Prognostic Impact of Clopidogrel Pretreatment in Patients With Acute Coronary Syndrome Managed Invasively

Accepted Manuscript Prognostic Impact of Clopidogrel Pretreatment in Patients with Acute Coronary Syndrome Managed Invasively Manuel Almendro Delia, MD, PhD, Luis González Torres, MD, Ángel García Alcántara, MD, PhD, Antonio Reina Toral, MD, PhD, José Andrés Arboleda Sánchez, MD, Juan Carlos Rodríguez Yañez, MD, Rafael Hidalgo Urbano, MD, PhD, Juan Carlos García Rubira, MD, PhD PII:

S0002-9149(15)00626-8

DOI:

10.1016/j.amjcard.2015.01.531

Reference:

AJC 20937

To appear in:

The American Journal of Cardiology

Received Date: 2 December 2014 Revised Date:

17 January 2015

Accepted Date: 20 January 2015

Please cite this article as: Delia MA, Torres LG, Alcántara ÁG, Reina Toral A, Arboleda Sánchez JA, Rodríguez Yañez JC, Hidalgo Urbano R, García Rubira JC, on behalf of the ARIAM-Andalucía group, Prognostic Impact of Clopidogrel Pretreatment in Patients with Acute Coronary Syndrome Managed Invasively, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.01.531. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Prognostic Impact of Clopidogrel Pretreatment in Patients with Acute Coronary Syndrome Managed Invasively

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Running title: Clopidogrel Pretreatment in Acute Coronary Syndrome

Manuel Almendro Delia, MD, PhD1, Luis González Torres, MD1, Ángel García Alcántara, MD, PhD2, Antonio Reina Toral, MD, PhD3, José Andrés Arboleda Sánchez, MD4, Juan

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Carlos Rodríguez Yañez, MD5, Rafael Hidalgo Urbano, MD, PhD1, Juan Carlos García

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Rubira, MD, PhD1, on behalf of the ARIAM-Andalucía group

Coronary Care Unit. UGC Área del Corazón Sevilla. Hospital Universitario Virgen

Macarena. Sevilla. Spain

ICU. Hospital Virgen de la Victoria, Málaga. Spain

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ICU. Hospital Virgen de las Nieves, Granada. Spain

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ICU. Hospital Regional de Málaga, Málaga. Spain

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ICU. Hospital de Puerto Real, Cádiz. Spain

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Corresponding author:

Manuel Almendro Delia

Coronary Care Unit. UGC Área del Corazón. Hospital Universitario Virgen Macarena. Sevilla. Spain Avd Dr Fedriani 3 41009. Sevilla. España Tlf: +034 955008122 Fax: +034 955008124 e-mail: [email protected]

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ACCEPTED MANUSCRIPT Abstract Pretreatment with antiP2Y12 agents prior to angiography in acute coronary syndromes (ACS) is associated with a reduction in thrombotic events. However, recent evidences have questioned the benefits of upstream antiP2Y12, reporting a higher incidence of bleeding. We analyzed the prognostic

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impact of clopidogrel pretreatment in a large cohort of invasively-managed patients with acute

coronary syndrome. In hospital safety and efficacy of clopidogrel pretreatment was retrospectively analyzed in patients included in the ARIAM Registry. Propensity score and inverse probability of

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treatment weighing analysis were performed to control treatment selection bias. Results were

stratified by acute coronary syndrome type. Sensitivity analyses were used to explore stability of the

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overall treatment effect. Of 9621 patients managed invasively, 69% received clopidogrel prior to coronary angiography. In ST elevation myocardial infarction group (STEMI), pretreatment was associated with a significant reduction in reinfarction (odds ratio 0.53 [95% confidence interval, 0.27 to 0.96]; p=0.027), stent thrombosis (odds ratio 0.15 [95% confidence interval, 0.06-0.38]; p<0.0001) and mortality (odds ratio 0.67 [95% confidence interval, 0.48 to 0.94]; p=0.020), with an increase in

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minor bleeding; but remained as a net clinical benefit strategy. Those benefits were not present in patients without ST elevation (NSTE-ACS). The weighting and propensity analysis confirmed the same results. An interaction between pretreatment duration and bleeding was observed. In conclusion,

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pretreatment with clopidogrel reduced the occurrence of death and thrombotic outcomes at the cost of minor bleeding. Those benefits exclusively affected STEMI cases. The potential benefit of routine

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upstream pretreatment in patients with NSTE-ACS should be reappraised at the present.

Keywords: pretreatment, clopidogrel, acute coronary syndrome, propensity score, percutaneous coronary intervention

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ACCEPTED MANUSCRIPT Introduction Dual antiplatelet therapy (DAPT) combining aspirin with an inhibitor of platelet P2Y12 receptor, is the cornerstone of antithrombotic treatment of ACS, and should be administered as soon as possible.[1-6] But these recommendations, do not reflect current clinical practice, in which time delays and

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percutaneous coronary intervention (PCI) techniques have been significantly improved, minimizing the potential benefit of pretreatment when PCI is performed early.[7,8] In relation to primary PCI (pPCI) in STEMI, the data supporting pretreatment are weaker and based on post hoc analysis of

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randomized clinical trials (RCT) [5,6,9] or observational studies.[6,10-11] However, based on the pathophysiology of STEMI that entails a higher thrombus burden and given the delay in the onset of

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action of antiP2Y12 observed in the real world, [12] pretreatment with antiP2Y12 before pPCI is widespread used, also supported by the low rate of urgent coronary artery bypass grafting (CABG) performed in STEMI.[13] Recent results from the ACCOAST study in which upstream therapy with prasugrel in NSTE ACS, was not associated with a reduction in the primary endpoint of efficacy but increased bleedings,[14] has revived controversy about the benefit of pretreatment prior to PCI.[6]

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Pretreatment with ticagrelor has not been evaluated in NSTE ACS, and results in STEMI cases further confirm the lack of benefit of pretreatment with new antiP2Y12.[15] We sought to evaluate the prevalence of pretreatment with clopidogrel prior to PCI and determine its efficacy and safety in

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Methods

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patients with ACS scheduled for an invasive strategy.

We design a retrospective observational study of patients prospectively enrolled in the

ARIAM-Andalucía Registry (Analysis of Delay in Acute Myocardial Infarction) between January 2002 and December 2012. The particularities of this registry have been previously described.[16] In brief, demographic, laboratory, and angiographic variables and occurrence of clinical events during the hospital course were collected from patients with definitive diagnosis of ACS admitted to Coronary Care Units of 49 centers through an online platform (www.ariam-andalucia.org). Patients with ACS in whom an invasive approach (coronary angiography) was performed during admission

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ACCEPTED MANUSCRIPT and who received clopidogrel constituted the study population. The principal investigators of each center gave its approval for data review and manuscript submission. The study follows the STROBE recommendations for observational studies. Clopidogrel pretreatment was defined as any dose of clopidogrel (300/600/ or 75 mg in

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clopidogrel chronically treated patients) administered at the time of the first medical contact prior to coronary angiography or PCI. Patients who were treated with clopidogrel in the catheterization

laboratory, either just before (less than six hours), or during PCI, constituted the no pretreatment

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group. The duration of pretreatment was estimated as the time elapsed between first medical contact and coronary angiography. Total ischemic time was defined as the time from the onset of symptoms

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to PCI.

