Role of the paclitaxel-eluting stent and tirofiban in patients with ST-elevation myocardial infarction undergoing postfibrinolysis angioplasty: the GRACIA-3 randomized clinical trial.

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Circulation: Cardiovascular Interventions is published by the American Heart Association. 7272 Greenville

DOI: 10.1161/CIRCINTERVENTIONS.109.920868

2010;3;297-307;

Circ Cardiovasc Interv

Fernández-Avilés

Armando Pérez de Prado, Joaquin J. Alonso, J. Alberto San Román and Francisco

Francisco Bosa, Ignacio Santos, Juan Sanchis, Armando Bethencourt, Juan López-Messa,

Pedro L. Sánchez, Federico Gimeno, Pablo Ancillo, Juan J. Sanz, Juan H. Alonso-Briales,

Randomized Clinical Trial

Myocardial Infarction Undergoing Postfibrinolysis Angioplasty : The GRACIA-3

Role of the Paclitaxel-Eluting Stent and Tirofiban in Patients With ST-Elevation

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Role of the Paclitaxel-Eluting Stent and Tirofiban in

Patients With ST-Elevation Myocardial Infarction

Undergoing Postfibrinolysis Angioplasty

The GRACIA-3 Randomized Clinical Trial

Pedro L. Sa´nchez, MD, PhD; Federico Gimeno, MD, PhD; Pablo Ancillo, MD, PhD;

Juan J. Sanz, MD, PhD; Juan H. Alonso-Briales, MD, PhD; Francisco Bosa, MD, PhD;

Ignacio Santos, MD, PhD; Juan Sanchis, MD, PhD; Armando Bethencourt, MD, PhD;

Juan Lo´pez-Messa, MD, PhD; Armando Pe´rez de Prado, MD, PhD; Joaquin J. Alonso, MD, PhD;

J. Alberto San Roma´n, MD, PhD; Francisco Ferna´ndez-Avile´s, MD, PhD

Background—A catheter-based approach after fibrinolysis is recommended if fibrinolysis is likely to be successful in patients with acute ST-elevation myocardial infarction. We designed a 2⫻2 randomized, open-label, multicenter trial to evaluate the efficacy and safety of the paclitaxel-eluting stent and tirofiban administered after fibrinolysis but before catheterization to optimize the results of this reperfusion strategy.

Methods and Results—We randomly assigned 436 patients with acute ST-elevation myocardial infarction to (1) bare-metal stent without tirofiban, (2) bare-metal stent with tirofiban, (3) paclitaxel-eluting stent without tirofiban, and (4) paclitaxel-eluting stent with tirofiban. All patients were initially treated with tenecteplase and enoxaparin. Tirofiban was started 120 minutes after tenecteplase in those patients randomly assigned to tirofiban. Cardiac catheterization was performed within the first 3 to 12 hours after inclusion, and stenting (randomized paclitaxel or bare stent) was applied to the culprit artery. The primary objectives were the rate of in-segment binary restenosis of paclitaxel-eluting stent compared with that of bare-metal stent and the effect of tirofiban on epicardial and myocardial flow before and after mechanical revascularization. At 12 months, in-segment binary restenosis was similar between paclitaxel-eluting stent and bare-metal stent (10.1% versus 11.3%; relative risk, 1.06; 95% confidence interval, 0.74 to 1.52; P⫽0.89). However, late lumen loss (0.04⫾0.055 mm versus 0.27⫾0.057 mm,P⫽0.003) was reduced in the paclitaxel-eluting stent group. No evidence was found of any association between the use of tirofiban and any improvement in the epicardial and myocardial perfusion. Major bleeding was observed in 6.1% of patients receiving tirofiban and in 2.7% of patients not receiving it (relative risk, 2.22; 95% confidence interval, 0.86 to 5.73;P⫽0.14).

Conclusions—This trial does not provide evidence to support the use of tirofiban after fibrinolysis to improve epicardial and myocardial perfusion. Compared with bare-metal stent, paclitaxel-eluting stent significantly reduced late loss but appeared not to reduce in-segment binary restenosis.

Clinical Trial Registration—URL: http://clinicaltrials.gov. Unique identifier: NCT00306228. (Circ Cardiovasc Interv. 2010;3:297-307.)

Key Words:acute myocardial infarction _䡲 fibrinolysis _䡲 postfibrinolysis angioplasty _䡲 tirofiban _䡲 IIb/IIIa inhibitors

䡲 paclitaxel _䡲 drug-eluting stents

T

he preferred reperfusion therapy in patients with acute ST-elevation myocardial infarction (STEMI) is primary percutaneous coronary intervention (PCI).1 _{However, many}

hospitals, even in the United States and Europe, lack PCI

facilities, and few provide around-the-clock staffing for these procedures.2 _{Thus, fibrinolysis is administered to eligible}

patients if primary PCI cannot be performed in a timely fashion. Recent studies have demonstrated that routine

ad-Received November 3, 2009; accepted June 10, 2010.

From the Hospital General Universitario Gregorio Maranõń (P.L.S., F.F.-A.), Madrid, Spain; Hospital Clínico de Valladolid (F.G., J.A.S.R.), Spain; Hospital General de Segovia (P.A.), Spain; Hospital Rio Hortega (J.J.S.), Valladolid, Spain; Hospital Virgen de la Victoria (J.H.A.-B.), Ma´laga, Spain; Hospital Universitario de Canarias (F.B.), Santa Cruz de Tenerife, Spain; Hospital Universitario de Salamanca (I.S.), Spain; Hospital Clínico Universitario (J.S.), Valencia, Spain; Hospital Son Dureta (A.B.), Palma de Mallorca, Spain; Hospital Rio Carrioń (J.L.-M.), Palencia, Spain; Complejo Hospitalario de Leon (A.P.), Spain; and Hospital de Fuenlabrada (J.J.A.), Madrid, Spain.

The GRACIA-3 (Grupo de Ana´lisis de la Cardiopatía Isque´mica Aguda) Investigators and centers are listed in the Appendix.

The online-only Data Supplement is available at http://circinterventions.ahajournals.org/cgi/content/full/CIRCINTERVENTIONS.109.920868/DC1.

