Pre PCI hospital antithrombotic therapy for ST elevation : striving for consensus

S. Michael Gharacholou, Brenda J. Larson, Christian C. Zuver, Ryan J. Wubben, Giorgio Gimelli & Amish N. Raval

Journal of Thrombosis and A Journal for Translation, Application and Therapeutics in Thrombosis and Vascular Science

ISSN 0929-5305

J Thromb Thrombolysis DOI 10.1007/s11239-012-0744-4

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J Thromb Thrombolysis DOI 10.1007/s11239-012-0744-4

Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarction: striving for consensus

S. Michael Gharacholou • Brenda J. Larson • Christian C. Zuver • Ryan J. Wubben • Giorgio Gimelli • Amish N. Raval

Ó Springer Science+Business Media, LLC 2012

Abstract Strong evidence exists in favor of rapid transfer Introduction of a patient suffering an ST-elevation myocardial infarction (STEMI) to the nearest hospital with primary percutaneous Half a million people suffer ST-elevation myocardial coronary intervention (PCI) capability, assuming the time infarction (STEMI) every year. Rapidly restoring blood from first medical contact to balloon inflation can be flow in the occluded culprit coronary artery offers the best achieved in less than 90 min. In many areas, PCI hospitals opportunity to preserve ventricular function, prevent have successfully collaborated with regional non-PCI failure and reduce mortality [1]. Primary percutaneous hospitals to provide primary PCI for STEMI; however, coronary intervention (PCI) is preferred over fibrinolysis significant variations exist in how these programs are provided that experienced operators can implement this executed. For example, the pre PCI hospital administration treatment within 90 min from first medical contact. How- of antithrombotic agents by emergency medical personnel ever, approximately 75 % of STEMI patients (roughly can include , , unfractionated , 350,000 patients per year) initially present to health care low molecular weight heparin, partial or full dose fibrino- facilities incapable of performing primary PCI [2]. Fur- lytics or combinations thereof. There is little consensus on thermore, it is estimated that between 7 and 30 % of the optimal cocktail, dose and route of administration. patients fail to receive lifesaving fibrinolytic therapy or Standardizing the pre PCI antithrombotic regimen across primary PCI, despite having no contraindications [3, 4]. hospital systems may be one approach to improve timely One-fifth of STEMI patients have contraindications to administration of these therapies, and potentially improve fibrinolytics and 70 % of these fail to receive timely pri- STEMI outcomes. mary PCI [2, 5]. These sobering statistics have reinforced the importance of standardized, system-wide delivery of evidence-based STEMI care. The ‘‘hub and spoke’’ care model for STEMI has recently emerged in many regions of the US. This structure allows hospitals without onsite PCI capabilities (spokes) to coordinate patient care with PCI hospitals (hubs) [6, 7]. The American Heart Association (AHA), in collaboration S. M. Gharacholou (&) Á B. J. Larson Á G. Gimelli Á with emergency medicine and third-party insurers, has A. N. Raval advocated for collaborative regional system approaches for Division of Cardiovascular Medicine, University of Wisconsin STEMI management [2]. The role of emergency medical Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, USA service (EMS) in any effective regional STEMI program is e-mail: [email protected] multifaceted and includes: recognition of probable STEMI, rapid transport to the most appropriate PCI capable facility, C. C. Zuver Á R. J. Wubben and administration of active therapy en route [1, 8, 9]. EMS Division of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, transport of STEMI patients from the scene to a PCI hos- WI 53792, USA pital has been associated with improved outcomes, even 123 Author's personal copy