The end point adjudication was conducted and monitored by each local research group, being predefined in the data collection form.[16] The primary efficacy end point was the occurrence of major cardiac and cerebrovascular events (MACCE) defined by the combination of cardiovascular

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death, and non fatal reinfarction or stroke/TIA (transit ischemic attack). Secondary efficacy outcomes were the occurrence of each of the components of MACCE, definitive stent thrombosis, according to Academic Research Consortium (ARC) definition[17] and cardiogenic shock.[16] The primary safety

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end point was the occurrence of major, minor or minimal bleeding according to the TIMI criteria.[18] The end point of net efficiency (NACE, net adverse cardiovascular events) was defined as the

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combination of the primary efficacy and the occurrence of any bleeding during hospitalization. Data analysis was performed stratified by type of ACS. Continuous variables are presented as

mean ± standard deviation or median [P25, P75] when appropriate and compared using the unpaired student’s t-test or its nonparametric equivalent (Mann-Whitney test). Categorical data are presented as frequencies and compared using χ2 test or Fisher's exact test. The association of clopidogrel pretreatment with the occurrence of MACCE, bleeding and NACE was obtained by adjusted stepwise multivariate logistic regression models, and expressed as adjusted OR (aOR) with their confidence interval (CI) at 95%. To control for treatment selection bias, two additional analyzes were performed:

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ACCEPTED MANUSCRIPT 1) Propensity Analysis. Propensity Score (PS) was defined as the probability of pretreatment with clopidogrel, according to a multivariate regression model in which 15 variables were included: age, sex, BMI, type of ACS, diabetes, previous infarction, prior antiplatelet therapy, renal failure, previous oral anticoagulation, history of stroke /TIA, GRACE risk score,

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previous PCI, prior COPD, Killip class on admission and transfer for Emergency Medical Systems (EMS). The matching was performed by the greedy method (1: 1 without

replacement). Goodness of fit was achieved if the standardized differences were ≤10%. 2) Regression analysis adjusted by IPTW (Inverse probability of treatment weighting) or

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regression analysis weighted by the inverse probability of treatment: The contribution of each subject or weighting in the pretreatment group was calculated as the inverse of PS [1 / PS],

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and [1/1-PS] for the control group. Such analysis ensures that the contribution of different input variables to construct the PS model does not differ between subjects in each group.[19]

Several subgroups including: inclusion time period (2002-2006 vs 2007-2012), dose of

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clopidogrel (600 mg vs ≤300 mg), time duration of pretreatment (<6h vs ≥6h), and type of reperfusion in STEMI (pPCI vs fibrinolysis) were considered for sensitivity analysis, using the test for interaction. The discriminative ability and calibration power of the regression models were evaluated using the C

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statistic and the Hosmer-Lemeshow test respectively. A two-sided p-value <0.05 was considered statistically significant. SPSS 19 (IBM, IBM Corporation, Somers, NY) and STATA 13 IC (STATA

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Corp., TX, USA) packages were used. Results

Of all patients included in the ARIAM-Registry, 9621 underwent coronary angiography and

received clopidogrel, constituting the study population (Figure 1). Of them, 6770 (69%) received upstream pretreatment with clopidogrel and 2851 (31%) did so during coronary angiography. Table 1 and 2 show the baseline characteristics, pharmacological treatment and angiographic data according to ACS type.

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ACCEPTED MANUSCRIPT Clinical outcomes in the pooled group are shown in Table 3. In the pretreated group, fewer MACCE was observed, with a significant reduction in the rate of reinfarction and stent thrombosis, with a numerical reduction in the mortality and a nominal increase in the rate of stroke, mainly driven by hemorrhagic stroke, 17 cases (0.25%) in pretreated vs. 2 patients (0.07%) in the non-pretreated

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group; p = 0.019, with no difference in the rate of ischemic stroke (0.74% vs 0.6%, p ns). The higher rate of hemorrhagic stroke was seen in the subgroup of patient with ST elevation pretreated with

clopidogrel who received fibrinolysis (0.2% vs. 0%, p = 0.013). The STEMI subgroup pretreated with clopidogrel showed the same reduction in ischemic events observed in the overall population, with a

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numerical reduction in mortality and a significant reduction in stent thrombosis.

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Total bleeds were lower in the pretreatment group, with a significant increase in minor bleeding but without significant increased in fatal bleeding (Table 3). These trends were also observed in STEMI subgroup without significant differences in the NSTE ACS subgroup. The subgroup of patients with STEMI who received clopidogrel pretreatment and lytics experienced higher rates of minor bleeding (0.3% vs. 0.1%, p = 0.026) with no differences in total major or fatal bleeding,

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although with higher rates of intracranial hemorrhages. The NACE outcome was favorable in the group that received pretreatment, but only in the

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subgroup with ST elevation, without evidence of net clinical benefit in the NSTE ACS group (Table

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In the adjusted multivariate analysis (Figure 2), pretreatment with clopidogrel was associated

with a significant reduction in MACCE including reinfarction, mortality, and stent thrombosis but only in the STEMI group, at the expense of a significant increase in minor bleeding, which resulted in a favorable net clinical benefit (p of interaction= 0.023). The results of the multivariate analysis adjusted for PS and IPTW are shown in Table 4. After adjusting for PS in 1668 pairs of STEMI cases and 620 cases of NSTE ACS (C statistic = 0.62, 95% CI [0, 53 to 0.70]) (Supplementary Figures S1 and S2), pretreatment with clopidogrel was associated again with a reduction in MACCE only in the STEMI group, with a significant decrease in the rate of 6

ACCEPTED MANUSCRIPT reinfarction and stent thrombosis and a nominal reduction in mortality with an increase in minor and minimal bleeding, but with a net clinical positive balance. In the IPTW analysis of 8560 patients (5426 with STEMI and 3134 with NSTE ACS) pretreatment behaved as a protective strategy respect reinfarction, stent thrombosis and mortality, but this benefit was only observed in the STEMI group.

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The predefined subgroup analysis showed no interaction between them (Figure 3) except for a reduction in the rate of bleeding in favor of the group with a shortest duration of pretreatment (p value for interaction = 0.048). Although no significant interaction was observed, the pretreated group who

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received thrombolysis showed an increased rate of bleeding compared to that treated with pPCI, in the same direction to those who received higher loading doses of clopidogrel.

