Review

Hospitals with and without percutaneous coronary intervention capability: considerations for treating acute coronary syndromes

Judd E. Hollander MD^a,?, C. Michael Gibson MD^b, Charles V. Pollack Jr MD^a

^aDepartment of Emergency Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104-4283, USA

^bCardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA

Received 8 April 2008; accepted 14 April 2008

Abstract The crucial aim in the emergency management of patients presenting with chest pain is the identification of acute coronary syndromes and the initiation of appropriate treatment. Institution- specific triage to initial medical or interventional therapies is influenced by the availability of percutaneous coronary intervention (PCI) facilities. Although the use of invasive strategies has increased, most US hospitals do not have PCI facilities. Pharmacological management is an integral part of all treatment strategies, regardless of the availability of interventional capability. Given the growing importance of invasive management strategies, a therapy that is compatible with both medical and invasive therapy options is becoming increasingly important. Aspirin and clopidogrel are recommended for patients with ACS regardless of the conservative or invasive Management strategy. With enoxaparin, patients with ACS can seamlessly transition from the medical management phase to the interventional management phase without the need for introducing a second anticoagulant in the cardiac catheterization laboratory. Fondaparinux can be used for patients with ACS treated medically, but should not be used alone during PCI because of the risk of catheter thrombosis. Bivalirudin can be used in Non-ST-segment elevation myocardial infarction patients who are managed invasively.

(C) 2009

Introduction

The crucial goal for the emergency physician in patients presenting with chest pain is the prompt identification of acute coronary syndromes and the initiation of appropriate, risk-directed treatment. Some of the challenges in the management of patients with ACS are the rapid and accurate risk stratification, and the institution-specific triage

^? Funding sources: The authors received editorial support in the preparation of this manuscript, funded by sanofi-aventis, Bridgewater, NJ.

* Corresponding author. Tel.: +1 215 6622767; fax: +1 215 6623953.

E-mail address: [email protected] (J.E. Hollander).

to initial medical or interventional therapies. The choice of Reperfusion strategy depends, among other factors, on the patient’s eligibility criteria, time since symptom onset, emergency department (ED) capabilities, patient preferences, physician preferences, and availability and experience of cardiac catheterization facilities. Although the use of in- vasive strategies has increased, most hospitals in the United States do not have the facilities to perform percutaneous coronary intervention (PCI) [1]; so the choice is often between managing the patient with pharmacological means alone or transferring the patient to a PCI-capable hospital. Both strategies require appropriate pharmacological treat- ment as a foundation for successful treatment.

0735-6757/$ - see front matter (C) 2009 doi:10.1016/j.ajem.2008.04.019

This review discusses the key considerations of hospitals with or without PCI capability on patient risk stratification and anticoagulant treatment in the context of new devel- opments and guidelines for the management of patients with ACS.

PCI capability in US hospitals

There has been a trend toward the increased use of PCI in patients with ACS since the early 1990s [2,3]. An evaluation of 1506 hospitals, carried out between 1994 and 1996 by the National Registry of Myocardial Infarction-2, found that 28.1% of hospitals in the United States had no angiography or PCI or coronary artery bypass graft (CABG) capability; 25.2% could perform angiography but not PCI or CABG; 7.4% could perform angiography and PCI; and 39.2% could perform angiography, PCI, or CABG [2]. Data from the American Hospital Association showed that 25% of acute- care hospitals were PCI capable in 2000 [4]. Despite 80% of US adults living within 60 minutes of a PCI-capable hospital, 58% of patients lived closer to a hospital without PCI capabilities; these statistics vary substantially across US regions [4]. In daily practice, the choice of a treatment strategy by the emergency physician or cardiologist for patients with ACS will be influenced by hospital PCI facilities and transfer feasibility.

Risk stratification

Given the spectrum of clinical presentations of patients with unstable angina /non-ST-segment elevation myo- cardial infarction (NSTEMI), effective risk assessment early after presentation is useful not only for the triage of patients to the optimal location for delivery of medical care, but also for the identification of higher-risk patients for whom invasive or aggressive medical interventions could be most beneficial.

Fig. 1 Treatment outcome in NSTEMI patients according to TIMI risk score according to the TIMI 11B trial [5]. Reprinted with permission [5]. Copyright 2000, American Medical Association. All rights reserved.

Fig. 2 In-hospital use of PCI, LMWH, and GP IIb/IIIa inhibitors according to GRACE risk score [13].

Several studies have shown that NSTEMI patients with the highest risk derive the greatest benefit from pharmacological therapies, such as enoxaparin [5] and platelet glycoprotein (GP) IIb/IIIa inhibitors [6], as well as from an interventional strategy [7]. For example, in an analysis of the Thrombolysis in Myocardial Infarction -11B trial, the difference in absolute risk between enoxaparin and unfractionated heparin (UFH) in death, myocardial infarction (MI), or revasculariza- tion increased with patient risk, according to the TIMI risk score (Fig. 1) [5].

In patients with ST-segment elevation MI (STEMI), current guidelines support primary PCI over fibrinolysis as the treatment of choice when feasible. However, there is no consensus on whether all patients benefit from an invasive strategy when applied in a community setting, including those hospitals without invasive treatment facilities. At least 2 studies [8,9] have independently shown that, in commu- nity-based patient samples, there is an increasing benefit with undergoing primary PCI compared with fibrinolysis in patients at higher overall risk. Thune et al [9] showed a significant reduction in mortality with primary PCI com- pared with fibrinolysis in patients at the highest risk (25.3% vs 36.2%, P b .02), with a similar mortality rate among low- risk patients (8.0% vs 5.6%, P = .11). Hence, the identification on admission of high-risk patients, who are most likely to benefit from the invasive strategy, is very important, especially if a community-wide strategy of invasive treatment for all patients with STEMI is not feasible. Despite this evidence, both invasive and pharmacological therapies remain paradoxically targeted at low-risk patients (Fig. 2) [10-13]. As a result, there remains a substantial opportunity to improve the use of new pharmacological and

invasive treatments especially among high-risk patients.

