backing up its use in comparison to placebo [3,4]. However, multiple trials have assessed UFH in comparison to other anticoagulants with now several thousands of patients treated with UFH in randomized clinical trials [80–86]. The ESC guidelines recommend routine use of heparin as a class I recommendation [3]. Similarly, the current ACC/AHA guidelines recommend UFH with a class I recommendation, with additional boluses as necessary to maintain therapeutic activated clotting time (ACT) levels [4]. Apart from specific situations (e.g. left ventricular thrombus) there is no evidence for long term anticoagulation following successful PCI.
Bivalirudin
Bivalirudin has fallen in, and subsequently out on favor over the years, based on the contemporary trials of the time. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS‐AMI) trial was published in 2008 [85], with 3602 patients with acute STEMI being randomized to heparin plus a GP IIb/IIIa inhibitor (which was notably used in over 90% of patients who presented with STEMI at the time of the trial [87]) or bivalirudin alone. Primary endpoints were major bleeding as well as death, reinfarction, target‐vessel revascularization for ischemia and stroke, within 30 days. Anticoagulation with bivalirudin alone, as compared with heparin plus GP IIb/IIIa inhibitors, resulted in a reduced 30‐day rate of net adverse clinical events (9.2% vs 12.1%; RR 0.76, 95% CI 0.63–0.92; P = 0.005), driven by a lower rate of major bleeding (4.9% vs 8.3%; RR 0.60; 95% CI 0.46–0.77; P<0.001), but with an increased risk of stent thrombosis within the first 24 h, which did not remain significant at 30 days. These results were sustained at three years [83], and appear not just to be related to reduced bleeding [84]. The European Ambulance Acute Coronary Syndrome Angiography trial (EUROMAX) [86], attempted to assess whether these findings were still valid when bivalirudin was started in the pre‐hospital setting, and with frequent use of radial access and novel P2Y12 inhibitors. In total, 2218 patients with acute STEMI were randomized to receive either bivalirudin or heparins (either UFH or LMWH) with optional GP IIb/IIIa inhibitors. The primary outcome at 30 days was a composite of death, or non‐CABG major bleeding. Bivalirudin reduced the risk of the primary outcome (5.1% vs 8.5%, RR 0.60, 95% CI 0.43–0.82; p = 0.001) and the risk of major bleeding (2.6% vs 6.0%, RR 0.43; 95% CI 0.28–0.66; p<0.001) but was associated with an increased risk of acute stent thrombosis (1.1% vs 0.2%, RR 6.11; 95% CI 1.37–27.24; p = 0.007).
In the contemporary era of 2nd generation DES, the How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention trial (HEAT‐PPCI) [88], randomized 1829 patients scheduled for angiography in the context of primary PCI to either heparin or bivalirudin, here without a prolonged PCI‐dose bivalirudin infusion post procedure, in keeping with the licensed recommendation at trial initiation. The primary efficacy outcome, a composite of all‐cause mortality, CVA, reinfarction, or unplanned TLR, occurred in 8.7% of patients in the bivalirudin group vs 5.7% of patients in the heparin group (RR 1.52, 95% CI 1.09–2.13, p = 0.01), with the primary safety outcome, BARC 3–5 major bleeding, occurring in 3.5% of patients in the bivalirudin group and 3.1% of patients in the heparin group (RR 1.15, 95% CI 0.70–1.89, p = 0.59). The superiority of heparin in terms of the primary efficacy outcome was principally driven by a reduced incidence of acute stent thrombosis. This study is noteworthy in that it achieved near 100% recruitment in all eligible patients.
