Abstract

Aims

To determine the impact of a strategy using enoxaparin for up to 8 days compared with unfractionated heparin (UFH) for 48 h as an adjunct to fibrinolysis for ST-segment elevation myocardial infarction (STEMI) on 1-year clinical outcomes.

Methods and results

Follow-up at 1 year (n = 20 275) was conducted by telephone in the ExTRACT-TIMI 25 trial to ascertain the endpoints of death, MI, and disabling stroke. The primary endpoint of death or non-fatal MI occurred in 1614 (15.8%) and 1732 (17.0%) of patients allocated to enoxaparin and UFH, respectively [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.86–0.98, P = 0.01]. The enoxaparin strategy significantly reduced non-fatal MI at 1 year (5.7 vs. 6.8%, HR 0.82, 95% CI 0.73–0.92, P < 0.001). The risks of death (10.5 vs. 10.6%, HR 0.98, 95% CI 0.91–1.07) and disabling stroke (1.1 vs. 1.2%, HR 0.97, 95% CI 0.75–1.26) were not reduced. The composite of death, MI, or disabling stroke favoured enoxaparin (HR 0.91, 95% CI 0.85–0.98, P = 0.007).

Conclusion

Compared with UFH for 48 h, a strategy using enoxaparin as an adjunct to fibrinolysis resulted in a sustained reduction in death or MI at 1 year with no additional benefit after 30 days. Mortality was not reduced at 1 year with the enoxaparin strategy.

The study was registered at ClinicalTrials.gov, NCT00077792.

See page 2077 for the editorial comment on this article (doi:10.1093/eurheartj/ehq173)

Introduction

Economic and logistic considerations remain a barrier to universal access to timely primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).1–3 A pharmacological strategy employing a fibrinolytic along with adjunctive anti-thrombin and anti-platelet therapies remains the most common approach worldwide to reperfusion therapy. Therefore, improvements to pharmacological reperfusion strategies are of substantial importance to public health. Enhancements to adjunctive anti-thrombin and anti-platelet therapies have improved the short-term outcomes of patients with STEMI undergoing fibrinolysis.4,5 We have shown that a strategy using enoxaparin for up to 8 days in fibrinolytic-treated patients with STEMI significantly reduced the risk of death or MI at 30 days compared with unfractionated heparin (UFH) administered for 48 h according to contemporary guidelines.6 An increased risk of bleeding associated with the enoxaparin strategy was offset by the reduction in fatal and non-fatal ischaemic events for a 14–18% improvement in net clinical outcome.6 The long-term impact of the enoxaparin strategy, including improved vessel patency and reduced early recurrent MI with a concurrent increase in bleeding, has not been evaluated previously in trials of sufficient sample size to detect small effects on mortality.

The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-Thrombolysis in Myocardial Infarction (TIMI) 25 Trial was a multinational, multicentre, randomized, double-blind, double-dummy, parallel-group trial of a strategy using enoxaparin compared with UFH in 20 479 patients with STEMI with planned fibrinolysis with either streptokinase, tenecteplase, alteplase, or reteplase.6 We investigated the long-term efficacy of the enoxaparin vs. UFH strategies in this large randomized trial with follow-up to 1 year.

Methods

Patient population

The design and primary 30-day results of the ExTRACT-TIMI 25 trial have been reported previously.6,7 Patients aged at least 18 years presenting with STEMI within 6 h of symptom onset were eligible.6 Exclusion criteria included contraindications to fibrinolysis, shock, or known renal insufficiency with a serum creatinine >220 µmol/L (2.5 mg/dL) for men and >175 µmol/L (2.0 mg/dL) for women.6 This study complied with the Declaration of Helsinki. The protocol was approved by the Institutional Review Board or Ethics Committee at each institution, and all patients provided written informed consent.

Study treatments

Study participants were to be treated with aspirin and a fibrinolytic in accordance with the approved label for the treatment of STEMI. Patients were randomized 1:1 to a strategy of either UFH or enoxaparin. UFH (or matching placebo) was to be administered according to the American Heart Association/American College of Cardiology guidelines for a minimum of 48 h and adjusted to the activated partial thromboplastin time.8 Enoxaparin (or matching placebo) was administered in a weight-based regimen according to the patient's age and renal function6 until completion of successful coronary revascularization, hospital discharge or for a maximum of 8 days (whichever came first).