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Discussion

The results of our study confirm the benefit of pretreatment with clopidogrel in reducing ischemic events and mortality during hospitalization, although only in the subgroup with STEMI. This benefit was associated with an increase in minor bleeding, but proving to be a net clinical benefit

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strategy. The sample size and confirmation of the overall results after using different methods to control for confounders and sensitivity analyses by subgroups give strength to the conclusions of our work and are similar to those obtained by a recent meta-analysis.[6] Other observational studies have

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reported similar results, but without making such a strict adjustment as we do in our sample.[10] In view of the progressive incorporation of new antiP2Y12, [1,2] future randomized trials evaluating

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pretreatment with clopidogrel in ACS seem unlikely, so until then, the results of quasi-experimental studies like ours, and data derived from meta-analysis, will be the strongest evidence available. Currently indication for clopidogrel pretreatment in ACS is supported by older studies that do not reflect actual clinical practice, [3-5] consisting of an early invasive approach. In this sense time from symptoms onset to coronary angiography in our work was around 48 hours in NSTE ACS cases, reflecting current clinical practice, and differs significantly from the median of 10 days observed in the PCI-CURE substudy.[3] our data are in line with the results of a recent meta-analysis including over 35,000 patients, in which a significant reduction in major coronary events (OR 0.54 95% CI

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ACCEPTED MANUSCRIPT [0.36-0.81], p = 0.003) and mortality (OR 0.50 95% CI [0.26 to 0.96], p = 0.04) was only observed in the subgroup of STEMI, without an increase in major bleeding.[6] This study also shows the neutral effect in mortality reduction of pretreatment in the NSTE-ACS group that has been recently corroborated by the results of the ACCOAST study in patients pretreated with prasugrel.[14] This

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results have been confirmed in a recent metaanalysis including 32,383 non-ST elevation ACS patients pretreatment with thienopyridines. [20] The authors reported that this strategy was associated with no significant reduction of mortality but with a significant excess of major bleeding regardless of the revascularization strategy used. [20] A possible explanation for these divergent findings is that the

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potential benefit of pretreatment with clopidogrel demonstrated in early trials,[3-5] could be now eclipsed by the use of new antiP2Y12 during early ad hoc PCI, taking advantage of its greatest and

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most predicable antiplatelet effect.[12-15] A strategy of "wait and see" the coronary anatomy to load with an antiP2Y12 agent in cases in which the angiography is done early, could avoid the inconvenience of delaying a possible surgical revascularization if unfavorable coronary anatomy for PCI is found, but assuming a lower inhibition of platelet aggregation at the time of PCI. Although the

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number of patients with NSTE ACS undergoing CABG in our sample was low (3%), other studies have reported higher rates around 8-10%, [13,21] so this issue could be of major interest in centers with higher surgical rates. Following this line, the excellent results obtained with ticagrelor in the

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CABG subgroup of the PLATO trial might enhance its role as the preferred antiplatelet agent prior to PCI, although this trial does not really test pretreatment with ticagrelor, its comparator clopidogrel ,

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was used in an open label fashion in nearly 50% of the study population.[22] We observed an increase in minor bleeding without increasing major or fatal bleeding

associated with pretreatment. These data are again consistent with others. [6-8,10,15] Our data also include a cohort of patients receiving fibrinolysis, as the PCI-CLARITY substudy. [5] Although we observed no significant interaction, patients treated with lytics in the pretreatment group suffered more bleeding as compared to those pretreated treated with pPCI, mainly intracranial hemorrhages. None of previous studies about pretreatment with antiP2Y12 published to date had focused on the net clinical benefit, [3-11] which is essential for translation of the results into daily clinical practice. In

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ACCEPTED MANUSCRIPT our patients with STEMI who were pretreatment with clopidogrel, this therapy showed net clinical benefit, which supports the guidelines recommendation to use it from the first medical contact. [1,2] Focus on the loading dose of clopidogrel to be administered, our work does not allow inferring the results from the subgroup analysis, since no significant interaction between the loading dose of

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clopidogrel and the occurrence of both ischemic and bleeding outcomes was found.[7-9] The benefits of clopidogrel pretreatment in patients with ST elevation, are plausible from a biological point of view given the higher thrombotic burden associated with this clinical condition as

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compared with NSTE ACS. Neutral results derived from recent studies with more potent agents as ticagrelor or prasugrel are intriguing. [14,15] An explanation for that issue may appears simplistic but

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probably might be in relation with the shorter duration of pretreatment in both studies and perhaps the slow onset of platelet inhibition reported with ticagrelor and prasugrel in the real world.[12] In our study, the exposure time to DAPT prior to PCI was associated with a significant increased in bleeding, a fact that could explain the lack of net clinical benefit observed in the subgroup of NSTE ACS, with a median duration of DAPT of 42 hours prior to ICP. In the STEMI subgroup the shorter

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duration of pretreatment, could explain a tendency in a reduction of major bleeding (OR 0.74, 95% CI 0.54 to 1.07; p = 0.07). The fact that our reperfusion times and pretreatment duration in STEMI, greatly exceed those of the ATLANTIC study (159 vs. 360 minutes and 45 vs. 180 minutes,

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respectively),[15] could explain the benefits of pretreatment seen in our work by the hypothetical higher level of inhibition of platelet aggregation reached at the time of PCI; however some questions

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remain unanswered, such as the mortality reduction associated with clopidogrel pretreatment in an observational study of patients with STEMI undergoing pPCI,[10] with higher reperfusion times than those reported by the ATLANTIC study.[15] Our work shows the limitations of an observational study but reflects daily clinical practice of a multicenter Registry. Despite trying to control the treatment selection bias using three methodological strategies, we cannot exclude that other confounding factors not included in the models may have interfered the final results. Corroboration of the results regardless of the method used for the adjustment provides robustness compared with other studies using less rigorous 9

ACCEPTED MANUSCRIPT adjustments.[3,10-11] The sensitivity results by subgroups analysis should be interpreted with caution and should be considered exploratory. The time intervals elapsed between the dose of clopidogrel and coronary angiography are estimated, as they were not specifically included on the data collection form. Our data focus only on in-hospital events, since these are more related to the loading dose of

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antiplatelet drugs during the acute phase than with the long-term maintenance dose. Acknowledgements: we specially want to thanks the support provided by Cosesoft Clinical (http://www.coresoft.es).

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Disclosures: None

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Heart Diseases in Andalusia (PICA).

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Funding: The ARIAM is funded by the Government of Andalusia within the Comprehensive Plan for

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ACCEPTED MANUSCRIPT 21. Senanayake EL, Howell NJ, Evans J, Ray D, Mascaro J, Graham TR, Rooney SJ, Pagano D. Contemporary outcomes of urgent coronary artery bypass graft surgery following non-ST elevation myocardial infarction: urgent coronary artery bypass graft surgery consistently outperforms Global Registry of Acute Coronary Events predicted survival. Eur J

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Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011;57:672-684.