S. M. Gharacholou et al. among patients who are administered fibrinolysis and are risk of moderate to severe bleeding (OR 1.14; 95 % CI transferred for PCI within 6 h of fibrinolysis [10]. Fur- 1.05–1.24, p = 0.003). There was no difference in 30-day thermore, there is interest in EMS-directed initiatives to cardiovascular , MI, or in the Clopidogrel and transport STEMI patients directly to centers capable of Aspirin Optimal Dose Usage to Reduce Recurrent performing PCI, rather than invoking interhospital transfer Events—Seventh Organization to Assess Strategies in from regional non-PCI hospitals; however, no controlled Ischemic Symptoms (CURRENT-OASIS 7) trial that trials testing this strategy have been performed. Generally, compared open-label high-dose (300–325 mg daily) aspirin paramedic units responding to calls for probable STEMI to low-dose (75–100 mg) aspirin in patients with acute are likely to initiate preparatory antithrombotic agents; coronary syndromes undergoing planned PCI [16, 17]. For however, variations exist in the type of , doses suspected STEMI, aspirin 162–325 mg as the initial dose and routes of administration. should remain the standard, with the exception of patients A principle goal in regional STEMI programs is to with true allergy to aspirin [18]. increase the proportion of STEMI patients who receive timely and successful reperfusion; however, a unified per- P2Y12 inhibitors spective on the optimal pre PCI hospital antithrombotic regimen has not been offered. Herein, we will review These agents work through inhibition of adenosine contemporary antiplatelet and antithrombotic therapy in diphosphate (ADP) induced platelet aggregation by inac- patients with STEMI referred for PCI. We will explore the tivating the P2Y12 receptor on the platelet surface, thereby potential time-dependent benefits of agents administered in preventing cross linking, and have led to improved out- the pre-hospital setting and highlight newer antithrombotic comes when combined with aspirin in patients treated with agents and their potential implications for STEMI man- intracoronary stents [19, 20]. Ticlopidine was a first gen- agement. Finally, we will share the rationale behind our eration ADP receptor antagonist for patients undergoing own regional, standardized approach to pre PCI hospital PCI and as secondary prevention in patients with a history antiplatelet and antithrombotic management. of stroke. However, severe side effects including neutro- penia and thrombotic thrombocytopenic purpura combined with twice daily dosing limited its use. Pre-PCI hospital oral antiplatelet considerations Clopidogrel, which is now more commonly used than ticlopidine, is effective in reducing cardiovascular events Aspirin in high-risk patients with acute coronary syndromes when combined with aspirin. Clopidogrel reduces risk irrespec- Aspirin irreversibly inhibits cyclooxygenase resulting in tive of upfront PCI or medical therapy, with benefits the inhibition of thromboxane A2 production, thereby observed as early as 24 h after initiating therapy [19, 21]. reducing the thromboxane A2-mediated amplification of Several clinical trials have subsequently evaluated whether platelet aggregation [11]. Aspirin levels peak within 1 h of the benefits of clopidogrel treatment in / oral administration to exert its antiplatelet effect, which non-STEMI could also be observed in patients with highlights the importance of pre PCI hospital administra- STEMI. The Clopidogrel and Metoprolol in Myocardial tion [12]. Non-enteric coated formulations of aspirin are Infarction Trial (COMMIT-CCS 2) randomized [45,000 preferred and patients should be instructed to chew aspirin patients with suspected MI (93 % had STEMI or left- to increase absorption and bioavailability. As compared to ) to clopidogrel 75 mg daily without a placebo, aspirin monotherapy has been shown to reduce loading dose or placebo on a background of antiplatelet short term vascular mortality after myocardial infarction therapy (aspirin 162 mg daily) and found a significant (MI) (absolute risk reduction of 2.4 %; number needed to reduction in the composite outcome of death, reinfarction, treat (NNT) of 47; p \ 0.001) [13]. Antiplatelet therapy or stroke (OR 0.91; 95 % CI 0.86–0.97; NNT = 112) [22]. administered in the pre-hospital setting improves ST-seg- Sabatine et al. [23] showed improved ischemic outcomes ment resolution prior to primary PCI and increases rates of and greater patency of the infarct-related artery when arterial patency [14]. clopidogrel was added to a standard regimen of fibrinolytic The optimal initial dose of aspirin in STEMI remains therapy, aspirin, and dose-adjusted unfractionated heparin uncertain. A retrospective study by Berger et al. [15]in (UFH) in patients with STEMI. Clopidogrel benefits 48,422 fibrinolytic-treated STEMI patients showed no patients with STEMI receiving fibrinolytic therapy, difference in 30-day mortality or ischemic-related out- resulting in a 36 % reduction in the odds of death, recurrent comes in patients treated initially with 162 mg of aspirin as MI, or an occluded infarct artery [24]. In a pre-specified compared with 325 mg of aspirin; however, the higher subgroup of the Clopidogrel as Adjunctive Reperfusion dose of aspirin was independently associated with greater Therapy—Thrombolysis in Myocardial Infarction 123 Author's personal copy

Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarctions

(CLARITY-TIMI 28) trial, 1,863 patients underwent PCI nongenetic factors, including comorbid health conditions, after treatment with fibrinolysis, half of whom received age, body mass, smoking status (via CYP1A2), and med- clopidogrel (300 mg loading dose followed by 75 mg ications (via CYP2C9) [33–35]. The association of genetic daily) while the other half received placebo [25]. Pre- polymorphisms of CYP2C19 with higher platelet reactivity treatment with clopidogrel, as compared to placebo, was and higher event rates has prompted interest in genotyping associated with fewer rates of death, MI, or stroke at patients, particularly those at higher ischemic risk; how- 30 days (3.6 vs. 6.2 %; adjusted OR 0.54; 95 % CI ever, outcomes data to guide antiplatelet strategy based on 0.35–0.85, NNT = 39) and greater patency in the infarct results obtained from genotyping are lacking. Finally, artery (86.9 vs. 80.8 %, p \ 0.001) [25]. Of note, there is identification of CYP2C19 variants still only accounts for a insufficient evidence to support a loading dose of clopi- small percentage of the variability in clopidogrel respon- dogrel in older adults (age [75 years) undergoing fibri- siveness [35]. These complex issues have promoted interest nolysis for STEMI [26]. Although the optimal loading dose in developing more potent ADP receptor blockers with less for clopidogrel has not clearly been established [27], a response variability. 600 mg load as compared to a 300 mg load achieves Prasugrel, like clopidogrel, is a prodrug and thieno- greater inhibition of platelet aggregation at onset pyridine that requires biotransformation to an active (approximately 2 h) and peak (approximately 6 h), and has metabolite; however, the efficiency of its absorption and been associated with both lower rates of cardiovascular metabolic activation are greater than clopidogrel. Conver- events without an increase in bleeding and improved short sion to the active metabolite (R-138727) occurs through term outcomes in STEMI patients undergoing PCI [28, 29]. hydrolysis by intestinal carboxylase, followed by oxidation Clopidogrel, especially when administered with concomi- via the CYP450 system [36]. Importantly, the major CYP tant antiplatelet and antithrombotic therapies, has been subtypes involved in metabolic activation are CYP3A and associated with increased risk of major bleeding. In the CYP2B6, with CYP2C19 having less importance, thus Clopidogrel in Unstable Angina to Prevent Recurrent obviating the issues related to responsiveness that have Events (CURE) trial, the combination of clopidogrel and been associated with the metabolism of clopidogrel. For aspirin as compared to aspirin alone was associated with prasugrel, this has the net effect of both rapid absorption higher rates of major bleeding (3.7 vs. 2.7 %, respectively; and metabolism, and attainment of peak plasma concen- relative risk (RR) 1.38; 95 % CI 1.13–1.67; p = 0.001) and tration of the active metabolite in approximately 30 min higher rates of blood transfusion C2 U (2.8 vs. 2.2 %, after dosing [37]. The Trial to Assess Improvement in respectively; RR 1.30; 95 % CI 1.04–1.62; p = 0.02), Therapeutic Outcomes by Optimizing Platelet Inhibition without observed differences in life-threatening or fatal with Prasugrel—Thrombolysis in Myocardial Infarction bleeding [21]. Efforts to minimize bleeding with clopido- (TRITON-TIMI 38) compared prasugrel to clopidogrel in grel therapy require appropriate dosing of in moderate-to-high risk acute coronary syndrome patients the acute setting and adhering to lower maintenance doses [38]. In this study, 26 % (n = 3,534) of patients presented of aspirin, as stacked antithrombotics markedly increase with STEMI and the endpoint was the composite outcome bleeding risk [30]. of cardiovascular death, MI, or stroke [38]. Prasugrel was Despite large-scale outcome studies supporting the use administered as a loading dose of 60 mg followed by a of clopidogrel across the spectrum of acute coronary syn- maintenance dose of 10 mg daily as compared to clopi- dromes, important limitations of the drug have been iden- dogrel at a loading dose of 300 mg followed by 75 mg tified. Clopidogrel is a prodrug, requiring bioactivation daily. In the TRITON study, prasugrel, as compared to in a 2-step process from several CYP450 enzymes, chiefly clopidogrel, was associated with significantly fewer pri- involving CYP2C19, to convert the prodrug to its phar- mary outcome events (9.9 vs. 12.1 %; p \ 0.001; macologically active form (R-130964) [31]. It is important NNT = 46) and fewer events of stent thrombosis (1.1 vs. to note that only about 15 % of the prodrug undergoes the 2.4 %; p \ 0.001; NNT = 77) but at a cost of more major process of bioactivation to become potentially available to bleeding (2.4 vs. 1.8 %; p = 0.03; NNH = 167), including exert its antiplatelet effect [32]. Observational studies have life-threatening and fatal bleeding. The greater antiplatelet shown that patients with genetic polymorphisms of effect with prasugrel increased the susceptibility of bleed- CYP2C19, particularly those with two copies of the ing in certain important subgroups such as those age CYP2C19*2 and CYP2C19*3 loss-of-function alleles, are C75 years, prior stroke or transient ischemic attack, or low poor metabolizers of clopidogrel, appear to exhibit less body weight (\60 kg) such that net clinical benefit with antiplatelet effect after standard clopidogrel doses, and prasugrel as compared to clopidogrel in these patients was have higher rates of cardiovascular events after MI and PCI not observed. However, these subgroups suffered more [32]. In addition, individual variability in clopidogrel bleeding complications irrespective of the treatment responsiveness may be associated with other genetic and assignment [38]. Information regarding pre-hospital 123 Author's personal copy