Risk definitions

The 2007 American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines [14] provide a list of indicators for the identification of high-risk NSTEMI patients who would benefit from an Early invasive strategy

(Table 1) [5,14-16]. In addition, a number of risk scores, including TIMI [5], Global Registry of Acute coronary events [15], and Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) [16], have been proposed and validated for identification of high-risk UA/NSTEMI patients (Table 1) [5,7,17-21]. Although physicians can stratify risks in a general way based on a patient’s age, hemodynamic stability, electrocardiographic findings, and cardiac markers, the integration of multiple risk factors is not possible without the support of multivariate models. For this reason, risk scores have demonstrated additional value beyond global risk assessment by physicians, using clinical parameters alone or predictions based on ST deviation or Troponin elevation at presentation [22,23].

The TIMI Risk scoring system (range, 0-7) is the simplest of the 3 risk scores because it uses the sum of 7 variables (1 point for each variable if present) [5]. In contrast, the PURSUIT and GRACE risk scores include both dichot- omous and continuous variables; and the calculation of risk is complex, requiring the use of computer-based programs based on published nomograms [15,16].

The relative clinical value of these risk scores has been assessed in unselected patients with undifferentiated cardiac chest pain. All 3 scores have been shown to accurately stratify risk among patients presenting with Undifferentiated chest pain [20,22-24]. The GRACE and PURSUIT risk scores were able to calculate cardiac events both at 30 days and at 1 year with greater accuracy than the TIMI risk score [22-24]; however, unlike the other 2 models, the GRACE score can be used for STEMI patients as well as those with NSTEMI. Nevertheless, the TIMI risk score has achieved wide acceptance and has proven to be an easy-to-use and useful adjunct to clinical judgment for the recognition and prioritization of patients presenting with ACS in everyday practice [20,21]. The TIMI score uses information routinely documented as part of the initial evaluation of patients with potential ACS (Table 1) [5,19]. Importantly, the TIMI risk score offers prognostic information independent of, and complementary to, data from biochemical markers. As such, the TIMI risk score might facilitate the early assessment of patients waiting for cardiac biomarker results and of patients who remain at high risk despite negative baseline cardiac markers [6]. A recently modified version of the TIMI risk

Prior CABG

High-risk score (eg, TIMI, GRACE)

CCS indicates Canadian Cardiovascular Society; TnI, troponin I; TnT, troponin T.

Initial serum creatinine level: per 1-mg/dL increase

High-risk findings from noninvasive Stress testing

Heart rate: per 20-beats/min increase

Systolic blood pressure: per 20-mm Hg decrease

New-onset or progressive CCS class angina in previous 6 wk

Severe anginal symptoms, eg, >=2 anginal events in the last 24 h

Significant coronary stenosis (eg, prior coronary stenosis

>=50%)

At least 3 risk factors for coronary artery disease

Use of aspirin in the last 7 d

Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy

PCI within 6 mo

Heart rate: per 30-beats/ min increase

Hemodynamic instability Systolic blood pressure:

per 20-mm Hg decrease

Cardiac enzyme findings

Elevated serum cardiac biomarkers

sustained ventricular tachycardia elevated cardiac biomarkers (TnT or TnI)

Age: per 10-y increase Sex

ST-segment deviation ST-depression Cardiac arrest at Signs of heart failure admission

Killip class: per increase in class

(Presumably) New ST-segment depression ST-segment deviation Signs or symptoms of heart failure, or new or

worsening mitral valve regurgitation Reduced left ventricular function (b40%)

Age: >=65 y Age: per 10-y increase

PURSUIT [16]

GRACE [15]

TIMI [5]

ACC/AHA NSTEMI guidelines, high-risk indicators [14]

Table 1 The ACC/AHA definition of high-risk NSTEMI and validated risk scores for risk stratification of NSTEMI patients

Characteristic Points assigned

Historical Age 65-74 y 2 Age >=75 y 3 Diabetes mellitus/hypertension or angina 1 Examination Systolic blood pressure 3 Heart rate 2 Killip class II-IV 2 Weight b67 kg 1 Presentation Anterior STE or LBBB 1 Time to treatment N4 h 1 Risk score (total) 0-14

Reprinted with permission [17]. STE indicates ST elevation.

score for NSTEMI has been published using only 4 of the 7 original variables (age >=65 years, ST-segment deviation

Table 2 The TIMI risk scores for risk stratification of STEMI patients [17]

>=0.5 mm, elevated troponin I, and coronary stenosis >=50%) and was found to be equally effective in the risk stratification of patients [25]. This simplified TIMI risk score could provide an effective and easy-to-use risk stratification tool; in general, the simpler the model and the more predictive it is

without the need for data only obtained at catheterization, the more useful it can be in the ED.

Independent of the development of the TIMI score for NSTEMI, a TIMI risk score for STEMI was created to predict 30-day mortality at presentation of fibrinolytic- eligible patients with STEMI. In this score, risk assessment was once again simplified by the arithmetic sum of 10 independent predictors of mortality, weighted according to risk (Table 2) [9,17]. The tool has been tested and validated in both a trial population and in a general ACS patient population. In the general ACS population, however, a slightly lower Discriminatory power was detected among patients older than 65 years. Nevertheless, the TIMI risk score for STEMI has been shown to be an accurate tool for the stratification of patients and could find use for the early identification of high-risk patients for direct or rapid transfer to a PCI facility [26]. Key considerations for risk stratifica- tion (Figs. 3 and 4) are listed in Table 3.