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ACCEPTED MANUSCRIPT Figure legends Figure 1. Study Flow Chart ACS: acute coronary syndrome

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Figure 2. Association of pretreatment with outcomes by adjusted multivariate analysis* TIA: transient ischemic attack, CI: confidence interval, MACCE: major adverse cardiac and cerebrovascular event , NACE: net adverse clinical event, aOR: adjusted odds ratio, STEMI: ST elevation myocardial infarction, NSTE ACS: non ST elevation acute coronary syndrome

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*Variables included in the regression model: age, gender, diabetes, hypertension, chronic kidney disease, COPD, GRACE risk score, total ischemic time, reperfusion type (STEMI), Killip class, prior myocardial infarction, prior stroke, prior antiplatelet tretament, number of coronary vessel disease. IIb/IIIa GP inhibitors and body mass index were added for bleeding and NACE analysis. Stent type (BMS vs. DES), and number of implanted stents were added for the analysis of stent thrombosis. MACCE STEMI: C statistic = 0.852 95%CI (0.808-0.897); p< 0.0001. Hosmer-Lemeshow test χ2 5.55; p=0.697 NSTE ACS: C statistic= 0.844 95%CI (0.814-0.874); p< 0.0001. Hosmer-Lemeshow test χ2 4.27; p=0.831

Figure 3. Sensivity subgroup analysis

pPCI: primary percutaneous intervention, MACCE: major adverse cardiac and

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cerebrovascular event , NACE: net adverse clinical event

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Data represent aOR with 95%CI´s and p value for interaction.

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Table 1 Baseline characteristics stratified by acute coronary syndrome type STEMI No pretreatment (n=2076)

p

Pretreatment (n=2797)

NSTE ACS No Pretreatment (n=775)

p

62±12 7346 (76%) 3761 (39%) 3004 (31%) 3970 (41%) 5048 (52.5%) 1495 (15.5%) 1389 (14.5%) 493 (5%)

61±12 3149 (79%) 1751 (44%) 1104 (28%) 1544 (39%) 1875 (47%) 738 (18.5%) 409 (10%) 187 (5%)

62±12 1587 (76%) 885 (43%) 616 (30%) 757 (36.5%) 1041 (50%) 118 (5.6%) 306 (15%) 40 (2%)

0.096 0.012 0.121 0.224 0.015 0.091 < 0.0001 < 0.0001 < 0.0001

64±12 2050 (73%) 901 (32%) 989 (35%) 1344 (48%) 1684 (60%) 576 (20%) 490 (17,5%) 226 (8%)

62±11 560 (72%) 224 (29%) 295 (38%) 315 (41%) 448 (58%) 63 (8%) 184 (24%) 40 (5%)

0.919 0.732 0.073 0.171 < 0.0001 0.199 < 0.0001 0.001 0.003

244 (2.5%) 487 (5%) 1027 (11%)

72 (2%) 166 (4%) 268 (6.7%)

14 (0.7%) 119 (6%) 214 (10%)

< 0.0001 0.015 < 0.0001

138 (5%) 160 (6%) 416 (15%)

20 (2.6%) 42 (5,4%) 129 (17%)

0.003 0.585 0.146

213 (2.2%) 2491 (26%)

51 (1.3%) 747 (18.8%)

40 (2%) 475 (23%)

0.03 < 0.0001

91 (3,2%) 976 (35%)

31 (4%) 293 (38%)

0.264 0.07

6049 (63%) 3572 (37%) 1041 (11%) 2531 (26%) 133 [110, 159]

3973 (66%) --

2076 (34%) --

< 0.0001 --

139 [117, 164]

136 [113, 166]

0.986 0.015

-2797 (78%) 770 (27.5%) 2027 (72.5%) 123 [100, 150]

-775 (22%) 271 (35%) 504 (65%) 127 [95, 162]

-< 0.0001 <0.0001 <0.0001 0.090 0.439

8801 (91.5%) 820 (8.5%)

3645 (92%) 328 (8%)

1853 (89%) 222 (11%)

2590 (92.6%) 207 (7.4%)

713 (92%) 62 (8%)

2475 (26%) 7146 (74%)

272 (7%) 3701 (93%)

1563 (75%) 513 (25%)

98 (3.5%) 2699 (96.5%)

542(70%) 233 (30%)

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Clinical presentation STEMI NSTE ACS Unstable angina NSTEMI GRACE risk score Killip class I-II III-IV Time period 2002/2006 2007/2012

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Variables Age (years) Men Current smokers Diabetes mellitus Dyslipidemia Hypertension Obesity Prior myocardial infarction Chronic obstructive pulmonary disease Chronic kidney disease Stroke/ transient ischemic attack Prior percutaneous coronary intervention Prior coronary by-pass Prior antiplatelet tx

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Overall (n=9621)

< 0.0001

< 0.0001

Values expresed as mean±SD, median [P25, P75] and n (%). GRACE: Global Registry of Acute Coronary Events , STEMI: ST-elevation myocardial infarction, NSTE ACS: non-ST elevation acute coronary syndrome, NSTEMI: non ST-elevation myocardial infarction, TIA: transient ischemic attack

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Table 2: Pharmacological treatment and angiographic characteristics

1070 (27%) 508 (13%) 3075 (77.4%) 258 (6,5%) 39 (0.9%) 1736 (43.5%)

575 (27.3%) 391 (19%) 1492 (72%) 33 (1.6%) 21 (1%) 852 (41%)

8771 (91%) 850 (9%) 12 [1.8, 50]

3377 (85%) 596 (15%) 3 [1.2, 19]

15 [4, 52] 8434 (88%) 3974 (41%) 4460 (46%) 436 (4.5%) 1.7±1

6 [3.3,22] 3705 (93%) 1667 (42%) 2038 (51%) 167 (4.2%) 1.7±1

593 (6%) 5124 (53%) 2439 (25%) 1465 (16%) 442 (4.6%) 3193 (33%) 1372 (14%) 1071 (11%) 116 (1.2%)

NSTE ACS No pretreatment (n=775)

0.973 < 0.0001 0.009 < 0.0001 0.990 0.048 < 0.0001

780 (28%) 77 (2.7%) 2383 (85%) 305 (11%) 4 (0,1%) --

255 (33%) 64 (8.2%) 625 (80%) 16 (2%) --722 (93%) 53 (7%) --

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1959 (94,4%) 117 (5.6%) --

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2713 (97%) 84 (3%) 42 [21, 73]

6,3 [3, 33] 1857 (89.4%) 1021 (49%) 836 (40%) 120 (5.8%) 1.6±1

0.175 < 0.0001 < 0.0001 < 0.0001 0.004 0.001

47 [26, 80] 2271 (81%) 931 (33%) 1340 (48%) 121 (4.3%) 1.8±2

52 [24, 135] 601 (77.5%) 355 (45.8%) 246 (32%) 28 (3.6%) 1.6±1

0.193 0,024 < 0.0001 < 0.0001 0.417 0.004

55 (2.6%) 1287 (62%) 540 (26%) 194 (9.4%) 39 (2%) 1145 (55%) 182 (9%) 186 (9%) 33 (1.6%)