Correspondence to Francisco Fernańdez-Avile´s, MD, Servicio de Cardiología, Hospital General Universitario Gregorio Maranõń, C/Doctor Esquerdo 46, 28007, Madrid, Spain. E-mail [email protected]

Circ Cardiovasc Intervis available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.109.920868

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junctive or early postfibrinolytic angiography and, if appro-priate, PCI may improve outcome.3–11 _{This approach}

com-bines the advantages of the rapid and simple use of fibrinolysis for myocardial salvage with those of stenting in achieving a normal stable flow and is a reasonably useful strategy in most patients even in the absence of ischemia at rest or after stress, arrhythmias, left ventricular dysfunction, or heart failure.12,13 _{However, the most effective dose and}

timing of antiplatelet therapy remains unresolved, as does the safety and efficacy of drug elution.

Editorial see p 294

Clinical Perspective on p 307

We performed an open-label, 2⫻2, controlled, randomized trial in STEMI patients receiving fibrinolysis, enoxaparin, and aspirin followed by early cardiac catheterization and coronary stenting to compare the efficacy of the paclitaxel-eluting stent with that of the conventional bare-metal stent in restenosis. We also determined the effect of tirofiban admin-istered 120 minutes after fibrinolysis but before PCI on epicardial and myocardial flow both before and after mechan-ical revascularization.

Methods

Patient Population

From October 2004 to August 2006, patients were enrolled from 20 Spanish hospitals, 13 of which had interventional facilities. The inclusion criteria were as follows: age 18 years or older; symptom onset within 12 hours before random assignment; chest pain lasting more than 30 minutes; ST-segment elevation of at least 0.1 mV in at least 2 limb leads, ST-segment elevation of at least 0.2 mV in 2 or more contiguous precordial leads, or left bundle-branch block or paced rhythm; and no severe heart failure (Killip class⬍3). The exclusion criteria were as follows: cardiogenic shock, defined as a systolic blood pressure ⬍90 mm Hg with no response to fluid administration or⬍100 mm Hg in patients with supportive treatment and no bradycardia; suspected mechanical complications of acute myocardial infarction; previous coronary artery bypass graft; non-cardiac disease that is likely to jeopardize the planned termination of the study; women of childbearing potential unless they had a negative pregnancy test result; active bleeding and recent surgery (within 2 weeks) that contraindicate the use of heparin, tirofiban, or platelet aggregation inhibitors; contraindications for thrombolysis (previous hemorrhagic stroke at any time, history of nonhemorrhagic cerebrovascular accident within the previous 12 months, intracere-bral neoplasm, active internal bleeding, suspected aortic dissection, uncontrolled hypertension⬎180/110 in several measurements, any other known intracerebral condition not covered in contraindications, current use of anticoagulants or heparin use within 8 hours, known bleeding diathesis, recent trauma [⬍4 weeks] including head trauma or traumatic or prolonged [⬎10 minutes] cardiopulmonary resusci-tation or recent major surgery or biopsy [⬍8 weeks], noncompress-ible vascular punctures, recent [⬍4 weeks] internal bleeding, preg-nancy, and active peptic ulcer); history of hypersensitivity to aspirin, ticlopidine, clopidogrel, heparin, tirofiban, or stainless steel; known renal failure, creatinine ⬎2.5 mg/dL; known impaired hepatic function that contraindicates the use of clopidogrel; known throm-bocytopenia (⬍100 000); participation in other trials; known mul-tivessel disease identified as not suitable for revascularization; and known peripheral vascular disease that makes cardiac catheterization difficult.

Approval was obtained from the relevant ethics committees at both national and institutional level. An informational brochure was provided to each patient who met the inclusion criteria, and informed written consent was obtained. All patients were then randomly assigned using a central telephone system, and the doctors who

informed the patient rang for the allocation. Blocking was used to generate the random allocation sequence and to ensure a close balance of the numbers in each group at any time during the trial. The block lengths were 4, 8, and successive 4 size blocks. Patients admitted to noninterventional hospitals were transported to the nearest interventional hospital and returned to the original hospital after angiography and revascularization.

Study Protocol and Interventions

After providing informed consent, patients who satisfied the inclu-sion and excluinclu-sion criteria were randomly assigned to 1 of 4 treatment groups: (1) metal stent without tirofiban, (2) bare-metal stent with tirofiban, (3) paclitaxel-eluting stent without tirofi-ban, and (4) paclitaxel-eluting stent with tirofiban. All patients received fibrinolysis and aspirin, and the use of tirofiban or paclitaxel-eluting stent was evaluated on this background therapy.

Patients randomly assigned to tirofiban received 150 mg to 325 mg of nonenteric coated aspirin orally (chewed) or 500 mg iv as soon as STEMI was identified. Immediate thrombolysis with tenecteplase was administered according to the instructions in the Summary of Product Characteristics for the treatment of STEMI (30 mg if body weight was less than 60 kg, 35 mg if it was 60 to 69 kg, 40 mg if it was 70 to 79 kg, 45 mg if it was 80 to 89 kg, and 50 mg if it was 90 kg or more). No enoxaparin bolus was given to these patients; enoxaparin was administered as a subcutaneous injection at 0.75 mg/kg. This subcutaneous dose was the only dose administered if the coronary intervention was successfully performed within 8 hours of randomization. Tirofiban was started 2 hours after tenecteplase with a fixed 25-␮g/kg intravenous bolus followed by 0.15␮g/kg/min in intravenous infusion for 24 hours. The infusion was reduced by 50% if severe renal failure (creatinine clearanceⱕ30 mL/h or creatinine ⬎2 mg/dL) was observed. The rationale for withholding tirofiban for 2 hours after fibrinolytic treatment was based on the pharmacoki-netics and pharmacodynamics of tenecteplase. In a previous study with 103 patients,14_{tenecteplase exhibited biphasic elimination from}

the plasma with a mean initial half-life of 22 minutes and a mean terminal half-life of 115 minutes. This mean terminal half-life of 115 minutes motivated the rationale for withholding tirofiban for 2 hours in order to avoid bleeding complications.

Patients randomly assigned to no tirofiban received 150 mg to 325 mg of non– enteric-coated aspirin orally (chewed) or 500 mg iv as soon as STEMI was identified. Immediate thrombolysis with tenect-eplase was administered, with the doses and mode of administration described above. An enoxaparin bolus of 30 mg followed by a subcutaneous dose of 1 mg/kg was administered in patientsⱕ75 years old. Patients over 75 did not receive the enoxaparin bolus and the subcutaneous injection was reduced to 0.75 mg/kg. This subcu-taneous dose was also the only dose administered if coronary intervention was successfully performed within 8 hours of random assignment.