Time stratification

According to the ACC/AHA guidelines, an ECG should be obtained in chest pain patients within 10 minutes of presentation to the ED [27]. This recommendation is based

Fig. 3 Initial stratification and pharmacological treatment pathway of patients with ACS in hospitals without PCI facilities. DM indicates diabetes mellitus; HTN, hypertension; STE, ST elevation; LBBB, Left bundle-branch block; rx, treatment; HR, heart rate; SBP, systolic blood pressure.

on findings from a number of studies including the National Heart Attack Alert Program, which showed that the timely acquisition of an ECG is critical for the effective manage- ment of STEMI patients who are undergoing Fibrinolytic therapy [28]. A recent study by Diercks et al [29], however, showed that clinical practice falls short of the current guidance, with a median time to ECG of 14 minutes among STEMI patients. Furthermore, often, patients ultimately diagnosed with UA/NSTEMI did not have a diagnostic ECG initially. Whereas a delayed ECG among STEMI patients was predictive of a 3-fold increase in adverse events (compared with an ECG performed within 10 minutes), an ECG of UA/NSTEMI patients was less time dependent [29]. Adverse outcomes become increasingly likely in UA/ NSTEMI patients if diagnosis is delayed by more than 2 hours. Typically, a diagnosis of UA/NSTEMI is only confirmed after an extended evaluation of cardiac serum markers, after serial ECGs, or on clinical grounds.

In NSTEMI patients being considered for PCI, an “early” invasive strategy should be performed within 4 to 24 hours [30]. In STEMI patients, time is more crucial; and initiation of Fibrinolytic treatment should be within 30 minutes, or PCI balloon inflation should be within 90 minutes [27]. A number of studies have shown that STEMI mortality increases significantly with delays to reperfusion therapy, whether the treatment strategy is fibrinolytic therapy or PCI [31-34]. Prompt restoration of blood flow to the occluded artery not only saves lives; but it also reduces infarct size,

minimizes myocardial damage, preserves left ventricular function, and decreases associated morbidity [35]. When performed expeditiously and expertly at hospitals that carry out a high volume of PCI procedures, primary PCI is superior to fibrinolytic therapy as a reperfusion strategy in STEMI [36-38], resulting in higher infarcted-artery patency and lower rates of reinfarction, stroke, and death [36,37,39]. However, the relative benefits of primary PCI over fibrinolytic therapy are greatest among STEMI patients at highest risk [8,9]. Paradoxically, however, treatment delays are more likely among patients with multiple risk factors; and so, the incremental benefit of early primary PCI over fibrinolytic therapy in everyday practice among high-risk patients may be nullified [40].

Key considerations for the Transfer of patients to a PCI facility

Physicians at hospitals without PCI capability have 2 treatment options for patients with STEMI: rapid patient transfer to a hospital with primary PCI capability or on-site fibrinolytic therapy. Evidence from meta-regressions [8,41] suggests that an invasive strategy ceases to be more beneficial than fibrinolytic therapy if treatment is delayed by more than 60 minutes. Other recent evidence suggests that longer delays, closer to 100 minutes, might be more accurate and consistent

Fig. 4 Initial stratification and pharmacological treatment pathway of patients with ACS in hospitals with PCI facilities.

with the underlying clinical pathology [42,43]. Although defining a universal time delay for any STEMI patient to determine treatment strategy is appealing, the delay whereby survival with primary PCI ceases to exceed that of fibrinolytic therapy also depends on patient characteristics, such as patient age, symptom duration, and infarct location. For example, this delay was 71 minutes among patients aged b65 years compared with 155 minutes in patients aged >=65 years, and

Table 4 Key considerations for time stratification STEMI NSTEMI

PCI-capable hospital

Optimize in-house protocols to Initiate appropriate

PCI balloon inflation within pharmacological management 90 min as soon as possible

Patients eligible for PCI based on risk stratification: if PCI facility is not available within

<=24-36 h, intensify

pharmacological management

Non-PCI-capable hospital, but with transfer possibility

Have in-house treatment Initiate appropriate

protocols for patient transfer, pharmacological management including door-to-transfer as soon as possible

and Door-to-balloon times

Patients eligible for transfer for Patients eligible for transfer for PCI based on risk PCI based on risk stratification: stratification: if PCI balloon if PCI facility is not available inflation within 90 min is within <=24-36 h, intensify feasible, transfer; if not, pharmacological management initiate fibrinolysis within 30

min

Low-risk patients: initiate fibrinolysis within 30 min

Non-PCI-capable hospital, without transfer possibility

Initiate fibrinolysis within 30 Initiate appropriate

min pharmacological management as soon as possible

94 minutes in patients presenting <=120 minutes after symptom onset compared with 190 minutes in patients presenting N120 minutes after symptom onset [43]. Results from a number of predominantly European studies, such as the primary angioplasty in Acute myocardial infarction patients from General community hospitals transported for percutaneous transluminal coronary angioplasty Units versus Emergency thrombolysis (PRAGUE) study [44], the PRimary Angioplasty in acute myocardial infarction patients from General community hospitals transported for percutaneous transluminal coronary angioplasty Units versus Emergency thrombolysis 2 (PRAGUE 2) study [45,46], the Danish Multicenter Randomized Study on Fibrinolytic Therapy versus Acute Coronary Angioplasty in Acute Myocardial Infarction (DANAMI) [47], the Air Primary Angioplasty in Myocardial Infarction (Air PAMI) study [48], the Maximal Individual Therapy of Acute Myocardial Infarction PLUS (MITRA PLUS) registry [49], and others [50,51], have

compared a strategy of thrombolysis vs transfer for PCI from hospitals without PCI capability. These trials have suggested that the advantage of primary PCI can be extended to patients transferred from referral hospitals with an average time from randomization (at the initial hospital) to first balloon inflation (at the PCI hospital) of approximately 90 minutes in the European trials and 120 minutes in a US trial [48].

Table 3 Key considerations for risk stratification

STEMI NSTEMI

Risk stratify patients according Risk stratify patients according to an accepted risk score, eg, to an accepted risk score, eg, TIMI risk score for STEMI simplified TIMI risk score for NSTEMI PCI-capable hospital Primary choice invasive Identify high-risk patients strategy irrespective of risk, most likely to benefit from an if no contraindications invasive strategy, but still initiate stabilizing pharmacological treatment a; treat low-risk patients pharmacologically Non-PCI-capable hospital, but with transfer possibility Identify high-risk patients most Identify high-risk patients likely to benefit from an most likely to benefit from an invasive strategy for invasive strategy for consideration to transfer a; consideration to transfer a but treat low-risk patients, who still initiate stabilizing are less likely to benefit from pharmacological treatment; a transfer for an invasive treat low-risk patients strategy, pharmacologically pharmacologically Non-PCI-capable hospital, without transfer possibility Treat patients Treat patients with appropriate pharmacologically pharmacological means (including fibrinolytics if no contraindications)

a Depending on time stratification.

