio (HR) 0.53 (95% CI 0.32–0.88), P = 0.01. In multiple Cox regression analysis which included adjustment for clinical variables and randomized treatment assignment, 30-day mortality after re-infarction varied by region (highest Latin America 29%, lowest Western countries 15%; P = 0.01). Other independent prognostic factors included age, time from randomization to re-infarction, and Killip class at randomization. The HR for PCI treatment of re-infarction was 0.18 [(95% CI 0.04–0.76), P = 0.02] in analyses which excluded deaths within 12 h.
Conclusion: Treatment of re-infarction with reperfusion therapies was markedly under-utilized, especially in non-western countries. PCI for re-infarction, in particular, was associated with a lower 30-day mortality, which may reflect both patient selection and effects of treatment.
Key Words: Re-infarction • Percutaneous coronary intervention • Mortality • Clinical endpoints committee
This paper was guest edited by Prof. Freek WA Verheugt, University Medical Center Nijmegen, The Netherlands
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Introduction |
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Fibrinolytic therapy reduces mortality in patients with acute ST-elevation myocardial infarction (STEMI) but is associated with a 2–6% incidence of re-infarction during the initial hospitalization.1–3 Early re-infarction is associated with an increased risk of mortality at 1 to 3 years.4–6 Given its prognostic importance, re-infarction is increasingly incorporated in the primary endpoint in clinical trials evaluating reperfusion and adjunctive therapies for STEMI. The treatment for re-infarction by the following day including re-administration of fibrinolytic therapy, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG) was associated with lower mortality, compared with conservative treatment including heparin, in two trials recruiting patients predominantly from Western countries which may represent effects of both reperfusion and revascularization.7 The HERO-2 trial was a large trial enrolling patients with STEMI, the majority of whom were recruited from Eastern European countries and Russia, which utilized a clinical endpoints committee (CEC) to adjudicate re-infarction during the index hospitalization, according to predefined criteria.8 Using data collected prospectively for re-infarction adjudication available to the CEC, we examined the associations between use of reperfusion treatments administered within 12 h of re-infarction, geographic regions, and 30-day mortality in patients in the HERO-2 trial.
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Methods |
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The HERO-2 trial was conducted in 539 hospitals in 46 countries, grouped into five international regions: Russia (n = 6057); Eastern Europe (n = 5877); Western Countries, which included Western Europe, United States, Canada, South Africa, Australia, New Zealand and Turkey (n = 2563); Latin America (n = 1820); Asia (n = 756). Patients with STEMI were randomized to receive either intravenous unfractionated heparin or bivalirudin immediately prior to commencing streptokinase. In brief, patients of any age were eligible if they presented within 6 h of the onset of chest discomfort lasting > 30 min, and had
1 mm of ST-elevation in two or more contiguous leads (or 2 mm of ST-elevation in two contiguous precordial leads in V1–V3) or presumed new left bundle branch block (LBBB). Other protocol details including inclusion or exclusion criteria are described elsewhere.8 The protocol was approved by each hospital's ethics committee and written informed consent was obtained from each patient.
Definitions of recurrent myocardial infarction
Re-infarction within 96 h and during the initial hospitalization were predefined major secondary endpoints in HERO-2. Electrocardiographs were recorded in all patients at baseline and then at 60 min following the start of the administration of streptokinase. The protocol recommended recording further electrocardiographs at the onset of suspected re-infarction, 24 h later, prior to hospital discharge and otherwise as physician-recommended according to good clinical practice. According to the protocol, investigators were requested to answer questions (Yes or No) on four different clinical scenarios on the case report form, and those recorded as ‘Yes’, or where the questions were answered ‘No’ but the investigator suspected re-infarction (or this was suspected after trial monitors or data centers' queries), were referred for adjudication by an independent blinded CEC according to criteria as previously described.8,9 In brief, re-infarction at < 18 h was defined as ischaemic chest pain lasting 30 min and recurrent ST-elevation of 1 mV in at least two contiguous leads, in patients with evidence of 1 mV ST recovery. Re-infarction occurring at > 18 h required an elevation of creatine kinase (CK) levels to greater than or equal to two times the upper limit of the reference range (ULRR) and/or elevation of CK-MB levels to greater than or equal to one times ULRR or new Q-waves of 30 ms in two contiguous leads distinct from the index STEMI or new LBBB. Re-infarction after PCI and CABG required elevations in CK and/or CK-MB levels of greater than three and five times the ULRR, respectively, or new Q-waves or new LBBB. Cardiac troponin levels were not included in the re-infarction definition.