0.0006 0.453 0.01 0.007 < 0.0001 0.008 < 0.0001 < 0.0001 < 0.0001

304 (11%) 1119 (40%) 727 (26%) 647 (23%) 202 (7.2%) --492 (17.6%) 34 (1.2%)

59 (7.6%) 295 (38%) 258 (33.4%) 163 (21%) 29 (3.7%) --151 (19.5%) 23 (3%)

0.072 0.340 < 0.0001 0.226 0.004 --0.205 0.001

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175 (4.4%) 2423 (61%) 914 (23%) 461 (11.6%) 172 (4.3%) 2048 (51.5%) 1190 (30%) 242 (6%) 26 (0.8%)

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2680 (29%) 1040 (11%) 7575 (78%) 612 (6%) 64 (0.7%) 2588 (27%)

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STEMI No pretreatment (n=2076)

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Drugs* IIb-IIIa Glicoprotein inhibitors Unfractionated heparin Low molecular weight heaprin Fondaparinux Bivalirudin Thrombolysis Clopidogrel (load dose) - ≤300 mg - 600 mg Clopidogrel-to-angiography (hours) # Angiography/PCI Symptons-to- angiography (hours) PCI ( with stent) - Bare metal stent - Drug eluting stent - Bare metal+Drug eluting stent No. of stents No. Vessel disease -0 -1 -2 -3 - Left main Primary PCI Rescue PCI Angiography without PCI Coronary by-pass

Pretreatment (n=3973)

Overall (n=9621)

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Values expressed as median±SD, median [P25, P75], and n (%). * During hospital stay # Valid for pretreatment group STEMI: ST-elevation acute coronary syndrome, NSTE ACS: non-ST elevation acute coronary syndrome, PCI percutaneous coronary intervention

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318 (4.7%) 262 (3.9%) 32 (0.5%) 52 (0.8%)

Bleeding • Major • Minor • Minimal • Fatal NACE

223 (3.3%) 36 (0.5%) 41 (0.6%) 145 (2%) 10 (0.15%) 499 (7.4%)

140 (4.9%) 19 (0.7%) 5 (0.2%) 75 (2.6%) 3 (0.1%) 282 (10%)

< 0.0001 0.926 0.001 0.964 0.583 < 0.0001

139 (3.5%) 26 (0.6%) 31 (0.8%) 85 (2%) 7 (0.17%) 340 (8.6%)

113 (5.4%) 16 (0.8%) 4 (0.2%) 62 (3%) 3 (0.14%) 235 (11.3%)

0.0004 0.818 < 0.0001 0.580 0.782 0.0006

84 (3%) 10 (0.36%) 10 (0.36%) 60 (2%) 3 (0.11%) 159 (5.7%)

27 (3.5%) 3 (0.38%) 1 (0.13%) 13 (1.7%) -47 (6%)

0.235 0.891 0.309 0.404 0.335 0.688

Stent thrombosis

7 (0.24%)

42 (0.62%)

0.003

7 (0.17%)

42 (2%)

< 0.0001

--

--

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Cardiogenic shock

398 (6%)

193 (6.8%)

0.097

304 (7.7%)

166 (8%)

0.635

94 (3.4%)

27 (3.5%)

0.867

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229 (5.8%) 188 (4.7%) 22 (0.5%) 41 (1%)

0.084 0.123 0.040 0.199

89 (3.2%) 74 (2.6%) 5 (0.18%) 11 (0.4%)

Pretreatment (n=3973)

0.021 0.113 0.031 0.041

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NSTE ACS (n=3572) No pretreatment (n=775) 23 (3%) 17 (2.2%) 10 (1.3%) 1 (0.13%)

p 0.762 0.246 < 0.0001 0.481

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Outcome *

STEMI (n=6049) No pretreatment (n=2076) 143 (7%) 116 (5.6%) 20 (0.9%) 14 (0.7%)

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MACCE • Death • Reinfarction • Stroke/TIA

Overall (n=9621) No pretreatment (n=2851) 166 (5.8%) 133 (4.6%) 25 (0.9%) 15 (0.5%)

Figures expressed as n (%) * Patients may have more than one event MACCE: major adverse cardiac and cerebrovascular event, NACE: net adverse cardiac event, NSTE ACS: Non ST-elevation acute coronary syndrome, STEMI: ST-elevation myocardial infarction, TIA: transient ischemic attack.

ACCEPTED MANUSCRIPT Table 4. Association of clopidogrel pretreatment with in-hospital outcomes A) Propensity score analysis. B) IPTW analysis A) STEMI (n=3336)

NSTE ACS (n=1240)

(95% CI)

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aOR

(95% CI)

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MACCE • Death • Reinfarction • Stroke/TIA

0.76 0.85 0.38 2.10

(0.56-1.03) (0.73-2.01) (0.15-0.93) (0.96-4.16)

0.081 0.237 0.035 0.098

0.84 0.95 0.31 2.66

(0.35-2.04) (0.49-1.83) (0.03-2.90) (0.47-20.6)

0.715 0.878 0.305 0.348

Bleeding • Major • Minor • Minimal

1.24 1.31 4.58 1.47

(0.17-8.76) (0.31-5.47) (1.15-18.2) (1.08-1.98)

0.829 0.704 0.031 0.005

1.02 1.10 1.35 1.84

(0.47-2.22) (0.49-2.48) (0.27-6.78) (0.72-4.08)

0.956 0.802 0.682 0.200

NACE Stent thrombosis

0.64 0.57

(0.50-0.81) (0.47-0.71)

0.001 < 0.0001

(0.68-1.2) --

0.520 --

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Variables included in the propensity score model: age, sex, BMI, ACS type, diabetes, prior myocardial infarction, prior stroke, previous antiplatelet treatment, previous treatment with K vitamin antagonists, GRACE risk score, prior PCI, COPD, Killip class at admission, transport by EMS. IIb/IIIa GPI treatment and CKD were added as covariates for the analysis of NACE and bleeding Type and No of implanted stents were added to the previous as covariates for the analysis of stent thrombosis

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MACCE STEMI: C-statistic = 0.838, 95% CI (0.879-0.882); p< 0.0001. Hosmer-Lemeshow test χ2 7.19, p=0.516 NSTE ACS: C-statistic = 0.886, 95%CI (0.835-0.937); p< 0.0001. Hosmer-Lemeshow test χ2 3.89, p=0.867

B)

STEMI (n=5426) (95% CI)

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aOR

NSTE ACS(n=3134) p

aOR

(95% CI)

p

0.57 0.59 0.41 1.76

(0.38-0.84) (0.38-0.94) (0.16-0.99) (0.59-5.22)