However, an analysis of the National Registry of

Myocardial Infarction (NRMI) data by Nallamothu et al [52] found that the median time arrival at the initial hospital to the first balloon inflation at the PCI hospital in the United States was 180 minutes, with less than 4% treated within 90 minutes and only 15% treated within 120 minutes. Overall, the median Transfer time from the initial hospital to the PCI hospital was 120 minutes; and the time from arrival at the PCI hospital to initiation of the procedure averaged 53 minutes. These results reveal an important discrepancy between the performance of primary PCI in transfer patients within a real-world setting and the strategy tested in randomized clinical trials. Transfer for

primary PCI in the United States is presently failing to achieve

established benchmarks in most STEMI patients.

Factors that impact on longer total door-to-balloon times are many and include the presence of comorbid conditions, the absence of chest pain as a presenting complaint, Delayed presentation after symptom onset, less specific ECG findings, and hospital presentation during off-peak hours

[52]. Notably, the transfer of patients to PCI hospitals that were nonteaching, were located in urban areas, and had a not-for-profit status was associated with shorter door-to- balloon times (b2 hours) in a higher percentage of patients compared with teaching hospitals in rural areas.

Therefore, physicians at hospitals without PCI capability who are planning to use a transfer strategy for STEMI patients need to be aware of their own total door-to-transfer times, and total door-to-balloon times if transferred. This information needs to be incorporated into clinical decision making when selecting between Reperfusion strategies. Furthermore, scru- pulous attention has to be given to the logistical details of transfer and the reengineering of process-of-care systems to make the transfer of patients for PCI a clinically viable option. It could be that physical barriers, such as geographical distance, make it difficult for rural facilities to achieve rapid times to treatment without a substantial investment of resources. On-site fibrinolytic therapy might be the best option for reperfusion therapy under these circumstances. The benefits associated with transfer in the randomized clinical trials were primarily related to reductions in recurrent MI. These benefits compared with fibrinolytic therapy are likely to be reduced in a real-word setting, where high rates of early cardiac catheterization are to be expected after fibrinolytic therapy in patients with STEMI. However, trials that evaluated “facilitated PCI” in STEMI as a strategy for combining fibrinolytic therapy and PCI within 1 to 4 hours, such as the recent Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial, showed no improvement in mortality or major adverse cardiovascular events compared with primary PCI, whereas there was an increase in bleeding risk [53,54].

It is important to note that, under certain circumstances, patient transfer might remain the best option for reperfusion, even when prolonged times to treatment are anticipated. Primary PCI is recommended for patients who are ineligible for fibrinolytic therapy or are in cardiogenic shock [55,56].

Table 5 Summary of 2007 ACC/AHA recommendations for anticoagulant treatment in NSTEMI patients [14]

Anticoagulant Grade

Conservative Enoxaparin IA

strategy UFH IA

Fondaparinux IB

Fondaparinux preferred in patients with IB an increased risk of bleeding

Enoxaparin and fondaparinux preferred IIaB over UFH

Invasive Enoxaparin IA

strategy UFH IA

Fondaparinux ^a IB

Bivalirudin IB

^a An additional bolus of intravenous UFH should be added, although this regimen has not been rigorously tested in prospective randomized trials.

Fibrinolytic strategy

Anticoagulant Recommendation Grade

Enoxaparin IA Fondaparinux IB UFH IC

Fibrinolytic strategy

Anticoagulant Recommendation Grade

Enoxaparin If the last subcutaneous dose was IB administered b8 h prior, no additional enoxaparin should be given; if the last subcutaneous dose was administered 8- 12 h earlier, an intravenous dose of 0.3 mg/kg enoxaparin should be given. Fondaparinux Should not be used as the sole IIIC anticoagulant to support PCI because of the risk of catheter thrombosis. An additional anticoagulant with anti-IIa activity should be administered. Fondaparinux Administer additional intravenous IC treatment with an anticoagulant possessing anti-IIa activity, taking into account whether GP IIb/IIIa receptor antagonists have been administered. UFH Administer additional boluses of UFH IC as needed, taking into account whether GP IIb/IIIa receptor antagonists have been administered. UFH Bivalirudin can be used in patients IC previously treated with UFH.

Regardless of the reperfusion approach used, successful treatment in STEMI depends on the ED having an Integrated and efficient protocol, which is regularly reviewed to accommodate changes in clinical practice arising from ongoing clinical trials [57]. Key considerations for risk stratification (Figs. 3 and 4) are listed in Table 4.

Table 6 Summary of 2007 ACC/AHA recommendations for anticoagulant treatment in STEMI patients [59]

General

Patients treated with a fibrinolytic strategy should receive anticoagulant therapy for a minimum of 48 h

and preferably for the duration of the index hospitalization, up to 8 d.

Regimens other than UFH are recommended if anticoagulant therapy is given for more than 48 h.

IC

IA

IA

Pharmacological treatment

ACC/AHA guidance in UA/NSTEMI

Stabilizing pharmacological treatment should be initiated early in the ED and should include aspirin (or clopidogrel if

aspirin intolerant), anticoagulants, nitroglycerin, ?-blockers, angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), and statins unless contraindicated [14,27,58]. An early and institution-specific decision then has to be made for each patient, based on risk assessment, for a strategy of initially conservative pharmacological or interventional (PCI) therapy. This decision will subsequently guide the choice of anticoagulant therapy (Table 5) [14]. The most recent ACC/AHA guidelines in UA/NSTEMI include 2 new anticoagulants, fondaparinux and bivalirudin, as well as UFH and low-molecular-weight heparin (LMWH). There is less evidence to support these new anticoagulants than to support LMWH, specifically enoxaparin.