Treatment of re-infarction
The clinical notes of each patient were reviewed retrospectively for treatment given for re-infarction, which was verified with the case record form. Further reperfusion therapy was defined as repeat administration of fibrinolytic therapy, or PCI within 12 h of re-infarction (two cases of CABG within 12 h are included in the PCI analysis). In patients who received both repeat administrations of fibrinolytics and PCI within 12 h, the first treatment is reported. Conservative treatments included the non-randomized use of antithrombin therapies. Data discrepancies regarding reperfusion therapy use recorded in source data and on the HERO-2 database were resolved by consensus.
Statistical analysis
Non-parametric Wilcoxon test of differences and 
2 tests were used to compare continuous and categorical variables respectively between groups; tests are two-sided unless stated. Adjustments have not been made for multiple comparisons unless indicated. Log-rank tests and Cox proportional hazard regression models were used to assess differences in mortality, at 30 days from randomization. Graphical and numerical methods based on cumulative sums of martingale residuals over follow-up times were used to test the proportional hazards assumptions for the Cox regression model.10 Mortality data were available in all patients up to 30 days following the index STEMI. Time-dependent Cox regression analysis was used to model the effect of re-infarction on 30-day mortality. In adjusted analyses, predictors from the HERO-2 risk factor model including age, region of enrolment, systolic blood pressure, and heart rate at randomization, time from onset to randomization, Killip class, prior angina, diabetes, location of MI, prior MI, hypertension, gender, and time from randomization to re-infarction were included as covariates. To attempt to avoid potential bias of treatment effects occurring as a result of patients dying before treatment could be administered, a ‘landmark’ analysis was performed by excluding deaths occurring within 12 h of re-infarction.10 The likelihood ratio test was used to determine the significance of treatment and region effects in multivariable analyses. A two-sided significant level of 0.05 was used.
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Results |
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Of 17 073 patients randomized in HERO-2 between November 1998 and May 2001, 679 patients with suspected re-infarction were identified by investigators on the CRF and a further 43 cases of suspected re-infarction were identified by data centres or study monitors. Of these cases, 552 had re-infarction confirmed following adjudication by the CEC (Figure 1). Patients with confirmed re-infarction, compared with the remainder in HERO-2, had some differences in baseline characteristics (Table 1), including older age, a higher frequency of female gender and non-smoking, and a more frequent history of prior hypertension, hypercholesterolaemia, prior MI, angina, and CABG.
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Treatment with bivalirudin reduced the rate of re-infarction (2.8 vs. 3.6%, P = 0.004). Mortality at 30 days after randomization for patients with confirmed re-infarction was 24%, compared with 10% for the other patients recruited in the HERO-2 trial (P < 0.001), and was similar in patients randomized to bivalirudin, compared to those randomized to heparin therapy (24.4 vs. 24.5%, P = 0.99). After adjustment for the factors from the HERO-2 risk model for 30-day mortality, the hazard ratio (HR) for mortality associated with re-infarction was 6.2 (95% CI 5.2–7.5), P < 0.001. The increase in mortality hazard associated with re-infarction was present in all geographic regions (Table 2). In a Cox model including patients with re-infarction only, geographic region was associated with mortality after re-infarction (P = 0.013), even after adjustment for other factors including reperfusion treatment < 12 h and time from randomization to re-infarction.
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Variations in the use of reperfusion therapy for re-infarction
In total, 66 patients (12%) were treated within 12 h of re-infarction with re-administration of fibrinolytic therapy, 45 patients (8.1%) had PCI (including two having CABG), and 441 (79.9%) had conservative management. Rates of use of reperfusion therapies for re-infarction in each randomized treatment assignment were similar. In Western countries (n = 112), the respective frequencies of these therapies were 34.8, 16.1, and 49.1% (Figure 2). Among the 413 (74%) patients with recurrence of ST-segment elevation on the electrocardiogram at the time of re-infarction, the overall rates of further fibrinolytic, PCI, and conservative therapies were 15.2, 9.0, and 75.8%, respectively, whereas in Western countries these rates were 42.5, 17.3, and 40.2%, respectively. In the remaining patients, re-infarction was diagnosed in retrospect due to elevations in cardiac marker levels, except in one with new Q-waves and three with LBBB.