0.005 0.026 0.050 0.309

0,72 0,81 0,76 3,41

(0.25-2.03) (0.24-2.75) (0.10-6.93) (0.05-2.26)

0.720 0.745 0.810 0.566

Bleeding • Major • Minor • Minimal

0.39 1.22 4.13 1.01

(0.35-1.38) (0.54-2.37) (1.14-15) (0.57-1.77)

0.303 0.883 0.05 0.990

0,88 0,74 1,31 1,67

(0.19-7.45) (0.08-7.14) (0.04-37) (0.39-7.18)

0.857 0.799 0.875 0.489

NACE Stent Thrombosis

0.50 0.14

(0.37-0.69) (0.04-0.62)

0.002 0.010

0,87 --

(0.42-1.78) --

0.708 --

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MACCE • Death • Reinfarction • Stroke/TIA

Variable included in the model MACCE: age, sec, diabetes, CKD, COPD, GRACE score, total ischemic time, reperfusion strategy (STEMI),Killip class, previous myocardial infarction, previous stroke, previous treatment with antiplatelet, No of vessel disease, NACE and bleeding: IIb/IIIa GPI use and BMI were added to the previous covariates Stent thrombosis: Type and No of stent were added MACCE STEMI: C-statistic= 0.855, 95% CI (0.825-0,885); p< 0.0001. Hosmer-Lemeshow Test χ2 11.12; p=0.195 NSTE ACS: C-statistic= 0,865, 95% CI (0.824-0.915); p< 0.0001. Hosmer-Lemeshow Test χ2 12.44; p=0.133

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Prognostic impact of clopidogrel pretreatment in patients with acute coronary syndrome

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managed invasively

Manuel Almendro Delia1, Luis González Torres1, Ángel García Alcántara2, Antonio Reina Toral3, José Andrés Arboleda Sánchez4, Juan Carlos Rodríguez Yañez5, Rafael Hidalgo Urbano1, Juan

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Carlos García Rubira1, on behalf of the ARIAM-Andalucía Group.

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Figure S1. Standardized differences before and after matching in the propensity score analysis

ACS: acute coronary syndrome, COPD: chronic obstructive pulmonary disease, EMS: emergency medical system, PCI: percutaneous coronary intrevention,

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Figure S2. Propensity score histogram distribution

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Appendix.

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List of investigators of ARIAM Anadalucia Group

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Provincia Almería: HAR el Toyo: Norberto Daz Ricoma, Francisco José Mellado Vergel; S.P. Almeria EPES: Itziar Vivar Diaz; UCI Inmaculada: Francisco Barredo Acedo, José Córdoba Escámez, Francisco José Delgado Vílchez, María Segovia Linares, Carlos Ortega Casanova, Daniel Sánchez Ortega, Francisco Javier Rodríguez Pérez, María Isabel Rodríguez Higueras, Dolores Ocaña Fernández, Javier García Águila; UCI Hospital Poniente: Javier Fierro Rosón, María Segovia Linares, Sofía García Ordóñez, Miguel Ángel Fernández Ibáñez, Miguel Ángel Diaz Castellanos, Emilio Robles-Musso Castillo, Francisco Manuel Parrilla Ruiz, Antonio Cárdenas Cruz, Josefa Peinado Rodríguez; UCI Hospital Torrecárdenas: Rocío Rodríguez Castaño, María Segovia Linares, Cecilia Carbayo Górriz, Francisco José Guerrero Gómez, Ana Calderón Rodríguez, José Ángel Ramos Cuadra, José Carlos Martín Rubí, Dolores María Mayor García. Provincia Cádiz: Clínica La Salud: Fernando María Pérez Pérez; DCCU Bahía de Cádiz: José Luis Cabilla Vargas; DCCU Chiclana-La Janda: Josele Benítez Parejo, Manuel Cobeña Manzorro; DCCU Jerez Costa Noroeste: Antonio Ramón Flores López; MI. San Fernando: José Luis García Moreno; S.P. Cadiz EPES: Juan Antonio Péculo Carrasco, Jesús Enrique Martinez Faure; UCI Hospital Jerez: José Julián Arias Garrido, Mª Jesus Galán Rodríguez, Manuel Gracia Romero, Andrés Sainz de Baranda Piñero; SCCU. Algeciras: Pedro Cobo Castellano; UCI Hospital La Línea: Ana María Cabrera Calandria, Alejandro Úbeda Iglesias, Mª Belen Nacle López, Josefa Morales Cortés, Luis Vallejo Sánchez, Mª Carmen Martínez Ramagge; UCI Hospital Puerta del Mar: Rafael Perestrello Salas, José Luis López Benítez, Manuel Sancho Jaldón, Pablo Javier Sánchez Millán, Antonio Sánchez Heredia, Manuel GómezSánchez Orezzoli, Rocío Monterosso Pintado, Juan Antonio Noria Serrano, Benjamín Hernández Alonso, Juan José Ravina Sanz, José Rubio Quiñones, Ángel Custodio Sánchez Rodríguez, Marcos Alcántarro Montoya, Mikel Celaya López, Isabel Galván Parra, Antonio Gordillo Brenes, José Manuel Jiménez Moragas, Miguel Montero de Espinosa Candau, Jesús Flores González; UCI Hospital Puerto Real: Isabel Díaz Torres, Miriam Ruiz Miralles, Juan Carlos Rodríguez Yáñez, Juan Antonio Córdoba Doña, Jorge Gómez Ramos, Rafael Perestrello Salas, Francisco José Romero Bermejo, Rosa María Yang Lai, Juan Manuel Sánchez Crespo. Provincia Córdoba: Cruz Roja Cordoba: José Ignacio García de la Cruz, Noelia Maria Muñoz Guillén, Manuel Ángel de la Cal Ramírez; HAR de Puente Geni: Manuel Arjona Ruiz de Arévalo, Henry Hernan Quintero Castro, Francisco Moreno Camuñez, Aquiles Lozano Rodriguez-Mancheño; HAR Valle del Guadiato: Antonio Doblas Delgado; S.P. Cordoba EPES: Rafael Muñoz Arcos, Coral Chacon, Antonio Mantero Muñoz, Jesús Brañas Garza; SCCU. Pozoblanco: María José Fernández Pérez, José Carlos LLamas Reyes, Margarita Luque Santos, Juan Antonio Panadero de Manuel, Mª Angeles Ruiz-Cabello Jiménez, Yelda María Hernández Montes, Juan Carlos Luque Moscoso; UCI Hospital Cabra, María del Carmen de la Fuente Martos, Eduardo Aguilar Alonso, Pedro Lara Aguayo, Eduardo Morán Fernández, Fuensanta Soriano Rodríguez, Maria Rojas Amezcua, Eugenia Poyatos, Roberto Toro Sánchez; UCI. Hospital Montilla: Francisco Caballero Güeto, Manuel López Obispo, José Antonio Guzmán Pérez, Francisco García Delgado, Emilio del Campo Molina, Rafael Artacho Ruíz, Manuel López Pérez; UCI Hospital Reina Sofía: Miguel Ángel Chirosa Rios, Rafael León López, Daniel Garcia Fuertes, María José Ferrer Higueras, José Alonso Sánchez, Inmaculada Alcalde Mayayo, Jose Carlos LLamas Reyes, José María

ACCEPTED MANUSCRIPT Dueñas Jurado, Ana Mula Gómez, Francisco Mazuelos Bellido, Javier Montero Pérez, Ignacio Muñoz, María de las Nieves Parias Ángel, Mª Pilar Reyes Parras, Gema Alonso Muñoz, Francisco Romero Salado, Heliodoro Sancho Ruíz, José María Segura Segura, Natalio Martín Montes.