Endpoints

All subjects were to be contacted by telephone at 6 months and 1 year after randomization for the ascertainment of the following events: death from any cause, recurrent MI, and stroke, which were also classified as disabling or non-disabling. Since the pharmacological effect of both of the randomized anticoagulant strategies dissipates completely before 30 days, data on bleeding were not collected after this time point. The primary endpoint for the 1-year analysis was death or non-fatal recurrent MI as defined previously.7 In addition, net clinical benefit at 1-year was defined by the protocol as death, non-fatal MI, or non-fatal disabling stroke. Endpoint events after 30 days were analysed as reported by the investigator without adjudication by a central Clinical Events Committee.

Statistical methods

Baseline clinical characteristics were reported using the median and 25th and 75th percentiles for continuous variables and proportions for categorical characteristics. All analyses of efficacy were conducted using the intent-to-treat principle. The cumulative incidence of the primary endpoint, death, MI, or disabling stroke, and the individual elements were described using the Kaplan–Meier failure estimates and compared between treatment groups using the log-rank test. Hazard ratios were calculated using a Cox proportional hazard model and tests to confirm the assumption of proportional hazards performed. Tests for interaction among subgroups of clinical interest were conducted using terms for the main effects and interaction in the Cox model. Patients with missing 1-year data were analysed to the extent of available follow-up and censored at the point of last study contact. P-values (two-tailed) <0.05 were considered to indicate statistical significance.

The investigators had free and complete access to the data. The raw database was provided to the TIMI Study Group and all analyses reported in this manuscript were carried out independently by the TIMI Study Group, whose members wrote this report and take responsibility for the data. All analyses were performed using STATA/SE 9.2 (STATA Corp, College Station, TX, USA).

Results

Patients

The baseline characteristics of the study population have been described previously and were well balanced between the randomized treatment groups.6 The median age of participants was 59 years, and 23% of participants were women. A history of diabetes mellitus was present in 15%, prior MI in 13%, and heart failure at presentation in 11% of subjects. Overall, 23% underwent percutaneous revascularization and 3% underwent coronary artery bypass grafting as part of management of the qualifying MI. Revascularization during the index hospitalization was more frequent among patients randomized to UFH (15.9 vs. 14.3%, P = 0.001). Follow-up through 1 year was available for 99.0% of the intention-to-treat cohort (enoxaparin, n = 10 153; UFH, n = 10 122).

Efficacy of the enoxaparin strategy at 1 year

The primary endpoint of death or non-fatal recurrent MI at 1 year occurred in 1614 patients allocated to the enoxaparin strategy compared with 1732 patients allocated to the UFH strategy [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.86–0.98, P = 0.01; Figure 1]. The effect of the enoxaparin strategy on death or MI at 1 year was homogenous across subgroups of clinical interest (Figure 2). In particular, there was no statistical evidence of heterogeneity among elderly patients for whom the early absolute rates of major bleeding are higher compared with younger patients.

Figure 1

Cumulative incidence of death or non-fatal myocardial infarction in patients randomized to the enoxaparin vs. the unfractionated heparin strategy. The P-value was determined using the log-rank test. The dashed vertical line indicates the comparison at Day 30, at which time, a reduction in the primary endpoint in favour of the enoxaparin strategy was seen (relative risk 0.81, 95% confidence interval 0.75–0.87). HR, hazard ratio.

Figure 1

Cumulative incidence of death or non-fatal myocardial infarction in patients randomized to the enoxaparin vs. the unfractionated heparin strategy. The P-value was determined using the log-rank test. The dashed vertical line indicates the comparison at Day 30, at which time, a reduction in the primary endpoint in favour of the enoxaparin strategy was seen (relative risk 0.81, 95% confidence interval 0.75–0.87). HR, hazard ratio.

Figure 2

Relative hazard rates and absolute event rates for the primary endpoint at 1 year in various subgroups. The primary endpoint was the composite of death from any cause or non-fatal recurrent myocardial infarction. The overall treatment effect of the enoxaparin strategy when compared with unfractionated heparin is shown by the diamond (whose left and right edges represent the 95% confidence interval). For each subgroup, the square represents the point estimate of the treatment effect and the horizontal lines represent the 95% confidence intervals. Fibrin-specific fibrinolytic agents included alteplase, tenecteplase, and reteplase. Time to treatment indicates the time from the onset of symptoms to the administration of study drug (median, 3.2 h). P-values for testing for interaction were as follows: sex (P = 0.24), age (P = 0.32), infarct location (P = 0.57), diabetes mellitus (P = 0.32), prior myocardial infarction (P = 0.38), fibrinolytic (P = 0.95), and time to treatment (P = 0.02).