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Factors influencing 30-day mortality after re-infarction
Compared to a 27% mortality rate with conservative treatment following re-infarction, mortality rates were 20% in patients treated with fibrinolytic therapy and 9% in those who underwent PCI, at < 12 h. The mortality HR for reperfusion therapies (fibrinolytics and/or PCI) compared to conservative treatment was 0.53 (95% CI 0.32–0.88), P = 0.01. Reperfusion therapies were associated with a lower risk when deaths within 12 h of re-infarction were excluded [HR 0.50 (95% CI 0.28–0.90), P = 0.018], but the HR was 0.62 [(95% CI 0.35–1.09), P = 0.10] after adjustment for other predictors of death following re-infarction including age, time to re-infarction, geographic region, and Killip class at randomization.
The effects of PCI and fibrinolytic therapy for re-infarction, compared to conservative therapy, following various modelling analyses are shown in Table 3 and Figure 3. PCI was associated with a lower mortality after adjustment for other factors associated with 30-day mortality, including and excluding region, and in analyses excluding deaths occurring at < 12 h after re-infarction [HR 0.18 (95% CI 0.04–0.76), P = 0.020]. The HR for re-administration of fibrinolytic therapy was 0.96 [(95% CI 0.46–2.00), P = 0.91] and there was a lower HR for 30-day mortality associated with PCI compared to repeat administration of fibrinolytic therapy [HR 0.27 (95% CI 0.08–0.89), P = 0.03].
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Discussion |
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The rate of re-infarction of 3.2% during the initial hospitalization confirmed by the CEC in HERO-2 was similar to the investigator-reported rates of 2–6% in other large trials of fibrinolytic and adjunctive therapies.1–3,6 Although randomization to receive bivalirudin compared to unfractionated heparin was associated with a reduced rate of re-infarction, bivalirudin did not influence mortality following re-infarction. The 2.4-fold increase in 30-day mortality in patients who suffered re-infarction compared to those without re-infarction in HERO-2, was similar to previous reports.4,6,11
Treatment of re-infarction with reperfusion therapy within 12 h of symptoms, compared to conservative therapy, was associated with lower 30-day mortality, which was mainly attributed to performance of PCI. The mortality following re-infarction was lowest in Western countries. When we considered the 74% of patients with further ST-elevation at the time of re-infarction, 60% of these patients in western countries received fibrinolysis and/or PCI within 12 h. This rate of reperfusion treatment of re-infarction was similar to those in both US and non-US centres in ASSENT-2 which were 66 and 65%, respectively.11 Additionally, the GUSTO 1 and ASSENT 2 studies included patients who received PCI or CABG either on the day of re-infarction or the following day.
The CEC adjudication process may have lead to more complete identification of re-infarction compared to previous trials, the rate of 74% recurrent ST-elevation was lower than 91% in the combined GUSTO-1 and ASSENT 2 study.7 In HERO-2, compared with these trials, more patients may have been identified retrospectively as having suffered a re-infarction, and therefore would not have been considered for further reperfusion therapies.
The reasons for the low rates of utilization of reperfusion therapies in non-Western countries may reflect country-specific patterns of medical care. Previous studies have shown significant differences between the care of STEMI patients within countries, as well as between countries and continents.12,13 Although the use of reperfusion therapies following STEMI varies widely, this variation alone has been shown to be insufficient to account for differences in mortality between regions.14 Across the five international geographic regions in the HERO-2 trial, the absolute mortality for patients with and without re-infarction varied, but the relative increase in mortality risk after re-infarction did not. Particularly in Russia, re-infarction was very rarely treated by fibrinolytic re-administration or PCI. In Latin America, although the rate of PCI was similar to Western Countries, the rate of fibrinolytic re-administration for re-infarction was much lower. The overall high rate of conservative treatment for re-infarction reflects the patterns of medical care observed in patients enrolled in HERO-2 in Eastern Europe and Russia, from where approximately 70% of enrollees came.15
Facilitated PCI, which is routine PCI immediately following fibrinolytic therapy, is not supported by data from the ASSENT-4 study,16 and is not recommended outside the setting of ongoing clinical trials. However, the performance of rescue PCI for ‘failed reperfusion’ has increasing support from clinical trials, particularly the Rescue Angioplasty vs. Conservative Therapy (REACT) study, which showed PCI was superior to repeat fibrinolysis or conservative therapy in patients who did not achieve 50% ST-segment resolution at 90 min following fibrinolysis.17 We had hypothesized that patients with re-infarction, and recurrent ST-segment elevation, would benefit from PCI within 12 h, and/or the re-administration of fibrinolytic therapy.18–20
We found that, on multivariable analysis, factors associated with increased 30-day mortality post re-infarction were the lack of reperfusion therapy, shorter time between randomization and re-infarction, increased age in years, geographical region, and worse Killip class on admission. However, while reperfusion therapy was associated with decreased 30-day mortality, after adjusting for several factors including region of recruitment of the patient, and deaths occurring within 12 h of re-infarction only PCI (and not further fibrinolysis) was associated with decreased 30-day mortality.