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Provincia Granada: DCCU Gran Capitan: María José Megías Cana; Escuela Andaluza de Salud Pública: María José Sánchez Pérez, Julia Bolívar Muñoz, María Esther Molina Montes; HAR de Guadix, José Vargas Rivas, Iván Aguilar Cruz; S.P. Granada EPES: Eladio Gil Piñero, Francisco Javier Ferrón García; SCCU. Virgen de las Nieves: Manuel Colmenero Ruiz, Rafael de la Chica Ruiz Ruano, Alberto Fernández Carmona, Mª del Mar Jiménez Quintana, Francisco Manzano Manzano, Rafael Melgares, Antonio Reina Toral, Manuel Fernando Passas Martínez, Iván Aguilar Cruz, Óscar Baún Mellado, Elena De Antonio Martín, Remedios Díaz Contreras, Manuel Garcia Delgado, Elisa Hernández Torres, José Miguel Perez Villares, Mª Eugenia Poyatos Aguilera, Antonio Reina Toral, Carlos Santos Box, Irma Leonor Slimobich, Maria Aguilera Barea, Eduardo Aguayo de Hoyos, Araceli Sánchez González, Patricia Castan Ribas; UCI. Clinica Inmaculada: Andrés Estivill Torrús: UCI. Hospital Baza: José Luis Bellot Iglesias; S: Agustín Aranda León, Matilde Arias Diaz, Miguel Ángel Díaz Castellanos, Andrés Estivill Torrús, Raimundo García del Moral Martín, Javier Ignacio Martín López, Juan Manuel Mercado Martínez, Agustín Aranda León, Ricardo Rivera Fernandez; UCI Hospital San Cecilio: José Martos Lopez, Susana Narbona Galdo, José Carlos Frías Pareja, Manuel Colmenero Ruiz, Fernando Barranco Ruiz, Francisco Javier Martin Ojeda, Lorena Olivencia Peña, Daniel Magaña Noguera, Mª Eugenia Poyatos, Antonio Enrique Valverde Mariscal, Ana Rallo Bonor, José Pomares Mora, Luis Peñas Maldonado, Rosario Fernández Fernández, Pilar Martínez Lopez, Ines Macias Guarasa, Ana Javaloyes Antón, Jose Manuel Soto Blanco, Rosario Ramírez Puerta, Diego Pedrosa García, Santiago Schiaffino Cano, Francisco González Marín, Mª Eugenia Yuste Osorio, José Luis Ballesteros, Carmen Espejo Medina, Alberto Fernández Carmona, Raimundo García del Moral Martín, Francisco Gonzalez Diaz.

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Provincia Huelva: DCCU Condado-Campiña: José María Quirós Gómez; S.P. Huelva EPES: Francisco Javier Alonso Urbita, Miguel Angel Paz Rodríguez; SCCU Hospital Juan Ramón Jiménez: Hipólito González Piñero, María Sánchez Santamaría, Manuel Rodríguez Carvajal, Aurora Hierro Delgado, Manuel Castillo Quintero, María del Pilar Ponce Ponce, Pedro Domínguez García, Mario Márquez Fernández, Antonia Tristancho Garzón; UCI Riotinto: Isidro Romero Barroso, Osama Barakat Shrem, Jesús Carbajal Guerrero, Enrique Pino Moya, Pedro Ortega Zarza, Alejandra Álvarez Saiz; UCI Hospital Infanta Elena: Juan Carlos Martínez Cejudo.

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Provincia Jaén: CCU. San Agustín: José Antonio Camacho Pulido, Agustín de Molina Ortega, Mercedes Jiménez Sánchez, Bartolomé Jurado Lara, José Manuel Jiménez Sanchez, Antonio José Montijano Vizcaino; HAR de Alcalá la Real: Amelia Peña Rodríguez; HAR de Alcaudete, Francisco Rosa Jiménez; HAR Sierra de Segura, Mª Dolores Arévalo Navarrete; LCU. Alto Guadalquivir: Miguel Ángel Fernández Sacristán, Manuel Castellano Hernández, Silvia Galindo Rodriguez, Alfonso Jesús Bayona Gómez; S.P. Jaen EPES: Susana De Castro García, Francisco Romero Morales; SCCU. Hospital Jaén: María Dolores Pola Gallego de Guzmán, Antonia Morante Valle, Juan Francisco Machado Casas, Manuela Expósito Ruiz, Manuel Ruiz Bailén, Luis Rucabado Aguilar, Ana María Castillo Rivera, Pedro Lucas Bustos, José Antonio Rodríguez Puche; UCI Hospital San Juan Cruz: Crispín Colmenero Aguilar, Mª del Mar Sánchez Zorrilla, Ángel Bartolomé Sanz. Provincia Málaga: Servicio Cardiologia. Vgn. Victoria: Fernando Cabrera Bueno; Coresoft: Rosa de la Fuente Gonzalez, Josele Benítez Parejo, Juan Miguel Torres Ruiz; Centro Salud de Coin: José María Ruiz San Basilio; Centro Salud San Pedro de Alcantara: Ignacio Perez-Montaut Merino; Servicio HAR de Benalmadena: Encarnación Cuéllar Obispo, Rafael Toscano Mendez, Miguel Martínez del Campo, Francisco de Asis Martos Perez; S.C. EPES: Fernando Rosell Ortiz, Francisca Ferron Galera, María del Mar Valverde, Veronica Rando, Luis Olavarría Govantes, José Javier García del Aguila, Javier Tomás, María Segovia Linares, José María Álvarez Rueda, Jesús Antona Archilla, Patricia Fernandez del Valle, Sergio