Patients underwent catheterization within 3 to 12 hours of random assignment. The infarct-related artery was dilated if there was total occlusion, the stenosis was greater than 50%, or the TIMI flow grade was less than 3. Stenting of culprit lesions was performed when they were morphologically suitable for stenting and when the procedure was expected to achieve an adequate result. To avoid thrombus compression and embolization, direct stenting was attempted when possible. The stenting procedure was carried out using Express stents (Boston Scientific, Natick, Mass) or TAXUS stents (Boston Scien-tific), for patients randomly assigned to the bare-metal stent or paclitaxel-eluting stent, respectively. When a large amount of myo-cardium was threatened by severe stenosis (⬎90% reduction in lumen diameter by visual estimation in a coronary segment with a reference diameter larger than 2.75 mm), stenting of nonculprit lesions was also performed.

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Immediate rescue angioplasty was undertaken when both chest pain and ST-segment elevation persisted at 3 hours after administration of tenecteplase.

Immediately after stenting, patients received a loading dose of 300 mg of clopidogrel and 75 mg daily for 1 year. Maintenance aspirin therapy was administered indefinitely at 80 to 325 mg once daily (coated or uncoated), unless contraindicated. The tirofiban infusion was stopped 24 hours after initiation. Finally,␤-blockers, angioten-sin-converting enzyme inhibitors, statins, and any additional postin-farction therapy were administered, as outlined in international guidelines.13,15

Study End Points and Definitions

The primary objectives of the study were, first, to compare the efficacy of the paclitaxel-eluting stent with that of the conventional bare-metal stent, and, second, to determine the effect of tirofiban administered 120 minutes after fibrinolysis but before PCI on epicardial and myocardial reperfusion in patients with STEMI treated with routine early postfibrinolysis PCI.

For the first objective, the primary efficacy end point was the rate of binary restenosis after 12 months of angiographic follow-up, as determined by independent quantitative angiographic analysis. Bi-nary angiographic restenosis was defined as a⬎50% narrowing of the lumen diameter in the target segment (defined as all portions of the vessel that received treatment within the stent zone, including the proximal and distal 5-mm margins).

For the second objective, the primary efficacy end point was the degree of epicardial and myocardial flow before and after mechan-ical revascularization. This was measured angiographmechan-ically using the angiographic perfusion score (APS). The APS combines grades of epicardial and myocardial perfusion before and after PCI to arrive at a single angiographic variable that is associated with infarct size and clinical outcomes.16_{The APS is calculated by summing the}

epicar-dial and myocarepicar-dial flow grades before and after PCI (total possible grade, 0 to 12). Full perfusion is defined as an APS of 10 to 12, partial perfusion as an APS of 4 to 9, and failed perfusion as an APS of 0 to 3.

Prespecified secondary endpoints included the safety of the paclitaxel-eluting stent in terms of rate of stent thrombosis, determi-nation of the interaction between the paclitaxel-eluting stent and the complicated myocardial infarction lesion in terms of reduction in intimal proliferation as evaluated by quantitative coronary angiog-raphy, and determination of the clinical efficacy and safety of full-dose fibrinolysis plus delayed tirofiban compared with fibrino-lysis alone, both in the whole cohort of patients and in different subgroups. The clinical definitions provided were identical to those used in the previous GRACIA 1 and 2 trials4,10_{; as for example major}

bleeding was defined as any bleeding complication causing death, need for surgery or transfusion, or extended time in hospital. We followed the Academic Research Consortium (ARC) criteria for classifying stent-related thrombosis events in an attempt to establish uniformity.17

Data Collection and Core Laboratory Analysis

Data were entered using a double entry system, and the accuracy of collected data were validated against medical records by an inde-pendent clinical research organization (Chiltern International, Spain S.A.). Data were then submitted to the data coordinating center (Hospital General Universitario Gregorio Maran˜o´n, Madrid). Clini-cal outcome was adjudicated by an independent cliniClini-cal events committee blinded to study group assignment. A separate data and safety monitoring board not affiliated with the study investigators reviewed data periodically throughout the trial to identify potential safety issues and monitor study conduct.

Coronary angiography was performed at baseline, at the comple-tion of the procedure, and after 12 months of follow-up. All angiograms were analyzed at an independent angiographic core laboratory (ICICOR, Valladolid, Spain) with a quantitative computer-based system (Medis, Leesburg, Va). The epicardial and myocardial flow grades were assessed by an experienced reader who was blinded to treatment assignment and clinical outcome.

Additional assessment of myocardial perfusion was performed using ST-segment analysis. The amount of ST-segment elevation was measured manually 20 ms after the J point. The sum of ST-segment elevation was measured from leads I, aVL, and V1to V6

for anterior myocardial infarction and leads II, III, aVF, V5, and V6

for inferior myocardial infarction. We divided patients into 3 groups according to the resolution of ST-segment deviation (complete,

ⱖ70% resolution; partial, ⬎30% but ⬍70% resolution; and no resolution,ⱕ30% resolution).

Statistical Analysis

The number of patients included in the study was based on an estimate of the sample size needed to identify a statistically signif-icant difference in the 2 principal endpoints. Thus, for the sample size calculation, we used 2 different variables: binary restenosis (categorical variable) and the APS (categorical variable).

For binary restenosis, we assumed that the restenosis rate in the bare-metal stent group would be 22% and that this rate would be clinically significant if it was reduced by 50% (from 22% to 11%) in the paclitaxel-eluting stent group. The predicted restenosis rate with the bare-metal stent and the assumed benefit with the paclitaxel-eluting stent were determined using data from the CADILLAC18_and

the TAXUS IV19_{studies. Based on the assumed restenosis rate, to}

have at least 80% power at the overall 5% significance level (2-tailed), the trial had to enroll a total of 436 patients. We expected a 20% loss to follow-up (a 12-month angiographic follow-up is required for this assumption).

For the APS, the sample size calculation was based on the assumption that full APS is present in approximately 50% of patients with STEMI who had received fibrinolytics16_{and that this rate would}

be clinically significant if it increased by 25% (from 50% to 62.5%) in the tirofiban group. On the basis of this assumption, with 80% power at the overall 5% significance level (2-tailed), the trial should enroll a total of 408 patients to show the superiority of treatment with tirofiban. We expected a 5% loss to follow-up (pre- and post-PCI angiography is required for this assumption).

