Methods

The HORIZONS-AMI trial was a prospective, open-label, dual-arm, factorial, randomized, multicenter trial in which bivalirudin alone was compared to heparin plus a glycoprotein IIb/IIIa inhibitor, and paclitaxel-eluting stents were compared to bare metal stents in patients with STEMI undergoing primary PCI. The study enrolled 3,602 patients from March 2005 to May 2007 among 123 hospitals in 11 countries. Consecutive patients aged ≥18 years who presented within 12 hours after the onset of symptoms and who had STEMI of ≥1 mm in ≥2 contiguous electrocardiographic leads, new left bundle branch block, or true posterior myocardial infarction were considered for enrollment. The exclusion criteria have been previously reported and included contraindications to the study medications, bleeding diathesis, planned surgery within 6 months that would require interruption of thienopyridine therapy, previous (within 30 days) stenting, or life expectancy <1 year. Patients were not excluded because of cardiogenic shock, previous cardiac arrest, or other high-risk conditions. The institutional review board or ethics committee at each participating hospital approved the study, and all patients gave written informed consent. Patients enrolled in this trial had presented either directly to a tertiary PCI hospital or to a non-PCI hospital and were subsequently transferred to a PCI hospital. Informed consent was obtained at the study PCI hospital, where patients were randomly assigned using a computerized, interactive, voice-response system in a 1:1 ratio to treatment with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor or bivalirudin alone. After coronary angiography, 3,011 patients with lesions eligible for stenting were subsequently randomized in a 3:1 ratio to either a slow rate-release paclitaxel-eluting stent (TAXUS Express, Boston Scientific, Natick, Massachusetts) or an otherwise identical uncoated bare metal stent (Express, Boston Scientific). Clinical follow-up examinations for all patients undergoing primary randomization was performed at 30 days, 6 and 12 months, and then yearly for 5 years.

Of the HORIZONS-AMI patients who underwent primary PCI (n = 3,340, 92.7%), only those presenting directly to a PCI-capable hospital were included in the present analysis (n = 2,440; Figure 1 ). Patients arriving to non-PCI hospitals who were subsequently transferred for primary PCI were excluded from the present analysis to avoid a potential referral bias. All study patients were stratified according to the day and time of arrival into on-hours and off-hours groups. On-hours was defined as weekdays from 8:00 a.m. to 5:00 p.m . Off-hours was defined as weekdays from 5:00 p.m. to 8:00 a.m. and all weekends and holidays (according to each country’s calendar holidays). The catheterization laboratory response teams remained off site in all participating hospitals during off-hours and were called in emergently for each individual STEMI case according to each hospital’s STEMI alert protocol.

Study population flow diagram. CABG = coronary artery bypass grafting; pPCI = primary percutaneous coronary intervention.

All end point events were adjudicated through the use of original source documentation by an independent committee who was unaware of the treatment allocation. The primary end points of the present study were death, major adverse cardiovascular events (MACE), and net adverse clinical events during the in-hospital, 1-year, and 3-year follow-up points. MACE was defined as death, reinfarction, stroke, or unplanned target vessel revascularization for ischemia. Net adverse clinical events included the composite of MACE and major bleeding not related to coronary artery bypass grafting. Major bleeding was considered as any of the following: intracranial, intraocular, or peritoneal bleeding; access site hemorrhage requiring surgery or a radiologic or interventional procedure; hematoma ≥5 cm in diameter at the arterial access site; a decrease in the hemoglobin level of ≥4 g/dl without an overt bleeding source or ≥3 g/dl with an overt source; and bleeding that required transfusion or reoperation. Bleeding was also assessed and adjudicated on the basis of the Thrombolysis In Myocardial Infarction and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scales. A subanalysis of the total ischemic time was performed to assess for differences between the patients treated on- and off-hours.

All study patients were given 325 mg oral or 500 mg intravenous aspirin in the emergency room, after which 300 to 325 mg was given daily during their hospitalization, followed by 75 to 81 mg/day indefinitely. A loading dose of clopidogrel (either 300 or 600 mg) or ticlopidine (500 mg), in case of clopidogrel allergy, was administered before catheterization, followed by 75 mg/day orally for ≥6 months. Heparin plus a glycoprotein IIb/IIIa inhibitor or bivalirudin alone was administered according to the randomization protocol of the original HORIZONS-AMI study design. Heparin was administered as an intravenous bolus of 60 IU/kg, with subsequent boluses targeted to an activated clotting time of 200 to 250 seconds. Bivalirudin was administered as an intravenous bolus of 0.75 mg/kg, followed by an infusion of 1.75 mg/kg/hour. Both antithrombin agents were discontinued, as specified by the protocol, at the completion of angiography or PCI but could be continued at low doses, if clinically indicated. A glycoprotein IIb/IIIa inhibitor was routinely administered before PCI in the control group and was administered in the bivalirudin group only in patients with no reflow or with large thrombus burden during PCI. Either abciximab (a bolus of 0.25 μg/kg followed by an infusion of 0.125 μg/kg/min; maximum dose 10 μg/min) or double bolus of eptifibatide (a bolus of 180 μg/kg followed by an infusion of 2.0 μg/kg/min, with a second bolus given 10 minutes after the first; no maximum dose was prespecified), adjusted for renal impairment according to the label, was permitted at the discretion of the investigator and was continued for 12 hours for abciximab or 12 to 18 hours for eptifibatide. After the establishment of a patent infarct vessel, eligible patients undergoing primary PCI were randomized to a paclitaxel-eluting stent or bare metal stent, as described. The study investigators were given the discretion to choose the vascular access site, guidewire type, thrombectomy catheter, and all other additional procedure-related techniques.