Figure 2

Relative hazard rates and absolute event rates for the primary endpoint at 1 year in various subgroups. The primary endpoint was the composite of death from any cause or non-fatal recurrent myocardial infarction. The overall treatment effect of the enoxaparin strategy when compared with unfractionated heparin is shown by the diamond (whose left and right edges represent the 95% confidence interval). For each subgroup, the square represents the point estimate of the treatment effect and the horizontal lines represent the 95% confidence intervals. Fibrin-specific fibrinolytic agents included alteplase, tenecteplase, and reteplase. Time to treatment indicates the time from the onset of symptoms to the administration of study drug (median, 3.2 h). P-values for testing for interaction were as follows: sex (P = 0.24), age (P = 0.32), infarct location (P = 0.57), diabetes mellitus (P = 0.32), prior myocardial infarction (P = 0.38), fibrinolytic (P = 0.95), and time to treatment (P = 0.02).

Examination of the individual elements of the primary composite endpoint reveals that the effect of the enoxaparin strategy was mediated by a significant 18% reduction in the risk of recurrent MI with no difference in mortality between the treatment groups at 1 year (Figure 3). The composite of death, MI, or disabling stroke also favoured the enoxaparin strategy (HR 0.91, 95% CI 0.85–0.98, P = 0.007; Table 1).

Table 1

Efficacy outcomes at 1-year with the enoxaparin vs. unfractionated heparin strategy

 Enoxaparin strategy (n = 10 256) UFH strategy (n = 10 223) HR (95% CI) P-value 
Lost to follow-up 75 (0.7) 72 (0.7) — — 

 
Death or non-fatal MI 1614 (15.8) 1732 (17.0) 0.92 (0.86–0.98) 0.01 
 Death 1075 (10.5) 1085 (10.6) 0.98 (0.91–1.07) 0.72 
 Non-fatal MI 539 (5.7) 647 (6.8) 0.82 (0.73–0.92)) <0.001 

 
Death, non-fatal MI, or disabling stroke 1638 (16.0) 1765 (17.3) 0.91 (0.85–0.98) 0.007 
 Disabling stroke 112 (1.1) 115 (1.2) 0.98 (0.75–1.26) 0.81 
 Enoxaparin strategy (n = 10 256) UFH strategy (n = 10 223) HR (95% CI) P-value 
Lost to follow-up 75 (0.7) 72 (0.7) — — 

 
Death or non-fatal MI 1614 (15.8) 1732 (17.0) 0.92 (0.86–0.98) 0.01 
 Death 1075 (10.5) 1085 (10.6) 0.98 (0.91–1.07) 0.72 
 Non-fatal MI 539 (5.7) 647 (6.8) 0.82 (0.73–0.92)) <0.001 

 
Death, non-fatal MI, or disabling stroke 1638 (16.0) 1765 (17.3) 0.91 (0.85–0.98) 0.007 
 Disabling stroke 112 (1.1) 115 (1.2) 0.98 (0.75–1.26) 0.81 

Event rates presented are the cumulative incidence at 1 year using the Kaplan–Meier method. MI, myocardial infarction.

Figure 3

Cumulative incidence of individual elements of the primary endpoints, death (left) and non-fatal myocardial infarction (right), in patients randomized to the enoxaparin vs. the unfractionated heparin strategy. The P-values were determined using the log-rank test. HR, hazard ratio.

Figure 3

Cumulative incidence of individual elements of the primary endpoints, death (left) and non-fatal myocardial infarction (right), in patients randomized to the enoxaparin vs. the unfractionated heparin strategy. The P-values were determined using the log-rank test. HR, hazard ratio.

Landmark analysis from 30 days to 1 year revealed that the reduction in death and MI was accrued during the first 30 days, with no additional reduction after 1 month. Specifically, after adjusting for revascularization prior to 30 days, neither death (HR 1.13, 95% CI 0.95–1.31) nor MI (HR 1.12, 95% CI 0.95–1.13) from 30 days to 1 year was reduced with the enoxaparin strategy.

Discussion

A strategy using enoxaparin reduced the incidence of death or recurrent MI and death, MI, or disabling stroke by 30 days, and provided a sustained and significant benefit through 1 year of follow-up among 20 479 patients receiving fibrinolysis for STEMI. This long-term benefit was mediated by the early robust reduction in recurrent MI. There was no additional reduction in MI after 30 days or reduction in mortality through 1 year.

