prehospital treatment of patients with a”>American Journal of Emergency Medicine (2012) 30, 12-17

Original Contribution

Prehospital treatment of patients with acute myocardial infarction with bivalirudin^?

Michael M. Hirschl MD ^a,?, Harald Mayr MD ^a, Friedrich Erhart MD ^b, Walter Brunner MD ^c, Friedrich Steger MD ^d,

Martin Gattermeier MD ^e, Franz Pfeffel MD ^f

^a3rd Medical Department, Landesklinikum St. Polten, A-3100 St. Polten, Austria

^bDepartment of Internal Medicine, Landesklinikum Mostviertel Amstetten, A-3300 Amstetten, Austria ^cDepartment of Internal Medicine, Landesklinikum Mostviertel Melk, A-3390 Melk, Austria ^dDepartment of Internal Medicine, Landesklinikum Mostviertel Scheibbs, A-3270 Scheibbs, Austria

^eDepartment of Internal Medicine, Landesklinikum Mostviertel Waidhofen/Ybbs, A-3340 Waidhofen/Ybbs, Austria

^fDepartment of Internal Medicine, Landesklinikum Voralpenklinik Lilienfeld, A-3180 Lilienfeld, Austria

Received 23 May 2010; revised 8 September 2010; accepted 9 September 2010

Abstract

Objectives: Patients with acute myocardial infarction are at high risk of dying within the first hours after onset of coronary ischemia. Therefore, pharmacological intervention should be started in the prehospital setting. This study investigates the effect of the prehospital administration of bivalirudin on short-term morbidity and mortality compared to heparin plus abciximab in patients with ST-segment-elevation myocardial infarction (STEMI).

Methods: One hundred ninety-eight patients with STEMI treated with bivalirudin in the prehospital setting were prospectively collected. Coronary angiography was performed to identify the infarct-related artery. In case of a percutaneous coronary intervention, bivalirudin was given according to the guidelines. The historic control group consisted of 171 consecutive patients from the same myocardial infarction network treated with unfractioned heparin and abciximab administration before the admission to the emergency department of the percutaneous coronary intervention center. The primary outcome parameter was the incidence of major adverse cardiac events (recurrent myocardial infarction, stroke, death, target vessel revascularization for ischemia) within 30 days after the primary event.

Results: The overall rate of major adverse cardiac events was significantly lower in the bivalirudin group compared to the abciximab group (7.6% vs 14.6%; P = .04). The number of major bleedings was significantly higher in the abciximab group compared to the bivalirudin group (11.8% vs 3.8%; P = .03). Conclusions: The use of bivalirudin in the prehospital setting leads to a reduced rate of major cardiovascular events compared to a standard treatment with abciximab plus heparin. Bivalirudin is a reasonable choice of treatment in the prehospital setting for patients with STEMI.

(C) 2012

^? The study was supported by the Karl Landsteiner Society (Institute of Coronary Artery Disease and Heart Rhythm disturbances).

* Corresponding author. Landesklinikum Waldviertel Zwettl, Abteilung fur Innere Medizin, Propstei 5, A-3910 ZWETTL, Austria. Tel.: +43 2822 504 8151; fax: +43 2822 504 8158.

E-mail address: [email protected] (M.M. Hirschl).

0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2010.09.010

Introduction

Primary percutaneous coronary intervention is the treatment of choice in patients with acute ST-segment- elevation myocardial infarction (STEMI) [1,2]. The optimal prehospital treatment before PCI consisted of aspirin, clopidogrel, and, in some countries, of heparin in combina- tion with glycoprotein IIb/IIIa inhibitors (GPIs) [3-6]. Several studies have demonstrated that bivalirudin, a direct thrombin inhibitor, is comparable to heparin plus GPI in the rate of Ischemic events and death but leads to a significant reduction of Bleeding complications in patients with acute coronary syndrome [7,8]. The HORIZONS-AMI trial showed an improved outcome in patients with STEMI treated with bivalirudin compared to standard treatment consisting of heparin plus GPI [9]. However, an increased rate of acute Stent thrombosis was noted in the bivalirudin group. This study investigates the effect of the prehospital administration of bivalirudin on short-term morbidity and mortality compared to the prehospital administered combi- nation of heparin and abciximab in patients with STEMI.

Methods

Study design

It is an observational study, which included patients with acute myocardial infarction over a 3-year period. The data of all patients with an STEMI diagnosed out of hospital by an emergency physician between April 1, 2006, and June 30, 2009, were consecutively collected. The study was approved by the Ethical Committee of the Government of the Federal State of Lower Austria. All patients gave their informed consent to use their data for study purposes.