S. M. Gharacholou et al. administration of study was not reported in minor bleeding rates were, however, higher with ticagrelor TRITON-TIMI 38, although patients with STEMI and as compared to clopidogrel (5.1 vs. 3.7 %, respectively; intending to undergo primary PCI could be treated with p = 0.02; NNH = 72) [43]. Since the timing from first study medication up to 24 h prior to their procedure. Most dose of study drug to PCI in patients with STEMI was a patients (74 %) received first dose of study medication median of 15 min in the PLATO trial, the study was not after insertion of intracoronary guidewire and up to 1 h designed to evaluate the role for administration of ticagr- after PCI (i.e., over half of patients were loaded after PCI), elor in the pre-hospital setting in patients with probable thus few patients were ‘‘pre-treated’’ with study medication STEMI. Its use in primary PCI are likely to be limited to [38, 39]. Importantly, there were no significant differences scenarios where perceived bleeding risk is low, concomi- between treatment assignment with regards to cardiovas- tant use has been appropriately dosed and cular mortality or overall mortality in TRITON-TIMI 38, monitored, and the clinician is planning to treat the patient with results driven by differences in nonfatal MI between with maintenance doses of aspirin B100 mg daily. If these treatment groups. Prasugrel should be administered cau- conditions are satisfied, ticagrelor may become an attrac- tiously given the apparent increased bleeding in at-risk tive alternative to clopidogrel due to its superior efficacy subgroups such as the elderly, those with a history of and could be adopted in pre-hospital administration of cerebrovascular disease, and low body weight [27, 40]. STEMI patients undergoing primary PCI. Ticagrelor is a reversibly binding noncompetitive oral P2Y12 receptor antagonist, does not require metabolic activation, is rapidly absorbed with a maximum plasma Glycoprotein IIb/IIIa inhibitors concentration at 90 min, and has linear and predictable pharmacokinetics [41]. Ticagrelor was compared to clopi- Glycoprotein (GP) IIb/IIIa inhibitors exert their antiplatelet dogrel in the Platelet Inhibition and Patient Outcomes effect through inhibition of the GP IIb/IIIa platelet surface (PLATO) trial which tested the hypothesis that ticagrelor receptor, thus inhibiting the final common pathway in would be superior to clopidogrel on the composite outcome platelet aggregation. The current role for GP IIb/IIIa of cardiovascular death, MI, or stroke in 18,624 patients inhibitors in patients with STEMI referred for primary PCI with acute coronary syndrome [42]. At 12 months, treat- is less clear, since prior studies of GP IIb/IIIa use in this ment with ticagrelor (180 mg load followed by 90 mg population did not represent a high percentage that were twice daily), as compared to clopidogrel (300 mg load also being treated on a background of both dual antiplatelet followed by 75 mg daily), was associated with a lower rate therapy (i.e., aspirin and thienopyridine) and anticoagula- of the composite outcome (9.8 vs. 11.7 %; p \ 0.001; tion [27]. Therefore, net clinical benefit (benefits minus NNT = 53), MI (5.8 vs. 6.9 %; p = 0.005; NNT = 91), risks/adverse sequlae) of GP IIb/IIIa inhibitors are less well and cardiovascular death (4.0 vs. 5.1 %; p = 0.001; established in the contemporary era of STEMI patients NNT = 91). In the subgroup of patients receiving intra- undergoing primary PCI. Initial development of GP IIb/ coronary stents, treatment with ticagrelor resulted in lower IIIa’s in early phase clinical trials were of oral GP IIb/IIIa rates of stent thrombosis (1.3 vs. 1.9 %; p = 0.009; inhibitors; however, these agents were associated with NNT = 167). In a secondary analysis of the 41 % of higher rates of both bleeding and mortality [44]. Abcix- patients from PLATO that presented with STEMI imab and the small molecule GP IIb/IIIa inhibitors, pri- (n = 7,544) and underwent primary PCI, there was a trend marily eptifibatide and tirofiban, have been shown in a towards similar benefits as observed in the parent trial, with pooled meta-analysis of randomized trials and observa- a 1.4 % absolute risk reduction (13 % RR reduction) in the tional registries to have comparable efficacy for reduction primary endpoint favoring ticagrelor (HR 0.87; 95 % CI of death and MI and similar rates of in-hospital major 0.75–1.01; p = 0.07), including a 0.8 % absolute risk bleeding in STEMI patients undergoing primary PCI, reduction (34 % RR reduction) in definite stent thrombosis suggesting non-inferiority of small molecule agents as with ticagrelor (HR 0.66; 95 % CI 0.45–0.95; p = 0.03) compared to abciximab [45]. Abciximab, as compared to [43]. Adverse events reported in follow up included higher placebo, did not reduce infarct size or clinical events at rates of dyspnea in patients treated with ticagrelor that 30 days in a contemporary randomized double-blinded appeared to be self-limiting and non-serious but was study of STEMI patients undergoing PCI who had been associated with a higher rate of study drug discontinuation. pre-treated with 600 mg of clopidogrel and 500 mg of There was no difference in major bleeding between aspirin [46]. The timing of administering GP IIb/IIIa’s in patients treated with ticagrelor as compared to patients STEMI patients was recently evaluated in 2,453 STEMI treated with clopidogrel, including no differences in patients assigned to half-dose fibrinolysis plus abciximab , fatal bleeding, or transfusion rates prior to PCI, abciximab prior to PCI, or abciximab between groups [43]. Non-procedure related major and administered at the time of PCI [47]. There were no 123 Author's personal copy

Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarctions observed benefits and higher rates of bleeding with PCI performed after failure of fibrinolysis based on pres- upstream abciximab as compared to abciximab at the time ence of clinical symptoms and incomplete (\50–70 %) of PCI, suggesting that timing for use of GP IIb/IIIa’s resolution of ST-segment elevation) is recommended since should be relegated to selective use in the catheterization at least a 40 % fibrinolytic failure rate can be expected lab based on angiographic and clinical factors. Thus, [27]. invoking use of GP IIb/IIIa inhibitors at STEMI-referral sites prior to transfer for primary PCI may not improve Pre-hospital anticoagulant considerations outcomes and could potentially introduce greater transfer delay due to dosing considerations and use of cumbersome There are several anticoagulant options for patients with intravenous drips. STEMI referred for PCI, including UFH, enoxaparin, Administration of fibrinolysis (half or full-dose) upfront fondaparinux, and bivalirudin (Table 1); however, optimal with or without GP IIb/IIIa inhibitors with the intent of use of anticoagulation relies on institutional-specific algo- proceeding directly to PCI has been referred to as facili- rithms for managing anticoagulation at the STEMI- tated PCI, though current recommendations advise against receiving center in order to reduce medication and dosing using labels such as facilitated or rescue in contemporary error, optimize anti-ischemic benefit while reducing STEMI management [27]. The use of facilitated PCI in bleeding risk, and to maintain flexibility in adapting the STEMI regional care systems has been described [48]; anticoagulation strategy based on clinically related factors however, higher rates of bleeding complications remain a (i.e., renal insufficiency, bleeding risk, adjunctive GP IIb/ significant impediment to more widespread adoption and IIIa use) [27, 51]. Familiarity with all major anticoagulants the totality of current evidence does not support this is essential given that a proportion of patients co-admin- approach routinely [49]. The addition of GP IIb/IIIa istered anticoagulants at the time of fibrinolysis may sub- inhibitors to fibrinolysis compared to fibrinolysis alone in a sequently be referred for rescue PCI. In this case, facilitated PCI strategy has been tested [50]. Despite appropriate anticoagulation at the correct doses will need to improved infarct-related artery flow at the time of angi- be continued during the PCI procedure. ography, clinical harm due to ischemic and bleeding The use of UFH for acute MI has demonstrated reduc- complications result in greater risk with a facilitated tions in mortality and reinfarction in an era prior to stan- strategy [49, 50], and current guidelines do not recommend dard use of aspirin, yet added benefits for UFH in the era of facilitated PCI as a routine reperfusion approach [27]. fibrinolytic therapy have not been convincing [52]. UFH Instead, the transfer of fibrinolytic treated STEMI patients has become the comparator in non-inferiority and active- to the nearest PCI-hospital for possible rescue PCI (i.e., control superiority studies of alternative anticoagulant

Table 1 Anticoagulants in the Pre PCI setting in STEMI Anticoagulant Bolus dose Maintenance dose Renal adjustment Cath lab considerations