A strategy using enoxaparin to support fibrinolysis in ST-elevation myocardial infarction

Fibrinolysis is associated with the release of fibrin monomers and activation of platelets that together create a prothrombotic milieu manifest by a substantial risk of early reinfarction among patients undergoing pharmacological reperfusion therapy. Compared with placebo, adjunctive therapy with an anti-thrombin significantly reduces the risk of recurrent MI and improves survival in patients receiving fibrin-specific and non-specific fibrinolytic agents.9,10 Compared with UFH, low molecular weight heparins offer more predictable anticoagulant effects, greater proximal inhibition of the coagulation cascade, and convenient subcutaneous administration.11 When studied against active control, enoxaparin improves short-term outcomes principally by reducing the risk of early re-occlusion. The results of angiographic studies in STEMI show that enoxaparin, like other low molecular weight heparins, enhances late patency of the infarct-related artery without a demonstrable effect on early reperfusion.12,13 As shown in pooled data from six randomized, controlled trials of an enoxaparin vs. UFH strategy, this effect on re-occlusion translates into a 25% (95% CI 14–35%) reduction in recurrent MI by 30 days.4 In addition, the enoxaparin strategy is associated with significant reductions in recurrent ischaemia requiring urgent revascularization and ischaemic stroke by 30 days.6 This reduction in fatal and non-fatal ischaemic events is only partially offset by an increased risk of bleeding such that net clinical benefit at 30 days favours the enoxaparin strategy over standard practice using UFH.6 The reduction in recurrent ischaemic events and stroke with the enoxaparin strategy may result both from the extended duration of administration compared with the contemporary use of UFH and from the favourable pharmacodynamic properties of low molecular weight heparins.6

Despite this significant reduction in early recurrent ischaemia and infarction, there was no detectable reduction in 1-year mortality in this largest randomized trial of enoxaparin performed to date. This finding is at odds with previous evidence for the strong relationship between recurrent MI and convalescent left ventricular function, and the latter with survival, as well as observational data linking recurrent MI to long-term mortality.14 Of note, however, the absence of a significant effect on survival is consistent with other trials of enoxaparin in STEMI,15 and with the absence of an improvement in survival with abciximab in patients with STEMI, despite their associated reduction in recurrent MI.16

Several explanations for this finding are possible. First, revascularization prompted by non-fatal recurrent ischaemia, occurring more frequently in the UFH group, may offset the benefit of reducing early recurrent ischaemia with the enoxaparin strategy. Secondly, with the anticoagulant strategy limited to the acute hospitalization, a convergence of outcomes with similar long-term therapy is plausible, especially with progressive enhancement of secondary preventive therapy, including angiography and revascularization after fibrinolysis. To this point, we have found previously that recurrent MI is associated with higher early, but not with higher late, mortality and that the relationship with mortality is attenuated by PCI.14 Moreover, in the present study, we found that there was no additional benefit of the enoxaparin strategy after 30 days. Thirdly, the absolute magnitude of the reduction in recurrent MI in ExTRACT-TIMI 25 was insufficient to translate into a measurable impact in survival over the duration of observation. Indeed, within the ExTRACT-TIMI 25 trial, we have shown that recurrent MI was independently associated with increased mortality risk.17 Nevertheless, based upon an estimated 10% absolute increase in mortality with recurrent MI,14 a 1% absolute reduction in recurrent MI would be expected to translate into a 0.1% lower mortality. It is unknown that if data regarding functional status, quality of life, or heart failure had been collected, they would have revealed an additional 1-year benefit of reducing recurrent ischaemic events with the enoxaparin strategy.

Fourthly, the possibility should be considered that long-term adverse consequences of bleeding may offset benefits related to a reduction in MI. Observational data have demonstrated an association between bleeding and higher mortality.18 However, the relationship is complex given the myriad of clinical characteristics associated with both bleeding and a higher mortality rate, and a causal relationship is not certain.19 We have found that intracranial haemorrhage (ICH) in this population was strongly associated with subsequent mortality. However, non-intracranial major bleeding and minor bleeding were not independently associated with late death after accounting for the influence of intervening procedures and clinical events, in particular the onset of cardiogenic shock, before a bleeding event.17 Because ICH did not differ between the enoxaparin and UHF strategies,6 it appears less likely that bleeding had a major influence on the 1-year mortality comparison in this trial. Nevertheless, we cannot exclude the possibility that the higher early rate of bleeding may have had an impact on the 1-year clinical outcome.

