Pre-hospital treatment on the way to percutaneous coronary intervention

Sep 2 2008

For patients with acute ST-segment-elevation AMI (STEMI) within 12 hours after symptom onset and with persistent ST-segment elevation, or new or presumednew left bundle-branch block with concomitant ST-segment elevation, restoring coronary blood flow as early as possible is the main goal of reperfusion strategies.

Because it is sometimes (in about 1/3 of patients presenting with signs of STEMI) difficult to determine exactly the time of onset of infarction, reperfusion therapy should be considered when there are clinical or electrocardiographic signs of ongoing ischaemia even if, according to the individual patient, symptoms started over 12 hours ago. Primary Percutaneous Coronary Intervention (PCI) is the recommended therapy of choice if performed by an experienced team as soon as possible after first medicalcontact. According to recent guidelines, the PCI related delay time should be under two hours in any case and significantly shorter in patients presenting early with an acceptable bleeding risk and with greater non-reperfused areas of myocardium (e.g. anterior wall).

An optimal pre-treatment on the way to primary PCI could thereby help to improve the clinical outcome.

Antiplatelet Agents

Aspirin should be given to all patients with acute STEMI as soon as possible after the diagnosis. Aspirin should be started at a dose of 150-325 mg in a chewable form (enteric-coated aspirin should be avoided. An alternative approach, especially if oral ingestion is not possible, is IV administration of aspirin at a dose of 250 mg. A lower dose (75-160 mg) is orally daily thereafter for life.

(NSAIDs - apart from aspirin - and selective COX-2 inhibitors have been demonstrated to increase the risk of death, reinfarction, cardiac rupture and other complications in STEMI patients. Accordingly, immediate discontinuation of these drugs is indicated at the time of an STEMI).

Clopidogrel is less studied in patients with acute STEMI treated with primary PCI, but there is clear evidence of its usefulness as an adjunctive antiplatelet therapy in patients undergoing PCI from the CREDO, PCI-CURE, and PCI-CLARITY-trials. Although the early, pre-hospital administration of clopidogrel (starting with a loading dose of 600 mg) has only recently being tested in a prospective randomized trial (CIPAMI), the general assumption is that this strategy might be beneficial. In summary, clopidogrel should be given early to all patients with STEMI referred for primary PCI with a 600 mg loading dose, which has been demonstrated to achieve a more rapid and stronger inhibition of platelet aggregation. This should then be followed by a daily dose of 75 mg for up to one year.

Most of the studies on the role of GPIIb/IIIa antagonists in STEMI have focused on abciximab rather than on the lower molecular weight agents: tirofiban and eptifibatide. Several randomized trials have assessed the value of periprocedural administration of intravenous abciximab in this setting. A systematic review of these trials showed that abciximab reduced 30-day mortality by 32% without affecting the risk of haemorrhagic stroke and major bleeding. The mechanism of benefit with abciximab is thought to be the improvement of microcirculation.Although smaller studies - meta-analyses and registries - reported a benefit of early, pre-hospital administration of abciximab with respect to clinical outcome, the only prospective randomized trial (FINESSE) showed that abciximab did not have a significant impact on the patency of infarct-related arteries. The upstream administration of a planned PCI procedure did not offer advantages compared to the administration in the cath lab (see below). Accordingly, the pre-hospital use of abciximab cannot be recommended at present. Abciximab is given intravenously as a bolus of 0.25 mg/kg bolus, 0.125 ìg/kg per minute infusion (maximum 10 ìg/min for 12 hours).

Antithrombins

Unfractionated heparin (UFH) is the standard antithrombotic therapy during PCI in STEMI. Unfractionated heparin is given as an intravenous bolus at a usual starting dose of 100 U/kg weight (60 U/kg if GPIIb/IIIa antagonists are used). Low-molecular weight heparins have not specifically been evaluated in conjunction with primary PCI in STEMI patients. An ongoing trial investigates the role of 0.5 U enoxaparin/kg body weight in comparison with UFH (ATOLL). Thus, there is at present no direct evidence to support their use instead of UFH in this setting. Accordingly, a pre-treatment with UFH (with 60 U/kg to enable the later use of abciximab during PCI) on the way to the cath lab, as frequently performed, would not complicate the procedure and potentially add benefit, although this has not been proven prospectively.

Bivalirudin, a direct thrombin inhibitor, has been investigated intensively as adjunct antithrombotic therapy in patients undergoing PCI. In the HORIZONS-AMI trial, 3,602 patients undergoing PCI were randomly assigned to receive either bivalirudin with provisional use of GP IIb/IIIa inhibitor or heparin (or enoxaparin) as well as a GP IIb/IIIa inhibitor. At the primary combined endpoint of 30 days, major adverse cardiac events or major bleeding was significantly reduced by bivalirudin with a 40% reduction in major bleeding, while the composite ischemic endpoint was similar in both groups. Bivalirudin is given as an intravenous bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hr and usually terminated at the end of the procedure. The early use of bivalirudin (either pre-hospital or in the emergency room in the organization phase for the cath lab) is still not investigated and therefore not recommended at present.

(Fondaparinux, a factor Xa inhibitor, has been compared with heparin or placebo in 12,092 STEMI patients treated with fibrinolytic agents or primary PCI or no reperfusion therapy. In the PCI subset, fondaparinux was associated with anon-significant 1 % higher incidence of death or recurrent AMI at 30 days and a higher catheter thrombois rate. It is not receommende for primary pCI neither during the catheter procedure nor before).

Facilitated PCI

Facilitated PCI is defined as a pharmacologic reperfusion treatment delivered prior to a planned PCI, in order to bridge the PCI-related time delay and to increase the quality of thrombolysis in myocardial infarction (TIMI) flow in the diagnostic angiogram of the infarct related artery before intervention.

Full-dose lytic therapy, half dose lytic therapy with a GPIIb/IIIa inhibitor and GPIIb/IIIa inhibitors alone have been tested for this indication. No evidence of a benefit with either of these agent could be demonstrated in the ASSENT-IV PCI trial (with TNK-tPA), in the meta-analysis of Keeley et al. (with GP IIb/IIIa-antagonsits), and in the FINESSE trial (with abciximab or a combination of half-dose lytic and full-dose abcicimab).In spite of the fact that pre-PCI patency rates were higher with lytic based treatments no mortality benefit but more bleeding complications were observed. The pre-PCI patency rates with upfront GPIIb/IIIa antagonist alone were not higher than with placebo and there was also a trend towards more bleeding. Accordingly, facilitated PCI as it has been tested in the trials cannot be recommended.