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Sanchez Trujillo; S.P. Malaga EPES: Manuela Martínez Lara, María Auxiliadora Naranjo Sánchez, Diana Anca, Irma Leonor Slimobich; UCI Carlos Haya: Javier Muñoz Bono, Macarena Cano García, Ana Maria Cabrera Calandria, Palma Benítez Moreno, Gabriel Alejandro Ballesteros Derbenti, Rocío Aragonés Manzanares, Ricardo Rivera Fernández, Teresa García Paredes, José Andrés Arboleda Sánchez, Ana María García Bellón, Manuel de Mora Martín, María Dolores Fernández Zamora, Joaquín Alberto Cano Nieto, Elena Diana Anca, Daniel Magaña Noguera, María Begoña Reina Monsó, José Miguel Álvarez Bueno, Antonio Vera Almazán, Mª Ángeles Roldán Jiménez, José Luis Muñoz Muñoz, Miguel Ángel Ramírez Marrero, José Moreno Quintana, María José Chaparro Sánchez, Inés Macías Guarasa, Gabino Jiménez Pérez, Julio Antonio Férriz Martín, José Carlos Escudero Valera, José Luis Delgado Prieto, Emilio Curiel Balsera, José Carlos Moreno Samos, Cristóbal A. Urbano Carrillo; UCI Quirón: Ana María Poullet Brea, José Antonio Benítez Lozano; UCI Hospital Antequera: Antonio Varela López, Pablo De Rojas Román, Alejandro Vázquez Vicente, Ramón Vegas Pinto, Mehdi Zaheri Beryanaky; UCI Hospital Axarquía: Mónica Delange van der Kroft, Javier Merino Vega, Francisco Castillo Guerrero, Carmen Martos Rodriguez, Jesus Ormazabal Galarraga, Mohamed Benazzouz Benkarroum; UCI Hospital Costa del Sol: María Dolores Briones Lopez, Josele Benítez Parejo, Julio Ortega Paso Viola, Francisco Rivas Ruiz, José Andrés Arboleda Sánchez, María Isabel Fernández García, Yolanda Fernández Jurado, Francisco Javier García Rodríguez, Francisco J. Lobato Mandueño, Daniel Magaña Noguera, Juan Francisco Prieto de Paula, José Benito Zaya Ganfornina, Gonzalo Suarez Alemán; UCI Hospital Ronda: María del Mar Luque Fernández, José María Castillo Caballero, Jose Maria Garcia Galvez, Jose Ignacio Mateo Sanchez; UCI Hospital Xani: Francisco Javier García Rodríguez, Manuel J. Delgado Amaya, José Antonio Benítez Lozano, Rocio Aragonés Manzanares, Juan Pablo de Rojas Roman, Emilio Curiel; UMI Hosp. Virgen Victoria: María Antonia Estecha Foncea, Maria Medina Sanchez, María Nieto González, Agustín Hernández Bayo, Angel García Alcántara, Jorge Vidal Hernández Rodríguez, José del Río Mata, María Victoria De la Torre Prados, Domingo Daga Ruiz, Diana Elena Anca, Pedro Pascual García, Irma Slimobich, Estefanía Cámara Sola, José Luis Carpintero Avellaneda, Jonathan Perez Vacas, Araceli Puerto Morlán, María Del Carmen Reina Artacho, Luis Ruíz del Fresno, Oscar Jerónimo Simón Padilla, Antonio Vallejo Baez, Nicolás Zamboschi, Cristina Salazar Ramírez; UMI. San Antonio: Juan Pablo de Rojas Román, Manuel J. Delgado Amaya, Rocío Aragonés Manzanares, Rocio Aragonés Manzanares, Maria Dolores Arias, Juan Pablo de Rojas Roman, Manuel J. Delgado Amaya.

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Provincia Sevilla: HAR de Ecija: Manuel Romero González; HAR de Moron de la Frontera: José Claros Rodríguez; HAR de Utrera: Isabel Hernández Utrera, Pedro Díaz Parejo; HAR Sierra Norte, Rafael Canto Neguillo, Manuel Aumesquet Nosea; NISA Sevilla-Aljarafe: Esperanza Fernández García, Alejandro Ramírez Sánchez, José Ignacio Sánchez Olmedo, María José Román Millán, Manuel Pérez Alé; S.P. Sevilla EPES: Francisco Bonilla Quintero, Maria del Mar Ruiz Montero, Auxiliadora caballero garcia; SCCU. Aljarafe: Flora María Villarrasa Clemente, Victor Jorge Amigo, Ana Esmeralda Barrero Almodovar, Olga Rufo Tejeiro, María del Carmen Pérez Paredes, José Luis García Garmendia, Sonia Luisa Gallego Lara, Cristóbal Colón Pallarés; UC Hospital Virgen Macarena: Francisca Francisco Aparicio, Manuel Almendro Delia, Emilia Blanco Ponce, Manuel Calvo Taracido, Juan Carlos García Rubira, Manuel Fernández Guerrero, Alejandro Recio Mayoral, Javier Mendoza Vázquez, Román Calvo Jambrina, María Rocío Gómez Domínguez, María José Valle Caballero, Kristel Elizabeth Medina Rodríguez, Manuel Iglesias Blanco, Rafael Hidalgo, Luis González Torres, Carlos González Matos, Pablo Bastos Amador, Michel Butron Calderón, Blanca Muñoz Calero, Luis F Valenzuela, Manuel Lobo González, Alejandro Espínola Pardo, Carolina Ortiz Cortés, María Pérez Rodríguez; UCI Infanta Luisa: Auxiliadora Caballero García, Juan Gonzalez Maestre; UCI Hospital Virgen del Rocio: Angel Sanchez Gonzalez, Zaida Ruiz de Azúa Lopez, Nieves Romero Rodriguez, María Julia Eslava Alva, Gloria María Valle Fernández, Rafael Martín Bermúdez, Beatriz Jáuregui Garrido, Ana María García Lombardo, Agustín Guisado Rasco, Ricardo Marco Sosa, Pedro Camacho Laraña, Rafael Hinojosa Perez, Judy Enamorado Enamorado, Esperanza Fernández Delgado,

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Mónica Fernández Quero, Angel Herruzo Aviles, Maria Cuaresma, Francisco Javier Jiménez Jiménez; UCI Hospital Merced: Irma Slimobich, Alvaro Porteo Bolaños, Emilio Muñoz Collado, Benjamín Hernández Alonso, Ladis Rene Enamorado Interiano, C. Alvarez, Daniel Del Toro Espinosa, Esperanza Fernández García; UCI Hospital Santa Isabel: Alejandro Luciani, Juan Fajardo López-Cuervo; UCI.Hospital Virgen de Valme: Christian Daniel Povis Lopez, Helena Sancho Fernandez, Dolores Herrera Rojas, José Antonio Sánchez Román, Cristina Calvo León, Juan Pedro Castilla Heredia, Tamara Contreras del Pino, Carmen Gomez Gonzalez, Antonio Lesmes Serrano, Francisco Lucena Calderón, María Angustias Sanchez Jimenez, Alejandro Úbeda Iglesias, Antonio Campanario Garcia, María Marín Herrero.