Troponin-Based Risk Stratification of Patients With Acute Nonmassive Pulmonary Embolism

CHEST

Original Research PULMONARY EMBOLISM

Troponin-Based Risk Stratification of Patients With Acute Nonmassive Pulmonary Embolism Systematic Review and Metaanalysis David Jime´nez, MD; Fernando Uresandi, MD; Remedios Otero, MD; Jose´ Luis Lobo, MD; Manuel Monreal, MD; David Martí, MD; Javier Zamora, MD; Alfonso Muriel, MD; Drahomir Aujesky, MD; and Roger D. Yusen, MD, FCCP

Background: Controversy exists regarding the usefulness of troponin testing for the risk stratification of patients with acute pulmonary embolism (PE). We conducted an updated systematic review and a metaanalysis of troponin-based risk stratification of normotensive patients with acute symptomatic PE. The sources of our data were publications listed in Medline and Embase from 1980 through April 2008 and a review of cited references in those publications. Methods: We included all studies that estimated the relation between troponin levels and the incidence of all-cause mortality in normotensive patients with acute symptomatic PE. Two reviewers independently abstracted data and assessed study quality. From the literature search, 596 publications were screened. Nine studies that consisted of 1,366 normotensive patients with acute symptomatic PE were deemed eligible. Pooled results showed that elevated troponin levels were associated with a 4.26-fold increased odds of overall mortality (95% CI, 2.13 to 8.50; heterogeneity ␹2 ⴝ 12.64; degrees of freedom ⴝ 8; p ⴝ 0.125). Summary receiver operating characteristic curve analysis showed a relationship between the sensitivity and specificity of troponin levels to predict overall mortality (Spearman rank correlation coefficient ⴝ 0.68; p ⴝ 0.046). Pooled likelihood ratios (LRs) were not extreme (negative LR, 0.59 [95% CI, 0.39 to 0.88]; positive LR, 2.26 [95% CI, 1.66 to 3.07]). The Begg rank correlation method did not detect evidence of publication bias. Conclusions: The results of this metaanalysis indicate that elevated troponin levels do not adequately discern normotensive patients with acute symptomatic PE who are at high risk for death from those who are at low risk for death. (CHEST 2009; 136:974 –982) Abbreviations: cTnI ⫽ cardiac troponin I; cTnT ⫽ cardiac troponin T; LR ⫽ likelihood ratio; OR ⫽ odds ratio; PE ⫽ pulmonary embolism

most patients with acute pulmonary A lthough embolism (PE) have an uncomplicated clinical course while undergoing standard anticoagulation treatment, the overall 3-month mortality rate exceeds 15%.1 Death from acute PE usually occurs before or soon after hospital admission.2 Patients presenting with clear signs of shock have high morbidity and mortality rates. It is generally accepted that these patients should be considered for thrombolytic therapy.3 One area of controversy focuses on the extension of the indication for thrombolytic therapy to a subgroup of patients who appear stable

at presentation but have impending right ventricular failure and a high risk of PE-related death. Thus, a major challenge is the identification of such potential For editorial comment see page 952 candidates for thrombolytic therapy by a simple, rapid, and noninvasive method. Studies of patients with acute PE have demonstrated an association between elevated serum levels of troponin and right ventricular dysfunction or adverse in-hospital outcome.4 However, the positive

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predictive value of an elevated troponin level is low, and the prognostic implications remain uncertain.5 Only a few studies have evaluated the prognostic significance of elevated levels of troponin in the subgroup of normotensive patients with acute PE in which alternatives to conventional anticoagulation (ie, thrombolysis) may be considered. In addition, some reports6 – 8 have suggested that cardiac troponin levels have a high negative predictive value with regard to early death. Few studies have evaluated the prognostic significance of low levels of troponin in the subgroup of normotensive patients with acute PE in which home therapy of acute symptomatic PE may be considered. A metaanalysis published in 20079 and a large cohort study10 have come to conflicting conclusions and have prompted further debate about the usefulness of the measurement of troponin levels for the risk stratification of PE patients. The metaanalysis pooled data for normotensive and hemodynamically unstable patients. Three more recent studies10 –12 were not included in the previous metaanalysis. To further clarify how well troponin levels predict mortality in normotensive patients with acute symptomatic PE and its usefulness for treatment decision making, this study aimed to review the literature systematically and perform an updated metaanalysis. Materials and Methods