Study setting and population

All patients with an STEMI diagnosed out of hospital within the Lower Austrian Myocardial Infarction Network were included. The network consisted of 5 emergency medical services and 5 primary care hospitals located in the western part of Lower Austria. The emergency medical services in Austria consisted of a physician with a specific education in emergency medicine and 2 paramedics. The PCI center is located in St Poelten, and the average distance from the emergency medical service stations to the PCI center was

82 km. ST-segment-elevation myocardial infarction was defined as (1) anterior myocardial infarction (>=2 mm ST- segment elevation in >=2 of the leads I, aVL, and V₁-V₆) or

(2) Inferior myocardial infarction (>=1 mm ST-segment elevation in >=2 leads II, III, aVF, and V₅-V₆). All patients with STEMI are transferred directly to Primary PCI with a treatment delay of less than 120 minutes from the first medical contact. The diagnosis of an STEMI was assessed by the physician of the emergency medical service alone.

Study protocol

Diagnosis of STEMI was confirmed by the emergency physician of the prehospital operating emergency medical service. Between April 1, 2008, and June 30, 2009, the medication given in the ambulance included 250 mg aspirin, 600 mg clopidogrel, a bolus of bivalirudin (0.1 mg/kg), followed by a continuous infusion of bivalirudin (0.25 mg/kg per hour). The emergency physician used this predefined treatment protocol in all patients with STEMI. However, the final decision to fulfill the criteria of the protocol depended only on the emergency physician on duty. Oxygen, nitroglycerine, ?-blockers, and morphine were administered as needed. Electrocardiogram (ECG) and peripheral oxygen saturation were monitored continuously during the transport to the PCI center. Blood pressure was measured every 5 minutes with an automated oscillographic blood pressure unit. After arrival in the emergency department (ED) of the PCI center, the patient was transferred immediately to the catheterization suite. Coronary angiography was performed to identify the infarct-related artery. In case of a PCI, an additional bolus of bivalirudin was given (0.5 mg/kg) followed by an increase of the continuous infusion (1.75 mg/kg per hour) until the guide wire was removed. At end of the procedure, the bivalirudin infusion was reduced to 0.25 mg/kg per hour and was administered for at least 4 hours. Primary PCI was done without the use of GPI. In case of bailout or thrombectomy, the use of an additional GPI was at the PCI operator’s discretion.

The data of the historic control group were collected between April 1, 2006, and March 31, 2008, and consisted of consecutive patients from the same myocardial infarction network diagnosed with STEMI using the same criteria. Treatment of these patients was similar to the bivalirudin group except that these patients had been treated with unfractioned heparin given 60 IU/kg (maximum dose of 4000 IU) intravenously followed by a continuous infusion of 1000 IU/h in the ambulance and abciximab (dose bolus, 0.25 mg/kg followed by a continuous infusion [dose, 0.125 ug/ kg/ per minute]) administration before the admission to the ED of the PCI center.

Measurements

The primary outcome parameter was the frequency of Major adverse cardiac events within the first 30 days after acute myocardial infarction in both treatment groups. Secondary parameters included overall mortality and bleeding complications.

MACE included the following events: death, reinfarction, target vessel revascularization for ischemia, and stroke. Fatal events were retrieved from the Statistical Department of the Austrian government, which collected the causes of death of all patients who died in a hospital in Austria. Patients who died of a noncardiovascular cause were considered event- free until death. Bleeding complications were divided into

major and minor bleedings. Major bleeding included intracranial, retroperitoneal, intraocular, or access site hemorrhage requiring radiologic or surgical intervention as well as the use of any blood product transfusion. All other bleeding was defined as minor bleeding. All patients discharged before day 30 were called on day 30 after the acute event by a physician to evaluate the time interval between discharge and day 30 with regard to MACE. In case of an event, the clinical record of the hospital was requested to evaluate the kind and clinical relevance of the event.

The data of all patients were prospectively registered in the database of the Lower Austrian Myocardial Infarction Network. Individual patient data were handled in a blinded fashion and the registry was performed according to the Helsinki criteria. The preclinical data were noted in an established STEMI record by the emergency physician on duty. Clinical events and bleeding complications were primarily kept in the records by the cardiologist on duty. The data from the preclinical records as well as from the clinical records were transferred into the myocardial infarction network database.

Data collection and analysis

Analysis of data with regard to MACE and bleeding complications were performed by 2 physicians (a cardiologist and an emergency physician) blinded to treatment. The patient characteristics and complications of both groups were compared using ?2 statistics for categorical variables and the Mann-Whitney U test for continuous variables. Analyses were performed using Statistical Package for Social Sciences, version 13.0 (SPSS, Chicago, Ill). The level of significance was determined as P b .05. The study was approved by the Ethical Committee of the Lower Austrian Government.