Clinical and research implications

In light of its early superiority and overall sustained benefit, a strategy using enoxaparin for up to 8 days is preferable to that of UFH for 48 h according to standard practice to support fibrinolysis for STEMI. Fondaparinux is an additional alternative to UFH that in patients with STEMI is associated with rates of severe and major bleeding that are similar to, rather than increased, compared with UFH. Because of the potential benefit of more prolonged anticoagulant therapy in patients receiving fibrinolytics, it has been recommended that anticoagulant therapy, with enoxaparin or fondaparinux, be administered for the duration of hospitalization (up to 8 days) after fibrinolysis for STEMI.20 Despite the early benefit of more potent and predictable anticoagulant therapy, the high mortality and the absence of a survival benefit at 1 year in ExTRACT-TIMI 25 identify a need for continued improvement in the acute and chronic management of patients with STEMI treated with pharmacological reperfusion therapy, as well as continued investigation of the tradeoffs between antithrombotic ischaemic efficacy and bleeding.

Primary PCI provides superior survival to fibrinolysis when it is offered rapidly in experienced centres.21 In addition, the use of bivalirudin to support PCI has shown diminished bleeding and improved mortality.22 However, the economic and logistic barriers to provision of universal, round-the-clock access to primary PCI are likely prohibitive in the majority of centres worldwide. Thus, the strategy of administering an optimal pharmacological reperfusion strategy is desirable in hospitals that cannot offer primary PCI or rapid transfer to a PCI facility. Data from several small trials suggest that a strategy of fibrinolysis followed by routine transfer for delayed coronary angiography may provide the optimal outcomes for patients presenting to non-invasive centres.23 Our results indicate that an early substantial reduction in recurrent MI can be achieved with a strategy using enoxaparin but leave room for improvement with respect to long-term survival. It is possible that this objective may be achieved by following enhanced fibrinolysis and sustained early patency with enoxaparin with subsequent coronary angiography and revascularization. Current guidelines from the European Society of Cardiology support consideration of routine angiography at 24 h in patients who have had successful fibrinolysis.24 Such a pharmacoinvasive strategy has the potential to preserve myocardium by providing timely reperfusion of the infarct-related artery, to reduce the risk of early reinfarction with superior antithrombotic therapy such as with the enoxaparin strategy and the use of clopidogrel, and to mitigate the risk of reinfarction over the longer term through routine delayed angiography and intervention when indicated. Therefore, we believe that a strategy of routine invasive evaluation may maximize the continuation of the early benefit achieved with the enoxaparin strategy. Although supported by emerging data,23 randomized trials testing such a strategy in conjunction with optimal pharmacological reperfusion regimens are needed.

Alternatively, additional enhancements to medical therapy may be possible. Extended anticoagulation with warfarin after MI sustains patency of the infarct-related artery and improves clinical outcomes but increases bleeding and requires cumbersome monitoring.25,26 The emergence of new oral anticoagulants, such as oral inhibitors of factor Xa and direct thrombin inhibitors, may overcome these limitations and are being investigated in patients after STEMI.27,28

Conclusion

Compared with UFH, a strategy using enoxaparin as an adjunct to fibrinolysis resulted in a significant and sustained reduction in death or MI at 1 year that was driven by a robust early reduction in recurrent MI. On the basis of early superiority with a durable treatment benefit, an anti-thrombin strategy using enoxaparin is preferable to one using UFH for patients undergoing pharmacological reperfusion therapy. The early reduction in MI with the enoxaparin strategy did not translate into a reduction in long-term mortality.

Funding

ExTRACT-TIMI 25 was funded by sanofi-aventis, Bridgewater, NJ, USA.

Conflict of interest: The TIMI Study Group has received significant research grant support from Accumetrics, Amgen, AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol–Myers Squibb, CV Therapeutics, Daiichi Sankyo Ltd, Eli Lilly and Co, GlaxoSmithKline, Integrated Therapeutics, Merck and Company, Millennium Pharmaceuticals, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, sanofi-aventis, Sanofi-Synthelabo, and Schering-Plough. D.A.M. has received honoraria for educational presentations from Eli Lilly and sanofi-aventis. He has served as a consultant for AstraZeneca, CV Therapeutics, GlaxoSmithKline, sanofi-aventis, Schering-Plough, and Genentech. K.A.A.F. has received grant support from sanofi-aventis, Bristol–Myers Squibb, and GlaxoSmithKline and honoraria for speaking from sanofi-aventis, and GlaxoSmithKline. H.D.W. has received research grant support from and has served as an advisor to sanofi-aventis. S.A.M. and C.H.M. have no additional relationships to report. E.M.A. and E.B. have received honoraria for educational presentations and have served as consultants to sanofi-aventis.

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