ACC/AHA guidance in STEMI

The 2007 update of the ACC/AHA guidelines in STEMI includes a series of new recommendations on the use of anticoagulants as ancillary therapy to reperfusion therapy (Table 6) [59]. Enoxaparin and fondaparinux have been included, along with UFH, as anticoagulant regimens with established efficacy in patients undergoing reperfusion with fibrinolytics. A recommendation is made to preferentially administer an anticoagulant for the duration of hospitaliza- tion, if up to 8 days, with a regimen other than UFH. Patients who received UFH or enoxaparin can continue to receive these anticoagulants without crossover when transitioning from fibrinolytic therapy to PCI. Fondapar- inux should not be used as the sole anticoagulant to support

Table 7 Key considerations for appropriate medical therapy

STEMI

PCI-capable hospital

UFH is treatment option for primary PCI.

NSTEMI

Enoxaparin and bivalirudin are treatment options for PCI; fondaparinux cannot be used as the sole anticoagulant during PCI.

Non-PCI-capable hospital, but with transfer possibility

Enoxaparin shows net clinical Enoxaparin is preferred over benefit over UFH in patients UFH, and patients can treated with fibrinolytics, seamlessly undergo PCI;

and patients can seamlessly fondaparinux cannot be used as transition to PCI. the sole anticoagulant during

PCI, which limits initiation of fondaparinux in patients who may transition to PCI. Bivalirudin can be used in patients managed invasively but not for initial medical management.

Non-PCI-capable hospital, without transfer possibility

Enoxaparin shows net clinical Enoxaparin and fondaparinux benefit over UFH in patients are preferred over UFH. treated with fibrinolytics.

PCI because of the risk of catheter thrombosis, and an additional anticoagulant with anti-IIa activity should be administered (Table 6) [14].

Anticoagulants—recent clinical trials

The 2007 ACC/AHA guideline updates in STEMI and NSTEMI incorporate the findings from prospective, rando- mized, clinical trials. Some of the key findings from trials published since the previous ACC/AHA guidelines are summarized below.

Stemi

Two large, randomized, double-blind trials have been published recently in STEMI patients evaluating alternative anticoagulants to UFH. The Enoxaparin and Thrombolysis Reperfusion for Acute myocardial infarction Treatment- TIMI 25 (EXTRACT-TIMI 25) trial compared enoxaparin with UFH in 20 506 STEMI patients treated with fibrinolytic therapy (streptokinase, tenecteplase, alteplase, or reteplase) and aspirin [60]. Study drugs were administered between 15 minutes before and 30 minutes after starting fibrinolytic treatment. Patients younger than 75 years were given a fixed 30-mg Intravenous bolus of enoxaparin followed 15 minutes later by a subcutaneous injection of 1 mg/kg, which was repeated every 12 hours. The enoxaparin dosing strategy was adjusted according to the patient’s age and renal function. The subcutaneous injection was reduced to 0.75 mg/kg twice daily in patients aged >=75 years and to 1 mg/kg once daily in patients with a creatinine clearance b30 mL/min. No initial intravenous bolus was given to patients with creatinine clearance b30 mL/min. At day 30, death or nonfatal MI occurred in 12.0% of patients treated with UFH compared with 9.9% in those receiving enoxaparin, representing a 17% relative risk reduction (P b.0001). However, enoxaparin was associated with a slightly increased rate of TIMI major bleeding compared with UFH (2.1% vs 1.4%, respectively; P b .0001). The net clinical end point of death, MI, or major bleeding favored enoxaparin over UFH (relative risk, 0.86; 95% confidence interval, 0.80-0.93) [60].

After fibrinolytic therapy, some patients undergo rescue

or adjunctive PCI; and the ExTRACT-PCI substudy evaluated whether enoxaparin is superior to UFH to support these procedures. After fibrinolysis, fewer patients treated with enoxaparin underwent PCI by 30 days (22.8% vs 24.2% with UFH, P = .027). In the subset of 4676 ExTRACT patients subsequently undergoing PCI within 30 days of randomization, death or MI occurred less frequently in enoxaparin-treated patients than in patients treated with UFH (10.7% vs 13.8%, respectively; P b .001). There were no differences in TIMI major bleeding rates (1.4% with enoxaparin vs 1.6% with UFH, P = .56) [61]. Thus, among patients who underwent PCI after fibrinolytic therapy,

enoxaparin administration was associated with a significant reduction in the risk of death or recurrent MI, without any significant increase in the risk of major bleeding.

A recent meta-analysis that included 27 131 STEMI patients compared enoxaparin with UFH and included data from the ExTRACT-TIMI 25 trial. A net clinical benefit of death, MI, or major bleeding was shown for enoxaparin compared with UFH (11.1% vs 12.3%, respectively; P =

.018) [62].

The Organization for the Assessment of Strategies for Ischemic Syndromes-6 (OASIS-6) trial was conducted in

12 092 patients to compare fondaparinux with “usual” treatment, which could consist of fibrinolytic treatment or primary PCI and UFH, or placebo [63]. Death or MI at day 30 was lower with fondaparinux than in the control group (UFH or placebo) (9.7% vs 11.2%, respectively; P = .008). TIMI major bleeding occurred at similar rates in the fondaparinux and control groups (1.0% vs 1.3%, respec- tively; P = .13). In the subgroup of 3769 patients undergoing primary PCI, there were no statistical differences between fondaparinux and UFH in the rates of death or MI (6.1% vs 5.1%, respectively; P = .19) and the incidence of severe bleeds (2.2% vs 1.7%, respectively; P = .27). However, there was a higher incidence of guiding-catheter thrombosis with fondaparinux compared with UFH (22 episodes vs 0 episode, respectively; P b .001) and more coronary complications, such as abrupt coronary artery closure, new angiographic thrombus, catheter thrombus, no reflow, dissection, or perforation (270 vs 225, respectively; P = .04) [63]. These results suggest that the value of fondaparinux in patients with STEMI could be limited to those who are not undergoing PCI.