All the analyses were performed according to the intention-to-treat principle. We analyzed the primary and secondary efficacy and safety end points using the␹2test or Studentttest. Additionally, we used the␹2 _{test for trend to analyze categorical variables or the}

ANOVA test to analyze quantitative variables, in each of the 4 groups. The data are presented as the mean and the standard error, medians and interquartile range, or proportions. A 2-tailed probabil-ity value of⬍0.05 indicated statistical significance.

Results

Patient Characteristics

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groups had a similar time delay between the onset of symptoms and randomization and between randomization and angiography. Fibrinolysis was administered immediately after randomization. Thus, randomization and fibrinolysis times are equivalent. The median transportation distance to the nearest PCI center was 45 km (range, 10 to 120 km) and the median transportation time was 61 minutes (range, 10 to 137 minutes). There were no differences in concomitant medication given during hospitalization, at discharge (Table 1), or after the 12-month follow-up in either group. After 12 months of follow-up, high proportions of patients were on

␤-blockers (85%), angiotensin-converting-enzyme inhibitors or angiotensin II receptor antagonists (58%), statins (81%), aspirin (96%), and thienopyridines (89%).

Postfibrinolysis angiography was performed in 419 of 433 (97%) patients (Figure 1). Eight patients died before angiog-raphy could be undertaken. One patient did not undergo angiography because of a clear false-positive diagnosis on arrival at the hospital, 1 because no vascular access was obtained, 1 because of cerebral hemorrhage, 1 refused an-giography and withdrew from the study after fibrinolysis was administered, and 2 because of their physician’s decision. Table 1 also shows baseline angiographic characteristics.

Angioplasty of the culprit lesion was attempted in 364 (87%) of 419 patients who underwent postfibrinolysis

an-giography; stents were implanted in all of these patients, of whom 57% underwent direct stenting. Stenting of nonculprit lesions was performed in 128 of 419 (31%) of the patients who underwent catheterization. No differences were found between the groups. Of the 55 patients who underwent angiography but did not undergo angioplasty, 21 had no significant angiographic stenosis. Among the remaining 34 patients, 27 were recommended for medical treatment be-cause of coronary artery disease that was unsuitable for PCI or revascularization by coronary bypass surgery and seven patients underwent predischarge coronary artery bypass sur-gery due to multivessel coronary disease that made stenting unsuitable. We found no differences among the 4 groups in the number of patients with no significant angiographic stenosis or in those treated medically or with bypass surgery. Tirofiban was administered to 204 (95%) of 214 patients in the tirofiban group. Bailout tirofiban was administered in 2 (1%) of 215 patients in the no tirofiban group who underwent angiography. Angiography did not reveal differences favor-ing postfibrinolysis tirofiban administration in TIMI grade 3 flow, TIMI grade 3 myocardial perfusion scores, or corrected TIMI frame counts, either in the initial angiography or after the procedure (Table 2). The rates of APS (the primary end points for evaluation of epicardial and myocardial perfusion) were similar in patients with and without tirofiban (Figure 2).

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Table 1. Baseline and Angiographic Characteristics

No Tirofiban⫹Bare-Metal Stent (n⫽110)

Tirofiban⫹Bare-Metal Stent (n⫽106)

No Tirofiban⫹Paclitaxel Stent (n⫽109)

Tirofiban⫹Paclitaxel Stent (n⫽108)

Baseline characteristic

Age, y 61.2_⫾1.28 60.6_⫾1.26 61.4_⫾1.19 60.8_⫾1.27

Median 63 61 62 61

Interquartile range 59⫺64 58⫺63 59⫺64 58⫺63

Male sex 93 (84.5) 92 (86.8) 87 (79.8) 86 (79.6)

Hypertension 46 (41.8) 47 (44.3) 44 (40.8) 51 (47.2)

Diabetes 21 (19.1) 15 (14.1) 23 (21.1) 21 (19.4)

Current smoking 56 (50.9) 55 (51.9) 51 (46.8) 48 (44.4)

Cholesterol⬎5.5 mmol/L 47 (42.7) 42 (39.6) 45 (41.3) 52 (48.1)

Family history 20 (18.2) 18 (17.0) 20 (18.3) 24 (22.2)

Previous myocardial infarction 8 (7.3) 4 (3.8) 4 (3.7) 9 (8.3)

Previous angina 13 (11.8) 16 (15.1) 10 (9.2) 22 (20.4)

Previous angioplasty 4 (3.6) 5 (4.7) 0 (0) 4 (3.7)

Heart rate, beats/min 71.4⫾1.49 76.1⫾1.58 74.4⫾1.51 75.4⫾1.37

Systolic blood pressure, mm Hg 133⫾2.49 136⫾2.13 135⫾2.09 134⫾2.24

Medical treatment at inclusion*

Aspirin 99 (90.0) 94 (88.7) 95 (87.2) 96 (88.9)

␤-blockers 10 (9.1) 12 (11.3) 11 (10.1) 17 (15.9) ACE inhibitors 9 (8.2) 5 (4.7) 10 (9.2) 11 (10.3)

ARA II inhibitors 4 (3.6) 2 (1.9) 4 (3.7) 9 (8.4)

Calcium antagonists 2 (1.8) 3 (2.8) 3 (2.7) 5 (4.7)

Time, h

Symptoms to fibrinolysis 3.43⫾0.20 3.75⫾0.21 3.57⫾0.19 3.62⫾0.21

Median 3.00 3.25 3.17 3.00

Interquartile range 3.04_⫺3.83 3.33_⫺4.17 3.19_⫺3.94 3.21_⫺4.03

Fibrinolysis to angiography 6.07⫾0.33 6.56⫾0.32 5.78⫾0.32 6.07⫾0.32

Median 5.08 5.83 4.62 5.08

Interquartile range 5.41_⫺6.73 5.92_⫺7.20 5.15_⫺6.40 5.43_⫺6.71

Angiographic features n⫽110 n⫽100 n⫽105 n⫽104

Infarct-related artery location

Left anterior descending 44 (40.4) 43 (43.0) 52 (49.5) 51 (49.0)

Left circumflex 15 (13.7) 17 (17.0) 12 (11.4) 10 (9.6)

Right coronary artery 50 (45.9) 40 (40.0) 41 (39.1) 43 (41.4)