The Bivalirudin in Acute Myocardial Infarction vs Heparin and GPI Plus Heparin Trial (BRIGHT) [89] which randomized 2194 emergency PCI patients to bivalirudin with a post PCI high‐dose infusion, heparin, or heparin and tirofiban, showed however no difference in 30 day and one year incidences of stent thrombosis (0.6% vs 0.9% vs 0.7% respectively, p = 0.77) and an overall decrease in net clinical adverse events (death, reinfarction, ischemia‐driven target vessel revascularization, stroke) or bleeding, driven by a reduction in bleeding events with bivalirudin. However, this multicenter study took place in China, and clopidogrel was used entirely as a P2Y12 inhibitor, given the lack of availability of prasugrel and ticagrelor at the time of the study. The Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 study [80], randomized STEMI patients with a planned primary PCI strategy to prasugrel and bivalirudin or clopidogrel and heparin, and did not show significant differences in net clinical outcome, but this must be interpreted in light of the fact that the trial was stopped early owing to slow recruitment.
In order to clarify this conflicting data, the Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) Antithrombin/Treatment duration nested trials [90], looked at a population of 7213 ACS (STEMI and non‐STEMI) patients randomized to either heparin or bivalirudin, and then subsequently randomized those in the bivalirudin group to receive or not to receive a post‐PCI bivalirudin infusion. Overall, the rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin and the post‐PCI bivalirudin infusion did not significantly decrease the rate of urgent target‐vessel revascularization, definite stent thrombosis or net adverse clinical events.
The Bivalirudin versus Heparin in ST‐Segment and Non‐ST‐segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence‐based Care in Heart Disease Evaluated according to Recommended Therapies Registry Trial (VALIDATE‐SWEDEHEART) [81], enrolled 3005 STEMI patients (amongst a larger cohort also including NSTEMI patients) treated with ticagrelor, prasugrel and cangrelor, without the planned use of glycoprotein IIb/IIIa inhibitors, who were randomly assigned to receive either bivalirudin or heparin during PCI, performed predominantly via the radial approach. There was no difference in the primary endpoint of death from any cause, MI, or major bleeding during the 180 days of follow up, in the STEMI sub‐group and in the study cohort overall. It should be noted that a total of 62% of patients received potent P2Y12 inhibitors at least 1 h before PCI, and 65% of patients received a prolonged infusion of high dose bivalirudin.
On the basis of the currently available evidence, ESC guidelines recommend consideration be given to use of bivalirudin, (Class IIa recommendation), particularly in those patients at high bleeding risk [3], AHA guidelines recommend bivalirudin as a class I recommendation [4].
Enoxaparin i.v.
The ATOLL trial randomly assigned 910 patients undergoing primary PCI for STEMI to either 0.5 mg/kg enoxaparin IV or unfractionated heparin (UFH), and looked at a primary endpoint at 30 days of death, complication of MI, procedure failure or haemorrhage [91]. It revealed a relative risk of 0.83 (95% CI 0.68–1.01; p = 0.06) for the primary endpoint for enoxaparin compared to UFH. A subsequent meta‐analysis [92], looked at 23 studies (observational and randomized) comparing enoxaparin vs UFH, including 10,243 (33.1%) patients presenting with STEMI. In those patients who underwent primary PCI, a particularly significant reduction in death was noted with enoxaparin (RR 0.52; 95% CI 0.42–0.64; P<0.0001), which was also associated with a reduction in major bleeding (RR 0.73; 95% CI 0.56–0.93; P = 0.01).
On the basis of these findings, enoxaparin has a class IIa recommendation in the ESC STEMI guidelines [3]. A specific recommendation is not made in the AHA guidelines [4].
Fondaparinux
On the basis of the Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS 6) trial [93], which assessed the efficacy of fondaparinux in STEMI patients (treated with and without primary PCI) and which showed that there were higher rates of periprocedural complications in the PCI arm, due principally to guiding catheter thrombus, fondaparinux is not recommend as a sole anticoagulant for primary PCI [3,4].
Rescue PCI
For those patients presenting to remote areas, from which it will not be possible to successfully transfer the patient to a primary PCI center within 120 mins, fibrinolysis should be considered [3,4]. The evidence base for fibrinolysis is impressive [94], but overall inferior to expedient PCI performed in an experienced center [1,2]. While previously there was some debate as to the appropriate timing of PCI following fibrinolysis, with early clinical trials revealing immediate PCI following full‐dose fibrinolysis (facilitated PCI) to be associated with poor clinical outcomes [95–97], current