Results

A total of 383 patients were included into the study. Fourteen patients (bivalirudin: n = 4, abciximab: n = 10) have been lost during follow-up. Overall, the data of 369 patients were used for further analysis. Of these, 198 (53.7%) were treated with bivalirudin and 171 (46.3%) received heparin plus abciximab. No differences in baseline char- acteristics were observed between both groups (Table 1). Time from onset of pain to first medical contact (144 +- 145 vs 132 +- 128 minutes; not significant) and Transfer times were comparable. The time interval from first ECG to the admission of the ED was similar in both treatment groups (73 +- 58 vs 79 +- 59 minutes; not significant; Table 2). Of 369 patients, 345 (93.5%) underwent primary PCI. The distribu- tion of the infarct-related artery and the number of stents used was similar in both treatment groups (Table 3).

The proportion of patients with MACE within the first 30 days is shown in Fig. 1. Overall, 40 major cardiovascular

Variable	Bivalirudin group (n =		198)	Heparin + abciximab group (n = 171)		P
Age (y)	64.6	(11.2)	65.5 (12.5)			.76
Men	129	(65%)	115		(67%)	.74
Hypertension	117	(59%)	98		(57%)	.75
Dyslipidemia	71	(36%)	63		(37%)	.91
Current smoker	71	(36%)	58		(34%)	.74
Diabetes	36	(18%)	31		(18%)	1.0
mellitus
Previous MI	22	(11%)	17		(10%)	.62
Previous CABG	18	(9%)	13		(8%)	.71
Previous PCI	32	(16%)	24		(14%)	.66
anterior MI	75	(38%)	66		(39%)	.92
Inferior MI	85	(43%)	79		(46%)	.53
No MI location	38	(19%)	26		(15%)	.34
CABG indicates coronary artery bypass graft.

events were noted during the follow-up period. The number of major cardiovascular events was significantly lower in the bivalirudin group compared to the historic control group (7.6% vs 14.6%; P = .04). Cardiovascular cause of death occurred in 16 patients (bivalirudin: n = 5, abciximab: n = 11; P = .08). The most frequently observed cause of death was reinfarction (bivalirudin: n = 3, abciximab: n = 7). Other causes of Cardiovascular death were stroke (n = 1) and heart failure (n = 1) in the bivalirudin group, and heart failure (n = 2), stroke (n = 2) in the abciximab group. Subacute stent thrombosis as a cause of a fatal reinfarction was observed in 2 patients of the bivalirudin group and 2 patients of the abciximab group. The combined overall mortality within 30 days was 3.5% (n = 7) in the bivalirudin group and 7% (n = 12) in the abciximab group (P = .16). Three patients died of nonCardiovascular causes of death (car accident [n = 1, bivalirudin], gastrointestinal bleeding [n = 1, abciximab], suicide [n = 1, bivalirudin]). Fig. 2 illustrates the componentsof MACEforeachgroup. Thecumulativesurvival without MACE for both groups is illustrated in Fig. 3. A significant difference in favor of bivalirudin was noted during the 30-day observation period (P = .043).

Table 1 General characteristic of patients with STEMI admitted to the ED

Significant fewer bleeding complications occurred in the bivalirudin group. The number of major bleedings-

Table 2 Time intervals from onset of symptoms to PCI in both groups

Variable Bivalirudin Heparin + abciximab P

group (n = 198) group (n = 171)

Onset of pain to first ECG (min)

First ECG-ED (min)

ED-PCI (min)

144 (145)

132 (128)

.24

73 (58)

79 (59)

.36

38 (36)

31 (38)

.31

Values are given as mean and SD.

12

Table 3 Catheterization suite data for patients receiving primary PCI stratified by treatment group

P = .08 11

P = .18

9

5

5

3 3

2 2

Bivalirudin Abciximab

10

Variable	Bivalirudin group (n = 198)	Heparin + group (n =	abciximab 171)	P
Killip class III and IV	14 (7%)	12 (7%)	1.0
TIMI score 0,	125 (63%)	96 (56%)	.20
1 prior PCI
Primary PCI	186 (94%)	159 (93%)	.83
CABG	8 (4%)	7 (4%)	1.0
No Intervention	4 (2%)	5 (3%)	.74
Infarct-related artery
Left main	20 (10%)	17 (10%)	.86
Left anterior	91 (46%)	75 (44%)	.75
descending
Left circumflex	36 (18%)	33 (19%)	.79
Right	51 (26%)	46 (27%)	.81
No. of affected vessels
One-vessel	103 (52%)	91 (53%)	.84
disease
Two-vessel disease	57 (29%)	48 (28%)	.91
Three-vessel	38 (19%)	32 (19%)	1.0
disease
No. of stents
Stenting	178	145
0	8 (4%)	14 (8%)	.12
1	113 (57%)	94 (55%)	.75
2	45 (23%)	41 (24%)	.81
>=3	20 (10%)	10 (6%)	.18

8

6

4

2

0

CV-Death Reinfarction Stroke Revascularization

Fig. 2 Components of MACE in each group.

intracranial, retroperitoneal, intraocular, or access site hemorrhage requiring radiologic or surgical intervention as well as the use of any blood product transfusion-was significantly higher in the abciximab group compared to the bivalirudin group (11.8% vs 3.8%; P = .03).