Nstemi

The efficacy and safety profile of enoxaparin compared with UFH in NSTEMI patients has been compared and published in 6 clinical trials since 1997, which have involved

21 945 patients. In a meta-analysis of these 6 trials, subcutaneous enoxaparin (1 mg/kg twice daily) significantly reduced the incidence of mortality and reinfarction compared with UFH (10.0% vs 11.0%, respectively; P = .043) without a significant increase in the incidence of major bleeds, including intracranial hemorrhage (6.3% vs 5.4%, respec- tively; P = .419) [62].

The most recent of these 6 trials, the Superior Yield of the New strategy of Enoxaparin, Revascularization, and glycoprotein IIb/IIIa inhibitors (SYNERGY) trial, rando- mized high-risk NSTEMI patients destined for an early invasive management strategy to either subcutaneous enoxaparin (1 mg/kg twice daily) or intravenous UFH [64]. The primary end point of death or MI at 30 days was similar between enoxaparin and UFH (14.0% vs 14.5%, respectively; P = .40). Significantly more TIMI-defined major bleeding occurred with enoxaparin (9.1% vs 7.6%, respectively; P = .008). However, in patients on consistent

therapy (who did not change therapy at randomization or at the time of PCI), the rate of death and MI was lower with enoxaparin than with UFH (13.3% vs 15.9%, respectively; P = .004). A higher rate of Global Utilization of Streptokinase and t-PA for Occluded coronary arteries- defined severe (GUSTO) bleeding occurred with consistent enoxaparin therapy compared with UFH (2.9% vs 2.1%, respectively; P = .05) [65]. These data demonstrate the importance of the consistent use of enoxaparin or UFH throughout the care pathway. A subgroup analysis of 4687 patients undergoing PCI in the SYNERGY trial demon- strated similar rates of death or MI at 30 days between enoxaparin and UFH (13.1% vs 14.2%, respectively; P =

.289), with higher TIMI-defined major bleeding with enoxaparin (3.7% vs 2.5%, respectively; P = .028) [66].

In the Organization for the Assessment of Strategies for Ischemic Syndromes-5 (OASIS-5) trial, the efficacy and safety of fondaparinux were compared with those of enoxaparin in 20 078 patients with NSTEMI [67]. In this trial, enoxaparin and fondaparinux had equal rates of death, MI, or refractory ischemia at 9 days (5.7% vs 5.8%, respectively; hazard ratio, 1.01; 95% confidence interval, 0.90-1.13). However, fondaparinux was associated with a significant reduction in major bleeding (4.1% with enox- aparin vs 2.2%, P b .001). The incidence of death at day 180 was significantly lower with fondaparinux compared with enoxaparin (5.8% vs 6.5%, respectively; P = .05). However, in the subgroup of patients undergoing PCI, the combined rate of death, MI, and refractory ischemia was similar with enoxaparin and fondaparinux at 9 days (9.3% vs 8.6%,

respectively) and at 30 days (10.4% vs 9.6%, respectively). Once again, fondaparinux was associated with an increase in the rate of guiding-catheter thrombus formation (29 episodes [0.9%] vs 8 episodes with enoxaparin [0.3%]) [67].

In the Acute Catheterization and urgent intervention Triage Strategy (ACUITY) trial, anticoagulation with the direct thrombin inhibitor bivalirudin (plus or minus GP IIb/IIIa inhibitors) was compared with UFH or enoxaparin (plus GP IIb/IIIa inhibitors) in UA/NSTEMI patients undergoing invasive management [68]. In patients receiv- ing bivalirudin plus GP IIb/IIIa inhibitors, the rate of death, MI, or revascularization (7.7% with bivalirudin vs 7.3%, P = .39) or major bleeding (5.3% with bivalirudin vs 5.7%, P = .38) at 30 days was similar to that in patients receiving UFH or enoxaparin plus GP IIb/IIIa inhibitors. Treatment with bivalirudin alone was associated with similar rates of ischemia compared with treatment with UFH or enoxaparin (7.8% vs 7.3%, respectively; P =

.32), but with lower rates of bleeding (3.0% vs 5.7%, respectively; P b .001).

In summary, results from these clinical trials indicate that both enoxaparin and fondaparinux are associated with a more favorable outcome than UFH. Fondaparinux cannot be used as the sole anticoagulant drug in PCI. Bivalirudin is a treatment option in the invasive manage- ment of NSTEMI patients.

Consistent use of same anticoagulant throughout care pathway

Data from the SYNERGY trial demonstrated the importance of consistent use of enoxaparin or UFH throughout the care pathway. Patients with ACS on enoxaparin can seamlessly transition from the medical management to the interventional management phase with- out the need for introducing a second anticoagulant in the cardiac catheterization laboratory [61,66]. Trials have shown that patients on enoxaparin or UFH can also switch to bivalirudin for PCI without a risk of increased bleeding if bivalirudin is given more than 8 hours after the last dose of LMWH or more than 6 hours after the last dose of UFH [69]. Because fondaparinux cannot be used as the sole antic- oagulant in patients with ACS undergoing PCI [63,67], data are needed on switching from fondaparinux to another anticoagulant at the time of PCI. However, it is debatable whether switching from fondaparinux to another antic- oagulant for PCI is preferable to using a single anticoagulant consistently throughout the care pathway. Key considera- tions for appropriate medical therapy (Figs. 3 and 4) are listed in Table 7.

Conclusions

Key considerations on risk and time stratification lead to differences in treatment strategies between hospitals with or without PCI capability. The relative benefits of an invasive treatment approach compared with medical therapy in patients with ACS are determined by patient risk and the timing of treatment. Pharmacological management is an integral part of all treatment strategies. Given the growing importance of invasive management strategies, a therapy, such as enoxaparin, that is compatible with both medical and invasive treatment options is becoming increasingly impor- tant. By contrast, fondaparinux has shown benefit in patients with ACS treated medically, but cannot be used as the sole anticoagulant drug in patients undergoing PCI. Bivalirudin can be used in NSTEMI patients managed invasively. Thus, hospitals without PCI facilities would benefit from using enoxaparin in EDs and in the transfer of patients because of its efficacy, safety profile, simplicity of administration, and seamless transition from the medical management to the interventional management phase.