UFH 60 U/kg IV 12 U/kg/h (maximum 1,000 U/h) None Supplemental boluses administered in (maximum OR may be omitted at non-PCI Cath lab to maintain ACT [ 250 if 4,000 U) hospital to minimize transfer delay GP IIb/IIIa use is not planned OR switch to bivalirudin Enoxaparin 30 mg IV (for 1.0 mg/kg SQ Q12H if \75 years Advise against using If last SQ dose of enoxaparin was age old (first dose to be administered enoxaparin if given within 8 h, no additional \75 years) 15 min after IV bolus) or 0.75 mg/ SCr [ 2.5 mg/dL in men enoxaparin needed. If last SQ dose of kg SQ Q12H if [75 years old or [2.0 mg/dL in women enoxaparin was given 8-12 h earlier, administer 0.3 mg/kg IV Fondaparinux 2.5 mg IV (if 2.5 mg SQ Q24H Not recommended if Supplement the fondaparinux-treated SCr \ 3.0 mg/ SCr [ 3.0 mg/dL patient with anticoagulant that dL) (patients were excluded possesses anti-IIa activity (either from OASIS-6 [55]) UFH or bivalirudin). Bivalirudina 0.75 mg/kg IV 1.75 mg/kg/h (infusion usually Reduced to 1 mg/kg/h Confirm oral antiplatelet therapy terminated at end of procedure) (CrCl \ 30 mL/min) or (aspirin and thienopyridine) have 0.25 mg/kg/h if on been administered dialysis (bolus remains unchanged) UFH unfractionated heparin, ACT activated clotting time, GP glycoprotein, SQ subcutaneously, IV intravenously, CrCl creatinine clearance, OASIS Organization for the Assessment of Strategies for Ischemic Syndromes a Primarily started in the cardiac catheterization laboratory upon patient arrival

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S. M. Gharacholou et al. strategies, yet drawing conclusions regarding comparative group as compared to those treated with UFH (22.0 vs. efficacy has been limited due to differences in dosing 0 %, respectively, p \ 0.001) [55]. In addition, there were across studies, characteristics of the study population, dif- numerically greater coronary complications in the fonda- ferences in duration of therapy in treatment arms, and parinux group as compared to the UFH group (270 vs. 225, monitoring strategies of anticoagulant effect [26]. respectively, p = 0.04). On this basis, supplemental anti- For STEMI, UFH has been a preferred anticoagulant in coagulation with UFH or bivalirudin is advised in fonda- the pre-hospital setting or when transitioning from the parinux-treated STEMI patients undergoing planned PCI. emergency department directly to the catheterization lab- If STEMI patients receive fondaparinux at the non-PCI oratory for primary PCI [18]. The recommended dosing for hospital, it is critical to communicate this information to UFH is 60 U/kg intravenously (not to exceed a 4,000 U the PCI hospital so that appropriate supplemental anti- bolus) followed by an infusion of 12 U/kg/h (not to exceed thrombotic therapy with anti-IIa activity can be provided to 1,000 U/h) with a goal activated partial thromboplastin support the PCI procedure (Table 1). time of 1.5–2.0 times the local laboratory reference values, Bivalirudin has recently emerged as an important anti- which usually approximates 50–70 s [18, 53]; however, the coagulant in primary PCI for STEMI. In the Harmonizing initial bolus may be modified based on whether adjunctive Outcomes with and Stents in Acute GP IIb/IIIa inhibitors are going to be used. Myocardial Infarction (HORIZONS-AMI) trial, bivalirudin There are limited data for either enoxaparin or fonda- (with provisional GP IIb/IIIa inhibitor for no-reflow or parinux as the sole anticoagulant in patients with STEMI after PCI) was compared to UFH plus a GP IIb/ undergoing primary PCI, yet these therapies may be started IIIa inhibitor (dose-adjusted eptifibatide or abciximab per upstream, at the non-PCI hospital, and strategies for the investigator’s discretion) on rates of major bleeding or switching, supplementing, or continuing the anticoagulant major adverse cardiovascular events at 30-days [56]. Biv- will need to be considered. Enoxaparin, a low molecular alirudin resulted in a lower rate of the primary endpoint weight heparin with a higher ratio of anti-Factor Xa to anti- (9.2 vs. 12.1 %, p = 0.005), driven by less major bleeding, Factor IIa activity than UFH, has been studied in fibrino- and an observed lower rate of cardiac death and all-cause lytic-treated patients with STEMI, and includes a specific mortality at 30-days. There was a higher rate of acute dosing regimen adjusted for age and renal function (\24 h) stent thrombosis in the bivalirudin treated patients designed to avoid excess bleeding events due to accumu- as compared to the UFH/GP IIb/IIIa group (1.3 vs. 0.3 %, lation of drug and extended anti-Factor Xa activity p \ 0.001). Some of the higher rate of stent thrombosis (Table 1)[54]. For the enoxaparin treated patient with may have been explained by a lower loading dose of STEMI that is referred for primary PCI and receives the clopidogrel (300 mg instead of 600 mg) and bivalirudin 30 mg IV loading dose prior to transfer, the weight-based monotherapy [27]. Thus, from a pre-hospital STEMI acti- supplemental subcutaneous dose should be administered in vation standpoint in patients being referred for primary 15 min by paramedic or emergency department personnel, PCI, it is important to recognize that the majority of if not given immediately after the IV loading dose. The patients in HORIZONS-AMI (76 %) were treated with rationale for the IV loading dose of enoxaparin in STEMI open label UFH as the initial anticoagulant, with sub- is related to the pharmacokinetic activity of enoxaparin, sequent secondary analyses suggesting that switching from which results in peak anti-thrombin and anti-Factor Xa UFH to bivalirudin, as compared to continued use of UFH activity 3–5 h after subcutaneous injection. with a GP IIb/IIIa inhibitor, may not only be associated Fondaparinux, a synthetic pentasaccharide that binds with lower rates of major bleeding, but also lower long- antithrombin and inhibits Factor Xa, exerts its antithrom- term cardiac mortality and reinfarction [57]. Indeed, in the botic effect through antithrombin-mediated neutralization interventional setting, patients initially treated with UFH of Factor Xa and subsequent inhibition of thrombin for- can be readily converted to bivalirudin to support the pri- mation. Subcutaneous injection results in near complete mary PCI procedure, with a proviso of a 30 min interval bioavailability of the drug and therapeutic drug concen- between dosing of the anticoagulants [56]. trations are reached approximately 2–3 h post-dose. Fondaparinux has been compared to placebo and UFH in a Antithrombotic approaches adopted by regional randomized trial of STEMI patients, including non-reper- primary PCI programs fused, fibrinolytic-treated, and patients undergoing PCI [55]. In the subset of the stratum that underwent primary Early primary PCI for STEMI and its time-dependant PCI, death or reinfarction rates among fondaparinux-trea- benefits have been known for some time [58]. Imple- ted patients were similar to patients treated with UFH (8.5 menting primary PCI in the US requires collaboration and vs. 8.2 %, respectively, p = 0.61), yet there were higher direct communication between EMSs, emergency medicine rates of guide catheter thrombus events in the fondaparinux physicians, and cardiologists. Additional complexities of 123 Author's personal copy

Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarctions delivering primary PCI in the US include resource utili- (e.g., arrival at non-PCI hospital to first device at PCI zation, staffing personnel, and economic and logistical hospital) door-to-balloon times of \90 min [64]. It would details regarding cardiac services in rural hospitals [6, 7]. appear that the same level of coordination and motivation Several organizations have developed standardized proto- that drives multi-center clinical trials is what is required cols within their regional network for antithrombotic to institute protocol standards for STEMI care in the therapies to be administered before or at the time of pri- patient care setting. mary PCI that aims for efficiency, simplicity, and an evi- dence based approach to STEMI care (Table 2). These Streamlining, simplifying, and maintaining efficacy programs have been effective in integrating rural commu- nity hospitals with a PCI center [48, 59–62], and have been Specific factors that are unique to certain regions must be implemented statewide [59] and across state borders [60]. taken into account when designing standardized STEMI One important limitation in STEMI care in the US has protocols. For example, inclement weather directly impacts been a lack of standardized guideline-driven protocols. the selection of transport strategies, which may be more of Instead, protocols tend to vary from region to region. a factor in the upper Midwest than in the Southeastern US Variable dosing of antithrombotics, selection of thieno- during the winter months. The local distribution of EMS pyridines versus GP IIb/IIIa inhibitors for adjunctive services including staffed helicopter units, paramedic units, antiplatelet therapy, and select use of facilitated PCI are or ‘‘basic’’ EMS units can affect time to STEMI recogni- examples that make outcome comparisons across regional tion on the electrocardiogram and qualifications to protocols difficult (Table 2). Notably, achieving goals and administer antithrombotic agents, for example. Variations benchmarks on pre-PCI hospital care and transport exist in level of integration between health providers and appears feasible in the conduct of clinical trials [63]; facilities, governance of local emergency systems, and however, achieving these goals and benchmarks in the willingness to invest in regional STEMI system of care. ‘‘real-world’’ setting has proven to be problematic. Reg- However, efforts to understand strategies that work and to istry studies show that \9 % of patients have total allow for comparative evaluation between programs

Table 2 Antithrombotic recommendations suggested for use by PCI centers for interhospital transfer patients with STEMI intended for primary PCI Program name Program location Antiplatelet strategy Anticoagulant strategy

