Introduction

Although the historical agent, unfractionated heparin (UFH), has never been evaluated against placebo in a randomized controlled trial, the use of an anticoagulant in patients with ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) is a high-level class I recommendation in the latest European guidelines . Although the best anticoagulant option for primary PCI – among UFH, enoxaparin and bivalirudin – has been the subject of numerous recent open-label studies and meta-analyses , it remains a matter of debate. Enoxaparin has been compared with UFH in one randomized trial , and large meta-analyses have suggested its superiority over UFH for ischaemic and haemorrhagic endpoints as well as mortality . Bivalirudin has been tested against high-dose (100 IU/kg) UFH – alone or in combination with glycoprotein IIb/IIIa receptor inhibitors (GPIs) – in three large studies , and consistently showed reduced rates of major bleeding at the cost of higher rates of acute stent thrombosis in two studies , resulting in a neutral effect on major adverse cardiovascular events (MACE) and mortality in all but one study . Recently, a single-centre trial compared low-dose UFH (70 IU/kg) to bivalirudin with provisional and balanced use of GPIs in both groups and a high rate of radial access . This trial found lower rates of MACE and major bleeding with UFH while also highlighting an increased risk of stent thrombosis with bivalirudin . Moreover, only one study has specifically included patients in the prehospital setting .

In the context of these conflicting results, the present study aimed to compare the in-hospital outcomes after prehospital administration of low-dose UFH or enoxaparin (both with optional use of GPIs) and bivalirudin in patients undergoing primary PCI for STEMI.

Methods

This retrospective observational study used data from the Brittany regional infarction observatory (Observatoire régional breton sur l’infarctus [ORBI]), which has previously been described . Briefly, ORBI prospectively includes all patients admitted to one of nine interventional cardiology centres ( Supplementary data, Text S1 ) in Brittany for STEMI (final diagnosis) within 24 hours of symptom onset. The centralized database used for the present study contains demographic and electrocardiographic data, treatments, time intervals and in-hospital events. This registry was approved by the Commission Nationale de l’Informatique et des Libertés and the study protocol was approved by the local ethics committee.

Out-of-hospital patients who received an injectable anticoagulant in physician-staffed mobile intensive care units (MICUs), were managed by primary PCI, and for whom complete data about in-hospital major bleeding complications were available were included in the present study. They were divided into three groups according to the anticoagulant received in the prehospital setting: UFH, enoxaparin (a low-molecular-weight heparin) or bivalirudin (a direct thrombin inhibitor).

The main efficacy outcome of the present study was in-hospital MACE, defined as a composite of all-cause mortality, non-fatal myocardial infarction, stroke, and definite stent thrombosis according to the Academic Research Consortium definition . The main safety outcome was in-hospital major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) definition . Other outcomes were in-hospital net adverse clinical events (NACE), defined as a composite of MACE and major bleeding.

Patients were managed according to participating centres’ local protocols, which recommended the use of a loading dose of aspirin (250–500 mg intravenously) and a P2Y ₁₂ receptor antagonist (clopidogrel 300–600 mg, prasugrel 60 mg or ticagrelor 180 mg) together with an intravenous bolus dose, as soon as possible in the MICU, of UFH (either 50 IU/kg with a GPI or 70 IU/kg without a GPI) or enoxaparin 0.5 mg/kg or bivalirudin 0.75 mg/kg (followed by a 1.4–1.75 mg/kg/h infusion for 4 hours after primary PCI).

High-degree atrioventricular block was defined as third- or second-degree type 2 atrioventricular blocks. Acute heart failure was defined as a Killip class > I at any time during the management of the patient. First medical contact was defined according to the 2008 European Society of Cardiology STEMI guidelines . Total ischaemic time was defined as the time between symptom onset and balloon inflation or aspiration thrombectomy.

Coronary angiography and primary PCI were performed according to each institution’s guidelines and standards, and data were stored on hard disks and analysed off-line by site operators.