Unclassified 1 0 0 0

No. of vessel disease

Nonstenotic vessels 3 (2.7) 5 (5.0) 7 (6.7) 6 (5.8)

Single-vessel disease 61 (55.4) 60 (60.0) 51 (48.6) 58 (55.8)

Double-vessel disease 33 (30.0) 23 (23.0) 31 (29.5) 25 (24.0)

Triple-vessel disease 13 (11.8) 12 (12.0) 14 (13.3) 12 (11.5)

Medical treatment at discharge n⫽104 n⫽98 n⫽100 n⫽99

Aspirin 99 (95.2) 96 (98.0) 93 (93.0) 97 (98.0)

Clopidogrel 93 (89.4) 83 (84.7) 89 (89.0) 91 (91.9) ␤-blockers 85 (81.7) 84 (85.7) 86 (86.0) 85 (85.9) ACE inhibitors 56 (53.9) 43 (43.9) 46 (46.0) 68 (68.7)

ARA II inhibitors 4 (3.8) 3 (3.1) 2 (2.0) 5 (5.1)

Calcium antagonists 3 (2.9) 3 (3.1) 2 (2.0) 5 (5.1)

Statins 81 (77.9) 79 (80.6) 83 (83.0) 81 (81.2)

Data are presented as n (%) or mean⫾standard error.

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Furthermore, ST-segment resolution was also similar in patients with or without tirofiban (Figure 3).

Angiographic follow-up at 12 months was completed in 299 of 346 (86%) eligible patients (Figure 1) at a median of 382 days, and data were analyzed at the core angiographic laboratory (Table 3). The rate of the major primary end point, analysis-segment binary restenosis (which includes measure-ments within the stent and 5 mm proximal and distal to the stent), was similar for both the bare-metal and paclitaxel-eluting stent: 11.3% (16/142) for the bare-metal stent and 10.1% (15/149) for the paclitaxel-eluting stent (relative risk, [RR], 1.06; 95% confidence interval [CI], 0.74 to 1.52;

P⫽0.89). In-segment late lumen loss was significantly lower for the paclitaxel-eluting stent than for the bare-metal stent (0.04⫾0.055 mm versus 0.27⫾0.057 mm, difference,⫺0.23 [95% CI,⫺0.39 to⫺0.07]P⫽0.003).

The 12-month clinical follow-up was complete for almost all patients (Figure 1). Table 4 shows the clinical outcomes and safety parameters. The combined rates of death, recurrent myocardial infarction, revascularization, and/or rehospitaliza-tion were similar for all 4 groups: 21.0% in patients randomly assigned to tirofiban compared with 15.5% in patients

ran-domly assigned to no tirofiban (relative risk with tirofiban, 1.19; 95% CI, 0.96 to 1.49;P⫽0.174) and 21.2% in patients randomly assigned to the paclitaxel-eluting stent as compared with in 15.3% patients randomly assigned to bare-metal stents (RR with paclitaxel-eluting stent; 1.20; 95% CI, 0.97 to 1.49;

P⫽0.141). The individual rates of death, reinfarction, revas-cularization, rehospitalization, and stent thrombosis were also similar in all 4 groups in the comparison between tirofiban and no tirofiban and in the comparison between the paclitaxel-eluting stent and the bare-metal stent after 12 months of follow-up (Table 4).

Table 2. Angiographic Characteristics of Both Epicardial and Myocardial Perfusion

Variable

No Tirofiban (n⫽215)

Tirofiban (n⫽204) P

At baseline

Infarct-related artery TIMI grade n⫽214 n⫽204 0.102

0 34 (15.89) 18 (8.82)

1 10 (4.67) 9 (4.41)

2 18 (8.41) 26 (12.75)

3 152 (71.03) 151 (74.02)

TIMI myocardial perfusion grade n⫽196 n⫽196 0.884

0 61 (31.12) 54 (28.57)

1 11 (5.61) 13 (6.88)

2 26 (13.27) 23 (12.17)

3 98 (50.00) 99 (52.38)

cTFC 40.33⫾1.93 36.63⫾1.68 0.461

cTFC post 26.60⫾1.42 28.24⫾1.38 0.300

After the procedure

Infarct-related artery TIMI grade n⫽191 n⫽178 0.670

0 4 (2.09) 1 (0.56)

1 3 (1.57) 2 (1.12)

2 8 (4.19) 9 (5.06)

3 176 (92.15) 166 (93.26)

TIMI myocardial perfusion grade n⫽173 n⫽162 0.518

0 23 (13.29) 17 (10.49)

1 21 (12.14) 16 (9.88)

2 34 (19.65) 27 (16.67)

3 95 (54.91) 102 (62.96)

cTFC 26.70⫾1.24 25.36⫾0.99 0.992

cTFC post 20.08⫾0.83 20.19⫾0.84 0.958

cTFC indicates corrected TIMI frame count.

Data are presented as n (%) or mean⫾standard error.

Figure 2.Epicardial and myocardial perfusion data for angiogra-phy, according to tirofiban treatment. The percentages of patients are shown according to the degree of the angiographic perfusion score (APS). The APS is calculated summing the epi-cardial and myoepi-cardial flow grades before and after PCI (total possible grade, 0 to 12). Full perfusion is defined as an APS of 10 to 12, partial perfusion as an APS of 4 to 9, and failed perfu-sion as an APS of 0 to 3.

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Table 4 also shows the number of patients who had bleeding and their descriptions during hospitalization. Major bleeding was observed in 13 of 214 (6.1%) patients receiving tirofiban and in 6 of 219 (2.7%) of patients not receiving it (RR with tirofiban, 2.22; 95% CI, 0.86 to 5.73; P⫽0.144). Among patients treated with tirofiban, 31 of 214 (14.5%) had at least 1 minor hemorrhage as compared with 20 of 219 (9.1%) patients not treated with tirofiban (RR with tirofiban, 1.27; 95% CI, 0.99 to 1.62;P⫽0.114). The combination of major and minor hemorrhages was more frequent among patients receiving tirofiban (RR with tirofiban, 1.39; 95% CI, 1.13 to 1.71; P⫽0.009). Bleeding significantly impacted all-cause mortality in our experience. One-year mortality rates were higher between patients with (8/19 [42.1%]) versus without (28/414 [6.8%]) major bleeding,P⬍0.001; between patients with (9/51 [17.6%]) versus without (27/382 [7.1%]) minor bleeding,P⫽0.025; and between patients with (15/68 [22.1%]) and without (21/365 [2.7%]) any bleeding (major or minor),P⬍0.001.