References

1. American Hospital Association. The annual survey of hospitals database: documentation for 2000 data. Chicago (Ill): American Hospital Association; 2000.
2. Rogers WJ, Canto JG, Barron HV, et al. Treatment and outcome of myocardial infarction in hospitals with and without invasive capability.

Investigators in the National Registry of Myocardial Infarction. J Am Coll Cardiol 2000;35:371-9.

1. Fox KA, Goodman SG, Anderson Jr FA, et al. From guidelines to clinical practice: the impact of hospital and geographical character- istics on temporal trends in the management of acute coronary syndromes. The Global Registry of acute coronary events (GRACE). Eur Heart J 2003;24:1414-24.
2. Nallamothu BK, Bates ER, Wang Y, et al. Driving times and distances to hospitals with percutaneous coronary intervention in the United States: implications for prehospital triage of patients with ST-elevation myocardial infarction. Circulation 2006;113:1189-95.
3. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000;284:835-42.
4. Morrow DA, Antman EM, Snapinn SM, et al. An integrated Clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes. Application of the TIMI risk score for UA/ NSTEMI in PRISM-PLUS. Eur Heart J 2002;23:223-9.
5. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879-87.
6. Kent DM, Lau J, Selker HP. Balancing the benefits of primary angioplasty against the benefits of thrombolytic therapy for acute myocardial infarction: the importance of timing. Eff Clin Pract 2001;4: 214-20.
7. Thune JJ, Hoefsten DE, Lindholm MG, et al. Simple risk stratification at admission to identify patients with reduced mortality from primary angioplasty. Circulation 2005;112:2017-21.
8. Yan AT, Yan RT, Tan M, et al. Management patterns in relation to risk stratification among patients with non-ST elevation acute coronary syndromes. Arch Intern Med 2007;167:1009-16.
9. Oliveira GB, Avezum A, Anderson Jr FA, et al. Use of proven therapies in non-ST-elevation acute coronary syndromes according to evidence-based risk stratification. Am Heart J 2007;153:493-9.
10. Bhatt DL, Roe MT, Peterson ED, et al. Utilization of early invasive management strategies for high-risk patients with Non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA 2004;292:2096-104.
11. Fox KA, Anderson Jr FA, Dabbous OH, et al. Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events . Heart 2007;93:177-82.
12. Anderson JL, Adams CD, Antman E, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST- Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/non-ST-elevation myocardial infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of thoracic surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1-e157.
13. Granger CB, Goldberg RJ, Dabbous O, et al. Predictors of hospital mortality in the Global Registry of Acute Coronary Events. Arch Intern Med 2003;163:2345-53.
14. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The Pursuit Investigators. Circulation 2000;101:2557-67.
15. Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, Clinical score for risk assessment at presentation: an intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation 2000;102:2031-7.
16. Scirica BM, Cannon CP, Antman EM, et al. Validation of the Thrombolysis In Myocardial Infarction risk score for unstable angina pectoris and non-ST-elevation myocardial infarction in the TIMI III registry. Am J Cardiol 2002;90:303-5.
17. Karounos M, Chang AM, Robey JL, et al. TIMI risk score: does it work equally well in both Males and females? Emerg Med J 2007;24: 471-4.
18. Pollack Jr CV, Sites FD, Shofer FS, et al. Application of the TIMI risk score for unstable angina and non-ST elevation acute coronary syndrome to an unselected emergency department chest pain population. Acad Emerg Med 2006;13:13-8.
19. Chase M, Robey JL, Zogby KE, et al. Prospective validation of the Thrombolysis in Myocardial Infarction risk score in the emergency department chest pain population. Ann Emerg Med 2006;48:252-9.
20. Ramsay G, Podogrodzka M, McClure C, et al. risk prediction in patients presenting with suspected cardiac pain: the GRACE and TIMI risk scores versus clinical evaluation. QJM 2007;100:11-8.
21. Yan AT, Yan RT, Tan M, et al. Risk scores for risk stratification in acute coronary syndromes: useful but simpler is not necessarily better. Eur Heart J 2007;28:1072-8.
22. Lyon R, Morris AC, Caesar D, et al. Chest pain presenting to the emergency department-to stratify risk with GRACE or TIMI? Resuscitation 2007;74:90-3.
23. Jaffery Z, Hudson MP, Jacobsen G, et al. Modified Thrombolysis in Myocardial Infarction risk score to risk stratify patients in the emergency department with possible acute coronary syndrome. J Thromb Thrombolysis 2007;24:137-44.
24. Bradshaw PJ, Ko DT, Newman AM, et al. Validation of the Thrombolysis In Myocardial Infarction (TIMI) risk index for predicting early mortality in a population-based cohort of STEMI and non-STEMI patients. Can J Cardiol 2007;23:51-6.
25. Pollack Jr CV, Diercks DB, Roe MT, et al. 2004 American College of Cardiology/American Heart Association guidelines for the management of patients with ST-elevation myocardial infarction: implications for emergency department practice. Ann Emerg Med 2005;45:363-76.
26. Sagarin MJ, Cannon CP, Cermignani MS, et al. Delay in thrombolysis administration: causes of extended door-to-drug times and the asymptote effect. J Emerg Med 1998;16:557-65.
27. Diercks DB, Kirk JD, Lindsell CJ, et al. Door-to-ECG time in patients with chest pain presenting to the ED. Am J Emerg Med 2006;24:1-7.
28. Pollack Jr CV, Braunwald E. 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST- segment elevation myocardial infarction: implications for emergency department practice. Ann Emerg Med 2007 [Epub ahead of print].
29. Nallamothu B, Fox KA, Kennelly BM, et al. Relationship of treatment delays and mortality in patients undergoing fibrinolysis and primary percutaneous coronary intervention. The Global Registry of Acute Coronary Events. Heart 2007;93:1552-5.
30. De Luca G, Suryapranata H, Ottervanger JP, et al. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation 2004;109:1223-5.
31. Brodie BR, Hansen C, Stuckey TD, et al. Door-to-balloon time with primary percutaneous coronary intervention for acute myocardial infarction impacts late cardiac mortality in high-risk patients and patients presenting early after the onset of symptoms. J Am Coll Cardiol 2006;47:289-95.
32. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mor- tality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283:2941-7.
33. Kleinschmidt K, Brady WJ. Acute coronary syndromes: an evidence- based review and outcome-optimizing guidelines for patients with and without procedural coronary intervention (PCI). Part III: fibrinolytic therapy, procedural coronary intervention, multimodel approaches, and medical prophylaxis with Low Molecular Weight Heparins. Hosp Med Consens Rep 2001:1-16.
34. Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 1997;278: 2093-8.
35. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13-20.
36. Canto JG, Every NR, Magid DJ, et al. The volume of primary angioplasty procedures and survival after acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators. N Engl J Med 2000;342:1573-80.
37. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. N Engl J Med 1997;336:1621-8.
38. Kent DM, Ruthazer R, Griffith JL, et al. Comparison of Mortality benefit of immediate thrombolytic therapy versus delayed primary angioplasty for acute myocardial infarction. Am J Cardiol 2007;99: 1384-8.
39. Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol 2003;92:824-6.
40. Boersma E, The Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter? A Pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in- hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006;27:779-88.
41. Pinto DS, Kirtane AJ, Nallamothu BK, et al. Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy. Circulation 2006;114:2019-25.
42. Widimsky P, Groch L, Zelizko M, et al. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE study. Eur Heart J 2000;21:823-31.
43. Widimsky P, Budesinsky T, Vorac D, et al. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial- PRAGUE-2. Eur Heart J 2003;24:94-104.
44. Widimsky P, Bilkova D, Penicka M, et al. Long-term outcomes of patients with acute myocardial infarction presenting to hospitals without catheterization laboratory and randomized to immediate thrombolysis or interhospital transport for primary percutaneous coronary intervention. Five years’ follow-up of the PRAGUE-2 Trial. Eur Heart J 2007;28:679-84.
45. Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733-42.
46. Grines CL, Westerhausen Jr DR, Grines LL, et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: the Air Primary Angioplasty in Myocardial Infarction study. J Am Coll Cardiol 2002;39:1713-9.
47. Szabo S, Zeymer U, Gitt A, et al. Benefit of onsite reperfusion therapy or transfer to primary PCI in STEMI patients admitted to hospitals without catheterization laboratory. Results of the MITRA PLUS Registry. Acute Card Care 2007;9:87-92.
48. Stenestrand U, Lindback J, Wallentin L, et al. Long-term outcome of primary percutaneous coronary intervention vs prehospital and in- hospital thrombolysis for patients with ST-elevation myocardial infarction. JAMA 2006;296:1749-56.
49. Vermeer F, Oude Ophuis AJ, vd Berg EJ, et al. Prospective randomised comparison between thrombolysis, rescue PTCA, and primary PTCA in patients with extensive myocardial infarction admitted to a hospital without PTCA facilities: a safety and feasibility study. Heart 1999;82: 426-31.
50. Nallamothu BK, Bates ER, Herrin J, et al. Times to treatment in transfer patients undergoing primary percutaneous coronary interven- tion in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation 2005;111:761-7.
51. Ellis S. Final results of the FINESSE (Facilitated Intervention with Enhanced reperfusion Speed to Stop Events) trial: evaluation of abciximab + half dose reteplase, abciximab alone, or placebo for facilitation of primary PCI for ST elevation MI. Abstract 1760. Congress of the European Society of Cardiology, September, Vienna, Austria; 2007.
52. Sinno MC, Khanal S, Al-Mallah MH, et al. The efficacy and safety of combination glycoprotein IIbIIIa inhibitors and reduced-dose throm- bolytic therapy-facilitated percutaneous coronary intervention for ST- elevation myocardial infarction: a meta-analysis of randomized clinical trials. Am Heart J 2007;153:579-86.
53. Grzybowski M, Clements EA, Parsons L, et al. Mortality benefit of immediate revascularization of Acute ST-segment elevation myocardial infarction in patients with contraindications to thrombolytic therapy: a propensity analysis. JAMA 2003;290:1891-8.
54. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med 1999; 341:625-34.
55. Peacock WF, Hollander JE, Smalling RW, et al. Reperfusion strategies in the emergency treatment of ST-segment elevation myocardial infarction. Am J Emerg Med 2007;25:353-66.
56. Cohen M, Diez J, Fry E, et al. Strategies for optimizing outcomes in the NSTE-ACS patient. The CATH (cardiac catheterization and antith- rombotic therapy in the hospital) Clinical Consensus Panel Report. J Invasive Cardiol 2006;18:617-39.
57. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of family physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008;117: 296-329.
58. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477-88.
59. Gibson CM, Murphy SA, Montalescot G, et al. Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST-segment elevation myocardial infarction in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol 2007; 49:2238-46.
60. Murphy SA, Gibson CM, Morrow DA, et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractio- nated heparin across the acute coronary syndrome spectrum: a meta- analysis. Eur Heart J 2007;28:2077-86.
61. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006; 295:1519-30.
62. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45-54.
63. Cohen M, Mahaffey KW, Pieper K, et al. A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: enoxaparin versus unfractionated heparin in non-ST- segment elevation acute coronary syndromes. J Am Coll Cardiol 2006; 48:1346-54.
64. White HD, Kleiman NS, Mahaffey KW, et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Am Heart J 2006;152:1042-50.
65. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, Yusuf S, Mehta SR, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354: 1464-76.
66. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16.
67. Gibson CM, Ten Y, Murphy SA, et al. Association of prerandomiza- tion anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (a REPLACE-2 analysis). Am J Cardiol 2007;99:1687-90.