Fig. 1 Frequency of MACE and cardiovascular death in both groups.

Discussion

A comparison between bivalirudin and abciximab combined with heparin both given in the prehospital setting have not been published until now. The frequency of major cardiovascular events within the first 30 days was signifi- cantly lower in the bivalirudin group. The study confirmed the advantages of bivalirudin representing fewer bleeding complications and a lower rate of major cardiac events. Similar results has been published by the HORIZONS-AMI study group, which demonstrated a reduction of net adverse clinical events in the bivalirudin group compared to abciximab even 1 year after the acute event. Our data demonstrated that the Prehospital use of bivalirudin had a beneficial effect on the frequency of major adverse cardiovascular events in patients with STEMI transferred to primary PCI. The results of the current study confirm the efficacy of bivalirudin in the management of patients with STEMI even in the prehospital setting. Our data are also in line with previous data demonstrating that the prehospital use of bivalirudin has no adverse effect on transportation time to the hospital. Sejersten et al [10] have demonstrated that

Fig. 3 Cumulative survival without MACE in both treatment groups.

bivalirudin can be easily administered in the prehospital setting without increasing the “scene time.” Bivalirudin can be stored without refrigeration and is easy to handle for the staff of the emergency medical service. These properties are important for its use in the prehospital setting.

In addition, we found a significant reduction of major bleeding complications in the bivalirudin group compared to heparin plus abciximab. These data are in line with the ACUITY study, which demonstrated a similar reduction in bleeding complications compared with heparin plus GPI in patients with unstable angina or non-STEMI [7]. Our bleeding rate of 3.8% in the bivalirudin group was nearly identical to the data provided by the HORIZON trial, which is the only randomized trial investigating bivalirudin vs heparin plus abciximab in patients with STEMI and primary PCI [9]. Bleeding complications in patients with acute coronary syndrome are associated with an increased morbidity and mortality [11-13]. The reasons for this increase are not quite clear but might result from an increase of ischemic events due to the activation of clotting or the pause in antithrombotic therapies because of bleeding. Other reasons may be hypotension or complications after transfu- sion. The present study support previous findings that the prehospital use of bivalirudin did not increase the rate of major bleeding events in the subsequent hospital stay.

A limitation of the study was the use of a historic control group. However, the management of patients did not differ in both groups neither in the prehospital nor in the hospital setting. The data were collected from consecutive patients treated with bivalirudin and compared with consecutive patients treated with heparin plus abciximab in the preceding years.

Patients with acute myocardial infarction are at high risk of dying within the first hours after onset of coronary ischemia [14]. It is crucial to initiate treatment as early as possible [15,16]. The current practice in Austria is to administer 250 to 500 mg aspirin, 300 to 600 mg clopidogrel, and unfractioned heparin in the ambulance to all patients diagnosed with STEMI [17]. However, unfractioned heparin might not be the best choice in this setting because it only inhibits soluble thrombin and also activates platelets. Therefore, heparin was combined with abciximab, which is very effective with regard of thrombin-mediated platelet activation but has a considerable risk of major bleeding complications [9]. In contrast, bivalirudin binds specifically to thrombin and inhibits both free and clot-bound thrombin. The substance also prevents thrombin-mediated platelet activation and aggregation. In addition, the half-life of bivalirudin is 25 minutes, which makes the antiocoagulation easily controllable in patients with STEMI [18].

Our study clearly demonstrated advantages of bivalirudin in the prehospital setting to patients with STEMI. Bivalirudin was easy to handle and did not increase the transfer times to the hospital. The prehospital administration of bivalirudin was more effective with regard to morbidity and mortality compared to a treatment of heparin plus abciximab. The rate

of bleeding complications was significantly lower in the bivalirudin group. Bivalirudin is a reasonable therapeutic alternative compared to standard of care with heparin and abciximab in the prehospital setting. However, larger randomized trials such as the future European Ambulance Acs Angiox Trial are necessary to provide long-term data about the efficacy and safety of bivalirudin in the prehospital setting.

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