Finally, we also performed a per protocol analysis (data not shown) for the primary and safety end points in patients who

strictly followed the protocol (protocol violations excluded). The results were similar to those presented above.

Discussion

This study shows that in STEMI patients treated with PCI after fibrinolysis, routine initiation of a glycoprotein IIb/IIIa inhibitor 2 hours after fibrinolysis in combination with aspirin, enoxaparin, and clopidogrel does not improve epicar-dial or myocarepicar-dial perfusion before or after PCI. Further-more, the use of a paclitaxel-eluting coronary stent in these patients did not significantly reduce binary restenosis overall in the 12 months after the intervention; however, it did reduce late loss and minimal luminal diameter.

The use of a platelet glycoprotein IIb/IIIa inhibitor has been evaluated elsewhere as adjunctive therapy in STEMI patients undergoing coronary reperfusion with either primary PCI or fibrinolysis. Among patients undergoing primary PCI, periprocedural administration of glycoprotein IIb/IIIa inhibi-tors improves outcome in patients with STEMI, compared with placebo.20,21 _{However, a separate issue is the optimal}

timing of glycoprotein IIb/IIIa inhibitor therapy. Although administration of a glycoprotein IIb/IIIa inhibitor in the ambulance or emergency department rather than in the catheterization laboratory is associated with a significant increase in pre-PCI angiographic perfusion, no difference in post-PCI angiographic perfusion, or in clinical outcomes has been observed.22 _{Further studies, as the FINESSE trial,}23

failed even to document a significant increase in pre-PCI TIMI flow grade of 3 when comparing patients receiving abciximab alone before PCI or undergoing primary PCI (14.1% versus 12.0%, P⫽0.219). In patients undergoing fibrinolysis, the antiplatelet potency of glycoprotein IIb/IIIa inhibitors made these drugs particularly useful when attempt-ing to restore coronary perfusion and reduce the incidence of recurrent ischemia.24,25_{Despite these hypothetical benefits, 2}

large clinical trials, testing the combination of half-dose of lytics and IIb/IIIa inhibitors, the GUSTO V and ASSENT-3, together with the meta-analysis by Keeley, showed that simultaneous combination therapy does not improve survival compared with conventional fibrinolytic therapy, and that it increases bleeding complications.22,26,27 _{To our knowledge,}

ours is the first study to evaluate the benefit of glycoprotein IIb/IIIa inhibitors administered 120 minutes after fibrinolysis but before early routine PCI to accelerate fibrinolytic recan-alization and to improve angiographic perfusion in patients with STEMI. Full doses of fibrinolysis followed by delayed full doses of glycoprotein IIb/IIIa inhibitors did not improve pre-PCI or post-PCI angiographic perfusion, and, as previ-ously shown with the simultaneous combination of both drugs (usually half doses of fibrinolysis and glycoprotein IIb/IIIa inhibitors), these agents also increase the rate of major bleeding. Thus, our results argue against routine treatment with glycoprotein IIb/IIIa inhibitors in this scenario and with this timing. We postulate several explanations for the lack of significant treatment benefit with delayed postfi-brinolysis use of tirofiban in our study. First, patients were treated with aggressive contemporary reperfusion therapies, including full doses of tenecteplase and enoxaparin, which may have reduced the potential incremental effect of

tirofi-Table 3. Angiographic Findings at 12 Months

Outcome

Bare-Metal Stent (n⫽210)

Paclitaxel-Eluting Stent

(n⫽209) P

Infarct-related artery 0.182

Left anterior descending, n (%)

87 (41.6) 109 (49.3)

Left circumflex, n (%) 32 (15.3) 22 (10.5)

Right coronary, n (%) 90 (43.1) 84 (40.2)

Preprocedure

Reference diameter, mm 2.91_⫾0.046 2.87_⫾0.041 0.425

Minimal luminal diameter, mm

0.87⫾0.041 0.88⫾0.042 0.844

Area of stenosis, % 88.05_⫾0.93 87.00_⫾1.08 0.463

Diameter of stenosis, % 70.86⫾1.26 69.77⫾1.37 0.562

Length of lesion, mm 44.08_⫾1.07 44.25_⫾1.21 0.915

Postprocedure

2.33⫾0.049 2.33⫾0.045 0.911

Area of stenosis, % 39.89_⫾1.11 39.17_⫾1.07 0.637

Acute gain, mm 1.55_⫾0.048 1.55_⫾0.047 0.910

12-Month angiographic follow-up

n⫽145 n⫽154

2.07⫾0.058 2.26⫾0.062 0.022

Area of stenosis, % 53.07_⫾1.57 46.47_⫾1.57 0.003

Late luminal loss, mm 0.27_⫾0.057 0.04_⫾0.055 0.003

Binary angiographic restenosis, n (%)

16/142 (11.3) 15/149 (10.1) 0.887

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ban. Furthermore, such a benefit may have been attenuated by the shorter time between initiation of symptoms and fibrino-lysis (median, 2.92 hours) or between fibrinofibrino-lysis and PCI (median, 5.16 hours). Thus, considering that tirofiban was administered at least 2 hours after fibrinolysis, the time gain for tirofiban was short in most patients.

A separate issue is the optimal timing between fibrinolysis and PCI, as trials show some overlap in the timing of PCI3–11,22,23,28 –31

and this leads to different, somewhat arbitrary definitions. Facilitated PCI involves pharmacological therapy before planned primary PCI for STEMI to achieve an open infarct-related artery before arrival at the catheterization laboratory. Trials have been conducted using fibrinolytic agents, glyco-protein IIb/IIIa inhibitors, and combinations of both. In contrast, adjunctive or early elective PCI is used in patients who are initially successfully reperfused with fibrinolysis and in whom early catheterization and, if appropriate, PCI is performed. Our trial would be better placed in the second definition, although the distinction between facilitated and adjunctive/early angioplasty is somewhat arbitrary.