Data are summarized as number (percentage) for categorical variables. Quantitative variables are expressed as median (interquartile range). As appropriate, qualitative data were compared using Chi ² test or Fisher’s exact test; quantitative data were compared using unpaired t test, Kruskal–Wallis test or Mann–Whitney U test. To evaluate the impact of the prehospital anticoagulant used on in-hospital outcomes, the percentages of patients who reached the main outcomes were compared using Chi ² tests or Fisher’s exact tests. Multivariable logistic regression analysis was performed to take into account potentially confounding variables. For both in-hospital MACE and major bleeding, two multivariable models were constructed:

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  an “adjustment model”, including all potential baseline confounders (on the basis of a significance level of 0.05 in univariate analysis) between groups to assess the independent relation between prehospital anticoagulant and outcomes;

  
  
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  a “predictors” model’, including all variables significantly associated with the outcomes at a significance level of 0.05 in univariate analysis to identify independent predictors of MACE and major bleeding.

Variables were removed in a stepwise selection process on the basis of a significance level of 0.10. To further assess the impact of GPI use, in a subsequent analysis, an interaction term between the prehospital anticoagulant used and GPI administration was introduced in the “predictors” models’. In case of interaction, outcomes were compared according to GPI administration. All probability values reported are two-sided. Statistical analysis was performed with the use of Statistical Package for Social Sciences, version 21 (SPSS, IBM, Chicago, IL).

Results

From June 2006 to December 2014, 8400 patients were enrolled in ORBI. Among them, 1720 patients who were treated between January 2009 and December 2014 met the inclusion criteria of the present study: 420 (24.4%) patients received UFH, 1163 (67.6%) received enoxaparin and 137 (8.0%) received bivalirudin ( Fig. 1 ). Main clinical characteristics and time intervals are shown in Table 1 according to the anticoagulant used in the MICU. The median age of the population was 62.0 years and 79.2% were men. All but seven patients who were previously admitted to the emergency department of a non-primary PCI-capable hospital were directly managed by the MICU.

Flow-chart of the study. BARC: bleeding academic research consortium; MICU: mobile intensive care unit; ORBI: Observatoire régional Breton sur l’infarctus ; PCI: percutaneous coronary intervention; UFH: unfractionated heparin.

Treatments and procedural characteristics according to the anticoagulant used in the MICU are listed in Table 2 . Differences in the use of P2Y ₁₂ receptor antagonists reflect both the temporal changes in drug availability over the study period and participating centres’ local standards of care; for example, the bivalirudin group almost exclusively received ticagrelor (93.4%). Most patients (98.5%) included in this study were treated between 2011 and 2014. Over this period, UFH was used in 22.0–28.8% of patients, with no significant difference between years ( P = 0.153). However, enoxaparin use differed significantly, with rates of 71.9% and 75.9% in 2011 and 2012 dropping to 60.1% and 61.1% in 2013 and 2014 ( P < 0.001). All but one patient who received bivalirudin were treated in 2013 and 2014, which represented 15.9% and 17.2% of patients included during these years ( P = 0.639). Anticoagulant switch was strongly discouraged by local protocols, but occurred in 138 patients (8.0%), whose comprehensive data can be found in Supplementary data, Text S2 . Upstream administration of GPIs was infrequent (6.0% of patients), and only occurred in the heparin-based regimen groups. Similarly, GPIs were necessary in bail-out situations for primary PCI failure or suboptimal results in only 36 patients (2.1%) without significant differences between the UFH, enoxaparin and bivalirudin groups: seven patients (1.7%), 27 patients (2.3%) and two patients (1.5%), respectively ( P = 0.758). However, elective administration of GPIs in the catheterization laboratory was used in 707 patients (41.1%), with significant differences between groups: 176 patients (41.9%) in the UFH group, 513 patients (44.1%) in the enoxaparin group and 18 patients (13.1%) in the bivalirudin group ( P < 0.001 overall; P = 0.491 for UFH vs enoxaparin; P < 0.001 for UFH or enoxaparin vs bivalirudin). Two-thirds of patients underwent radial access, which was increasingly used over the study period (from 16.7% in 2010 to 81.7% in 2014; P < 0.001). Similarly, drug-eluting stents were implanted in 4.2% of patients in 2010, rising to 43.0% in 2014 ( P < 0.001). Overall, the rate of angiographic success of primary PCI–as assessed by the presence of a final Thrombolysis in myocardial infarction (TIMI) flow grade 3 in the culprit lesion – was 95.2%, without a significant difference between groups ( P = 0.495), although the pre-primary PCI rate of TIMI flow grade 0 was higher in the bivalirudin group despite extensive use of newer P2Y ₁₂ receptor antagonists in this group ( P = 0.014 for bivalirudin vs UFH; P = 0.019 for bivalirudin vs enoxaparin; P = 0.557 for UFH vs enoxaparin).

Table 2

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