There are several potential explanations for these findings. The overall rate of reperfusion treatment following the re-infarction was low and our study has insufficient power to determine whether re-administration of fibrinolytics as well as PCI may have lead to differences in mortality. Many patients with re-infarction may have had severe non-culprit coronary artery stenoses and thus may have benefited from revascularization, as well as reperfusion, achieved by successful PCI. PCI may be required together with fibrinolytic and antithrombotic therapies to improve long-term outcomes, as high rates of PCI following fibrinolytic administration, especially in the first 2 h after STEMI symptom onset, are associated with low mortality rates.21 A report from the TIMI group suggests that the influence of rates of PCI on mortality is equally applicable to re-infarction as to the index infarction.6
In the report from the GUSTO I and GUSTO III trials, mortality was increased at 30 days and 1 year in those patients with re-infarction.4 In GUSTO-V, patients with re-infarction within 7 days of the index MI, compared to those without re-infarction, had a markedly higher mortality [HR 3.08 (95% CI 2.53–3.75), P < 0.001],22 and even when those patients who died within the 7 day period for assessment of re-infarction were removed, the excess mortality remained significant [HR 6.65 (95% CI 5.43–8.16), P < 0.001]. However, the TIMI group6 reported that for those suffering re-infarction after fibrinolytic therapies but surviving to discharge, there was no increase in 1 year mortality, compared to patients without re-infarction.
The HERO-2 trial was not powered to identify a significant difference in 30-day mortality between bivalirudin and heparin following re-infarction. Though bivalirudin reduced re-infarction rates, because of the low frequency of re-infarction of 3.2%, evaluation of a potential effect of this therapy on mortality following re-infarction would require a study of tens of thousands of randomized patients. However, due to the prognostic significance of re-infarction, evaluation of the effect of new therapies such as bivalirudin on the composite endpoint of re-infarction and 30-day mortality are of clinical importance.
Limitations
While CEC-adjudicated re-infarction was the major pre-specified secondary endpoint in the HERO-2 trial, and electrocardiograms, cardiac marker profiles, and clinical data were collected prospectively, our study has limitations. The protocol defined times for obtaining cardiac marker levels and electrocardiographs after ischaemic episodes or revascularization procedures, though these data were not invariably available for endpoint adjudication by the CEC. The number of patients who died in the early hours following onset of re-infarction, prior to investigators obtaining either electrocardiographs and/or blood samples for cardiac markers, is unknown. This may have influenced our findings. On the HERO-2 case report form, data on initial fibrinolytic therapy and first PCIs were recorded, but any subsequent use of these treatments was determined from hospital records. Also, six patients who underwent PCI for suspected re-infarction and did not meet the pre-specified criteria of elevated cardiac marker levels for re-infarction (i.e. had ‘aborted’ re-infarction), these have not been included in this analysis and other such patients treated with either PCI or further fibrinolytic therapy may not have been referred to the CEC.
Importantly, as the treatments for re-infarction were not randomized, physician or patient selection of therapies may have affected our findings. However, by excluding all patients who died within 12 h of re-infarction, known as landmark analyses, we aimed to reduce the risk of patients not being treated because they were in extremis and their physician felt they were probably unsalvageable. Such analysis showed treatment of re-infarction with PCI was still associated with a lower risk of death. Finally, the relatively low rate of PCI reported from East European countries and Russia may not reflect current practice.
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Conclusions |
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In the HERO-2 study, 3.2% of patients who underwent fibrinolytic treatment for acute STEMI suffered in-hospital re-infarctions and these patients had approximately 2.5-fold higher 30-day mortality. Most patients with re-infarction had recurrent ST-elevation and the majority of these did not receive reperfusion therapy (with fibrinolytics and/or PCI). The treatment of re-infarction by PCI within 12 h was associated with lower mortality. Because of the prognostic importance of re-infarction, further prospective studies are required to improve therapies, and to enhance the utilization of such therapies.
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Acknowledgements |
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We thank the investigators, co-ordinators, and data centre staff who provided extra data for this study and Charlene Nell and Khaleda Murad for secretarial assistance.
Conflict of interest: H.D.W. has been a consultant for The Medicines Company. J.K.F. has a small research grant from Boehringer Ingelheim. P.A. has had research grants from The Medicines Company and Advisory Board and Speaker fees from CSL Limited.
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This paper was guest edited by Prof. Freek WA Verheugt, University Medical Center Nijmegen, The Netherlands
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