There are few data on the use of drug-eluting stents in STEMI.32–39 _{Information is restricted to drug-eluting stents}

used during primary PCI, when they appear to be associated with a marked and sustained reduction in the rate of restenosis and the attendant risks of repeat revascularization after PCI. Concerns exist, however, over the safety of these stents, particularly in terms of the risk of stent thrombosis. To the best of our knowledge, no randomized trial has specifically examined the efficacy and safety of drug-eluting stents in the setting of postfibrinolysis adjunctive routine PCI for STEMI. Our results demonstrate that implantation of a paclitaxel-eluting stent during adjunctive routine postfibrinolysis PCI was safe but did not result in overall decreased angiographic in-segment binary restenosis. On the other hand, the use of a paclitaxel-eluting stent did lead to a decrease in the extent of late lumen loss, as compared with the use of a bare-metal stent, thus suggesting a reduced risk of restenosis. We postulate several explanations for the lack of significantly reduced binary restenosis (primary end point) with the use of the paclitaxel-eluting stent in our study. First, we

underesti-Table 4. Clinical Outcome at 12 Months

Variable

Bare-Metal Stent (n⫽216)

Paclitaxel-Eluting Stent (n⫽217) P

No Tirofiban (n⫽219)

Tirofiban (n⫽214) P

Cardiovascular event

Death 15 (6.9) 21 (9.7) 0.392 15 (6.9) 21 (9.8) 0.346

Nonfatal myocardial infarction 3 (1.4) 5 (2.3) 0.724 3 (1.4) 5 (2.3) 0.499

Ischemia-driven revascularization 10 (4.6) 9 (4.2) 0.992 11 (5.0) 8 (3.7) 0.676

PCI 10 (4.6) 8 (3.7) 0.802 10 (4.6) 8 (3.7) 0.849

CABG 0 (0) 1 (0.5) 1.000 1 (0.5) 0 (0) 1.000

Stent thrombosis 5 (2.3) 4 (1.8) 0.751 4 (1.8) 5 (2.3) 0.749

Definite 3 (1.4) 2 (0.9) 0.685 2 (0.9) 3 (1.4) 0.682

Probable 2 (0.9) 2 (0.9) 1.000 2 (0.9) 2 (0.9) 1.000

Any of the previous cardiovascular events

33 (15.3) 46 (21.2) 0.141 34 (15.5) 45 (21.0) 0.174

Bleeding complications during hospitalization

Major bleeding 11 (5.9) 8 (3.7) 0.632 6 (2.7) 13 (6.1) 0.145

Intracranial 4 (1.8) 5 (2.3) 1.000 2 (0.9) 7 (3.3) 0.102

Nonintracranial requiring transfusion 6(2.8) 3 (1.4) 0.338 4 (1.8) 5 (2.3) 0.749

Nonintracranial requiring additional surgery

1 (0.5) 0 (0) 0.499 0 (0) 1 (0.5) 0.494

Minor bleeding 24 (11.2) 27 (12.4) 0.779 20 (9.1) 31 (14.5) 0.114

Access site 15 (6.9) 9 (4.2) 0.288 9 (4.1) 15 (7.0) 0.268

Gastrointestinal 3 (1.4) 7 (3.2) 0.338 4 (1.8) 6 (2.8) 0.540

Gingival 5 (2.3) 5 (2.3) 1.000 4 (1.8) 6 (2.8) 0.540

Hematuria 4 (1.8) 4 (1.8) 1.000 1 (0.5) 7 (3.3) 0.035

Epistaxis 1 (0.5) 3 (1.4) 0.623 2 (0.9) 2 (0.9) 1.000

Other 2 (5.9) 2 (3.7) 1.000 2 (0.9) 2 (0.9) 1.000

Any bleeding 35 (16.2) 33 (15.2) 0.878 24 (11.0) 44 (20.6) 0.009

Death, reinfarction, revascularization, or major bleeding

40 (18.5) 48 (22.1) 0.417 35 (16.0) 53 (24.8) 0.031

Readmission 19 (8.8) 27 (12.4) 0.282 20 (9.1) 26 (12.1) 0.388

Index hospitalization, d 8.2_⫾0.37 8.0_⫾0.41 0.864 7.8_⫾0.40 8.4_⫾0.37 0.051

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mated the power of the effect of bare-metal stent implantation on the rate of follow-up binary restenosis (11% and not 22%).18,36,37,39_{Our strategy of postfibrinolysis PCI represents}

a different approach to mural thrombus in damaged plaque from that of primary PCI, and, consequently, reduced neoin-timal proliferation must be confirmed in future studies. Second, studies carried out since the initiation of our trial have shown that late loss is more reliable than restenosis rates at determining neointimal proliferation between drug-eluting and bare-metal stents, particularly in early efficacy studies.40,41_The

mean late lumen loss was significantly lower (0.04⫾0.055 versus 0.27⫾0.057 mm, P⫽0.003) in the paclitaxel-eluting group than in the bare-metal group in our study, as we failed to define binary restenosis, instead of late lumen loss, as our primary end point.

Some important limitations must be admitted regarding the interpretation of our results. First, we use surrogate endpoints to compare four strategies of postfibrinolysis PCI rather than rely on clinical outcomes. However, the mechanistic end points chosen are validated, and core laboratory– blinded interpretation of the data were performed. Second, it is not unthinkable that earlier administration of tirofiban might have led to different results, although the bleeding rates might be increased by the concomitant administration of fibrinolytic treatment and tirofiban. Third, and very importantly, this trial did not properly address the issue of rescue angioplasty for failed fibrinolysis, as it was designed before recent findings documenting the importance of early resolution of ST-segment elevation as an independent guide for the indication rescue angioplasty.42_{Fourth, the use of an angiographic end}

point to assess restenosis implied that repeat angiography could strongly affect the repeat revascularization rates, which tend to be largely increased compared with those that occur in the setting of clinically driven repeat angiography. In our experience, 11 of 299 (3.7%) patients with 12-months angio-graphic follow-up underwent repeat revascularization under this condition. Finally, as stated, the study was undersized (bare metal stent restenosis was 11%, not 22%), and clopi-dogrel was not given on admission, as is now recommended by the guidelines.

Despite these limitations, our results have important impli-cations for the use of tirofiban and paclitaxel-eluting stents in patients with STEMI undergoing early routine postfibrinoly-sis angioplasty. First, the routine use of tirofiban at least 120 minutes after fibrinolysis but before PCI was not superior to fibrinolysis alone for improvement of epicardial and myocar-dial perfusion. Furthermore, patients in the tirofiban group had a 1.1- to 1.7-fold increased risk of major and minor bleeding that significantly impacted 1-year all-cause mortal-ity in our experience. Second, compared with bare-metal stents, paclitaxel-eluting stents significantly reduced late loss but appeared not to reduce in-segment binary restenosis.