The following points were prospectively obtained: (1) time of symptom onset, available for 2,416 cases (99%), (2) time of arrival to the PCI hospital (door time), available for 2,368 patients (97%), (3) catheterization laboratory arrival time, available for 2,434 patients (99%), and (4) first balloon inflation time, available for 2,177 patients (89%). These data were used to determine the following 5 intervals: (1) symptom-to-door time, (2) door-to-balloon (DTB) time, (3) total ischemic time (TIT), equal to the sum of the symptom-to-door and DTB times, available for 2,088 patients (86%), (4) total procedure time, and (5) hospital length of stay.

Categorical outcomes were compared using the chi-square test or Fisher’s exact test. Continuous data are reported as the median and interquartile range and were compared using the Wilcoxon rank sum test. Differences in mortality, MACE, and net adverse clinical events between the on- and off-hours primary PCI patients during the follow-up period were assessed using the Kaplan-Meier method and compared using the log-rank test. Multivariate logistic regression analysis was conducted to evaluate the adjusted effect estimates associated with presentation during off-hours for primary PCI. For the analysis, the prespecified end point variables of death, MACE, and net adverse clinical events were considered the dependent variables of interest. The following variables were included in the multivariate regression analysis models: age, gender, Killip class II to IV, baseline Thrombolysis In Myocardial Infarction flow of 0 or 1, creatinine level, hemoglobin level, 10% decrease in left ventricular ejection fraction, randomization to bivalirudin, history of diabetes mellitus, smoking history, DTB, TIT, left anterior descending infarct artery, and administration of clopidogrel.

Results

Of the 2,440 patients included in the present substudy, 1,205 (49%) arrived to a PCI hospital during on-hours and 1,235 (51%) during off-hours. The median age was 60.2 years (interquartile range 52.4 to 69.7), with 76.6% men and 16.8% diabetics. The baseline demographic characteristics are listed in Table 1 . The on-hours patients had, on average, a greater prevalence of previous angina (p = 0.008), and those presenting during off-hours were more likely to report a history of hyperlipidemia (p = 0.043) and to be of Killip class II-IV (p = 0.01). The study medications, angiographic findings, and procedure characteristics are summarized in Table 2 . Patients in the on-hours group were more likely to receive a 600-mg loading dose of clopidogrel (on-hours 66.4% vs off-hours 61.8%; p = 0.021). The culprit artery was the right coronary artery in 41.7% and left anterior descending artery in 40.9%; 4.2% of patients had multiple vessels treated. The PCI procedures during on-hours were characterized by a greater use of aspiration thrombectomy catheters (on-hours 14.4% vs off-hours 10.4%; p = 0.004). Stents were implanted in ≤93.4% of patients; 74.9% were paclitaxel-eluting stents and 25.1% were bare metal stents, with symmetric distribution between the on- and off-hour groups.

The intervals recorded during the study are summarized in Table 3 . The symptom-to-door time (p = 0.66) and total procedure time (p = 0.11) were similar between the 2 groups; however, the patients with STEMI who presented during off-hours had significantly longer delays and prolonged “emergency room to catheterization laboratory arrival time” (53 vs 47 minutes; p = 0.037), DTB time (92 vs 75 minutes; p <0.0001), and TIT (209 vs 194 minutes; p <0.0001). No differences were observed in the median hospital length of stay (p = 0.26).

The mean death rate for the study population was 2.4%, 4.2%, and 6.5% during the in-hospital, 1-year, and 3-year follow-up period, respectively ( Table 4 ). The patients with STEMI admitted during off-hours had comparable adjudicated rates of death, MACE, and net adverse clinical events at both short- and long-term follow-up. A greater in-hospital reinfarction rate was observed in the off-hours group (p = 0.021); however, the reinfarction rates were not significantly different at 1 and 3 years of follow-up. The Kaplan-Meier survival curves for the 3 primary end points are shown for the 36-month study period ( Figure 2 ).

Table 4

In-hospital, 1-year, and 3-year clinical outcomes of on- and off-hours patients

	In-hospital Outcome			1-y Outcome			3-y Outcome
	On-hours (n = 1,205)	Off-hours (n = 1,235)	p Value	On-hours (n = 1,205)	Off-hours (n = 1,235)	p Value	On-hours (n = 1,205)	Off-hours (n = 1,235)	p Value
Major adverse cardiovascular events ∗	45 (3.7%)	57 (4.6%)	0.277	133 (11.3%)	149 (12.3%)	0.482	252 (21.9%)	264 (22.1%)	0.830
Death	23 (1.9%)	35 (2.8%)	0.134	43 (3.6%)	56 (4.6%)	0.238	75 (6.5%)	78 (6.5%)	0.934
Reinfarction	7 (0.6%)	19 (1.5%)	0.021	41 (3.6%)	46 (3.9%)	0.664	83 (7.5%)	82 (7.1%)	0.803
Target vessel revascularization for ischemia	24 (2.0%)	22 (1.8%)	0.703	78 (6.8%)	81 (6.9%)	0.979	147 (13.1%)	160 (13.9%)	0.622
Any stroke	3 (0.2%)	2 (0.2%)	0.684	10 (0.9%)	10 (0.8%)	0.951	21 (1.9%)	17 (1.5%)	0.465
Net adverse clinical events †	114 (9.5%)	123 (10.0%)	0.677	201 (17.1%)	213 (17.4%)	0.798	311 (26.8%)	328 (27.3%)	0.784
Major bleeding (noncoronary artery bypass graft)	81 (6.7%)	84 (6.8%)	0.938	91 (7.6%)	93 (7.6%)	0.976	101 (8.6%)	107 (8.9%)	0.821

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