Reperfusion of Acute Myocardial State of NC Aspirin 162 mg to 325 mg Bolus: UFH 70 U/kg Infarction in North Carolina Clopidogrel 300 mg to Maintenance: None during Emergency Departments (RACE) 600 mg or Prasugrel 60 mga transfer [59] Geisenger STEMI protocol [62, 65] Central PA Aspirin 325 mg Bolus: UFH 70 U/kg Clopidogrel 600 mg Maintenance: None during transfer Stat Heart Program [61] Central IL Aspirin 324 mg Bolus: UFH 70 U/kg Clopidogrel 300 mg (maximum of 7,000 U) GP IIb/IIIa inhibitor Maintenance: 15 U/kg/h (abciximab or eptifibatide) (maximum of 1,000 U/h) Minneapolis Heart Institute Level 1 Regional sites within Aspirin 325 mg Bolus: UFH 60 U/kg Myocardial Infarction Program [48] 200 miles of Clopidogrel 600 mg (maximum of 4,000 U) Minneapolis, MN Maintenance: 12 U/kg/h (maximum of 1,000 U/h) Mayo Clinic STEMI Protocol [60] Regional sites within Aspirin regimen not Bolus: UFH 60 U/kg 150 miles of reported but high rates (maximum of 4,000 U) Rochester, MN of use ([95 %) Maintenance: 12 U/kg/h Clopidogrel not used (maximum of 1,000 U/h) University of Regional sites within Aspirin 325 mg Bolus: UFH 60 U/kg Wisconsin-Madison 100 miles of Clopidogrel 600 mg (maximum of 4,000 U) Madison, WI Maintenance: None during transfer UFH unfractionated heparin, GP glycoprotein a Operations manual (available at http://www.nccacc.org)

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S. M. Gharacholou et al. require consensus on antithrombotic strategies for STEMI capability to make clinical decisions and institute care patients referred for primary PCI. related to pre PCI hospital antithrombotics. The geographic At the University of Wisconsin-Madison, paramedics in distribution of non-PCI centers in our STEMI referral Dane County (Madison, WI) activate the cardiac cathe- program at the University of Wisconsin-Madison is illus- terization laboratory based on their own interpretation of trated in Fig. 1. electrocardiogram acquired at the scene, and administer a In our program, we initiate antiplatelet therapy with standard pre-treatment regimen of antithrombotic therapy aspirin 325 mg chewed at first contact with EMS. In patients en route (Table 2). Adjunctive medications, such as nitro- unable to take oral agents and who do not have a nasogastric glycerin and analgesics, are also administered for symptom tube in place, a 300 mg aspirin suppository can be admin- relief. For STEMI outside of Dane County, the decision to istered [9]. For fibrinolytic treated patients in the non-PCI travel directly by ground or helicopter (Med Flight) from emergency room, a clopidogrel loading dose of 300 mg in the regional non-PCI hospital, or through a Med Flight patients B75 years of age is administered. A strategy of intercept (i.e., convenient landing zone near the scene) is administering clopidogrel 75 mg without a loading dose can rapidly determined by radio communication between be used in patients [75 years old with STEMI undergoing emergency room physicians and Med Flight dispatch. fibrinolysis, but careful attention to the adjunctive antico- Factors such as flight conditions, road conditions, and agulant dose is imperative [22]. For primary PCI, we rec- travel distances are rapidly assessed. The University of ommended rapid clopidogrel loading of 600 mg, as has Wisconsin-Madison Med Flight Helicopter transport pro- been used in contemporary primary PCI trials [46]. How- gram is uniquely staffed by board-certified emergency ever, it should be noted that the optimal clopidogrel loading physicians (MD/DO) that significantly enhances the team’s dose in patients with STEMI referred for primary PCI has

Fig. 1 STEMI referral sites and their geographic relationship to the University of Wisconsin- Madison as represented by ground distance (mileage) and nautical miles (rings)

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Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarctions not been conclusively determined from clinical trials [27]. References Our choice of clopidogrel is based on the favorable safety profile (in comparison to prasugrel or ticagrelor), regional 1. Antman EM, Anbe DT, Armstrong PW et al (2004) ACC/AHA provider familiarity, and regional ease of access to the drug. guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Car- On arrival in the STEMI receiving hospital’s cardiac cath- diology/American Heart Association Task Force on Practice eterization lab, a formal checklist is entered that includes Guidelines (Committee to Revise the 1999 Guidelines for the queries that aspirin and clopidogrel were administered, their Management of Patients with Acute Myocardial Infarction). doses and time of administration. This approach is critical to Circulation 110:e82–292 2. 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