Acknowledgments

We thank Javier Botas and Rafael Gabriel (methodological advice) and Igor Martín and Itziar Go´mez (database management and statistical help). We also thank the investigators and the coordinators of the GRACIA-3 trial and all the medical and nursing staff in the recruitment and intervention centers who made the trial possible. Most of all, we thank all the patients who participated in the trial.

Sources of Funding

This study is an academic clinical trial. The sponsors of the study have no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and was responsible for the decision to submit for publication. Unrestricted grants to fund the study were obtained from Red Tema´tica de Enfermedades Cardio-vasculares (RECAVA) of the Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation), from the Fondo de Investiga-cio´n Sanitaria (FIS: PI040308, PI040235, PI040361, PI042035, PI042686, PI040166, PI040276, PI 040306, PI040309, PI040350, PI040478, and PI0402037) of the Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation), and from the Junta de Castilla y Leo´n.

Disclosures

None.

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CLINICAL PERSPECTIVE

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1

The participants in the GRACIA 3 study were as

follows:

Operations Committee

— F.

Fernández-Avilés (principal investigator and chair), J.J. Alonso, P. L. Sánchez

(co-principal investigator);

Steering Committee

—

F. Fernández-Avilés, P. L. Sánchez, J. J.

Alonso, Rafael Gabriel, Javier Botas;

Data Coordinating Center

(Hospital General

Universitario Gregorio Marañón, Spain) —

S. Vázquez, M. J. Lorenzo, L. Fernández;

Clinical

Events Committee

— J. Torres (chair), J. López, L. de la Fuente;

Safety Committee

J. L. Arroyo, R. Rubio, P. Alonso;

Electrocardiographic

(ECG) Core Laboratory

(Hospital

Puerta de Hierro, Spain)

— J. Goicolea (director);

Imaging Core Laboratory

(Instituto de

Ciencias del Corazón, Valladolid, Spain)

— R. Arnold, M. E. Vázquez, H. Gutiérrez;

Clinical

Centers (listed in order of

number of patients enrolled):

Instituto de Ciencias del

Corazón, Valladolid, Spain: F. Fernández-Avilés, P. L. Sánchez, J. A. San Román, F.

Gimeno, C. Hernández, P. Mota, M. Pineda, A. Revilla, H. Gutiérrez, R. Arnold, G. Peña,

R. Sanz, B. Ramos; Hospital General de Segovia, Spain: P. Ancillo, M. J. Espina, M. J.

López, M. Sopetran, S. Macías, J. J. Cortina, R. Pajares; Hospital Río Hortega, Valladolid,

Spain: J. J. Sanz, J. Blanco, L. Fernández, M. C. González, V. Fraile, J. A. Berezo;

Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain: J. Alonso Briales, J.

M. Hernández, M.F. Jiménez-Navarro, E. de Teresa; Hospital Universitario de Canarias,

Santa Cruz de Tenerife, Spain: F. Bosa, M. Gisela, A. Sánchez-Grande, M. Vargas, A.

Barragán, M. J. García, M. Bethencourt; Hospital Universitario de Salamanca, Spain: I.

Santos, C. Martín-Luengo, P. Pabón, F. Martín, J. Rodríguez-Collado, M. Cascón; Hospital

Universitario Son Dureta, Palma de Mallorca, Spain: A. Bethencourt, M. Fiol, V. Peral, O.

Galdes, A. Gomez, J. Velasco, A. Carrillo, M. Aceña, E. M. Ribas; Hospital Clínico

at HOSPITAL UNIV. REINA SOFIA on January 7, 2011 circinterventions.ahajournals.org

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Oltra, F. J. Chorro, A. Llacer; Hospital Río Carrión, Palencia, Spain: J. López-Messa, A.

M. Gutiérrez, M. A. Gómez, J. Sóquez, C. B. de la Fuente, L. Tamayo, A. Domínguez, M.

Prieto, J. Collado, R. Pájaros, R. Pascual; Complejo Hospitalario de León, Spain: F.

Fernández-Vázquez, A. Pérez de Prado, C. Pascual, R. Carbonell, J. C. Cuellar, B.

González, N. Alonso, A. Diego; Hospital Vall d´Hebrón, Barcelona, Spain: B. García, E.

Domingo, A. Soto, I. Anivarro, L. Muela, I. Vila, E. Koplyski, V. Serra, O. Alcalde, D.

García-Dorado; Hospital General Yagüe, Burgos, Spain: A. Montón, F. Callejo; Hospital

de la Princesa, Madrid, Spain: L. Martínez-Elbal, C. Romero; Hospital Juan Ramón

Jiménez, Huelva, Spain: J. Díaz, A. Serrador, R. Cardenal, A. Hierro, J. C. Martín;

Hospital La Paz, Madrid, Spain: I. Roldán, M. Hernández, G. Galeote, P. López; Hospital

de Fuenlabrada, Madrid, Spain: J. J. Alonso, J. Márquez, J. M. Serrano, A. Alonso, C.

Vaquerizo, C. Velayos; Hospital Do Meixoeiro, Vigo, Spain: A. Iñiguez, J. A. Baz, M. San

Martín, H. Villaverde; Complejo Hospitalario de Orense, Spain: R. Rodríguez, E.

Rodríguez; Hospital Miguel Servet, Zaragoza, Spain: J. A. Diarte de Miguel, I. Calvo.

Centers with interventional facilities:

Instituto de Ciencias del Corazón, Valladolid, Spain;

Hospital Clínico Virgen de la Victoria, Málaga, Spain; Hospital Universitario de Canarias,

Santa Cruz de Tenerife, Spain; Hospital Universitario de Salamanca, Spain; Hospital

Universitario Son Dureta, Palma de Mallorca, Spain; Hospital Clínico Universitario,

Valencia, Spain, Complejo Hospitalario de León, Spain; Hospital de la Princesa, Madrid,

Spain; Hospital Juan Ramón Jiménez, Huelva, Spain; Hospital la Paz, Madrid, Spain;

Hospital do Meixoeiro, Vigo, Spain; Hospital Miguel Servet de Zaragoza, Spain.

Centers

without interventional facilities:

Hospital General de Segovia, Spain; Hospital Río

Hortega, Valladolid, Spain; Hospital Río Carrión, Palencia, Spain; Hospital General

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