reporting of proportions of patients in different categories surrounding a predefined cut point for elevation defined by the local laboratories; separate reporting within the cohort of normotensive patients; and analysis of all-cause mortality within the cohort of normotensive patients. Type of troponin assay, definition of normotensive status, study sample size, and duration of follow-up did not determine study eligibility. We applied no language restriction. Literature Search A computerized search of Medline and EMBASE from 1980 through April 2008 was conducted to identify eligible studies. Studies published in abstract form were excluded because of the concern that non-peer-reviewed data might introduce bias into the report. We used a sensitive search strategy for prognosis studies.13,14 We used the terms “venous thrombosis” (MeSH) or “pulmonary embolism” (MeSH) or “PE” (text word); “troponin” (MeSH) or “cardiac biomarkers” (text word); “incidence” (MeSH) or “explode mortality” (MeSH) or “follow-up studies” (MeSH) or “mortality” (subheading) or “prognosis*” (text word) or “predict*” (text word) or “course” (text word). Full articles of all potentially appropriate abstracts were reviewed. Hand searching of cited bibliographies and investigator files complemented the literature search. Study Selection and Data Extraction Two investigators (D.J. and D.M.) independently assessed the identified articles to determine study eligibility. Based on brief study details (eg, title and abstract), the reviewers excluded nonrelevant studies. For relevant studies, the reviewers independently carried out data extraction using a standardized form designed a priori. Consensus or discussion with a third reviewer resolved eligibility and data extraction discrepancies or uncertainties.

Study Eligibility

Study Quality Assessment

All studies of patients with PE were considered eligible for the metaanalysis if they fulfilled the following criteria: original publication; inclusion of normotensive patients with an objectively confirmed diagnosis of acute symptomatic PE; measurement of cardiac-specific troponin levels (cardiac troponin T [cTnT] or cardiac troponin I [cTnI]) in nanograms per milliliter, or the

Although quality criteria for assessing randomized controlled trials exist, the literature lacks a generally accepted list of such criteria for observational studies.15–17 Two investigators (D.J. and D.M.) independently assessed the quality of the eligible studies, as recommended by Hayden et al,18 by grading six potential sources of bias related to study participation, study attrition, prognostic factor measurement, outcome measurement, confounding measurement and control, and analysis. We classified the control of confounding as follows: (1) poor, if little or no attempt was made to control for known basic confounders (ie, age, sex, comorbidities, anticoagulant treatment, or prognostic indexes); (2) adequate, if analyses controlled for age and comorbidities; and (3) good, if analyses controlled for the majority of the confounders.

Manuscript received March 10, 2009; revision accepted April 14, 2009. Affiliations: From the Respiratory Department (Dr. Jime´nez), the Cardiology Department (Dr. Martí), and the Biostatistics Unit (Drs. Zamora and Muriel), Ramo´n y Cajal Hospital, Madrid, Spain; the Respiratory Department (Dr. Uresandi), Cruces Hospital, Bilbao, Spain; the Respiratory Department (Dr. Otero), Virgen del Rocío Hospital, Sevilla, Spain; the Respiratory Department (Dr. Lobo), Txagorritxu Hospital, Vitoria, Spain; the Medicine Department (Dr. Monreal), Germans Trias i Pujol Hospital, Barcelona, Spain; the Division of General Internal Medicine (Dr. Aujesky), University of Lausanne, Lausanne, Switzerland; and the Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences (Dr. Yusen), Washington University School of Medicine, St. Louis, MO. Correspondence to: David Jime´nez, MD, Respiratory Department, Ramo´n y Cajal Hospital, Colmenar Rd, Kilometer 9.100, 28034 Madrid, Spain; e-mail: [email protected] © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). DOI: 10.1378/chest.09-0608 www.chestjournal.org

Data Synthesis We a priori created a 2 ⫻ 2 table based on troponin level categories (positive ([high level] and negative [low level]) and overall death. For each study, we determined the incidence of short-term, all-cause mortality for the positive and negative troponin groups, and we calculated an odds ratio (OR) and its 95% CI. We pooled ORs across studies by using a DerSimonian and Laird random-effects model approach. Statistical heterogeneity between groups was measured using the Cochran Q statistic (p value ⬍ 0.1 [indicative of heterogeneity; ␹2 test]) and the Higgins I2 statistic (heterogeneity was defined as low if ⬍ 25%, moderate if between 25% and 50%, or high if ⬎ 50%). We CHEST / 136 / 4 / OCTOBER, 2009

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evaluated the effect of the different troponin cutoff levels for the prediction of death. We fitted a summary receiver operating characteristic curve and analyzed the relationship between sensitivity and specificity of troponin to predict overall mortality by means of the Spearman rank correlation coefficient. Although the positive and negative predictive values give outcome probabilities for particular test results, they depend on the prevalence of the outcome in the study sample, and they may be difficult to generalize beyond the study. Thus, we calculated likelihood ratios (LRs) to see if we could discern patients at high vs low risk for death. We separately analyzed studies that used troponin I and those that used troponin T, and studies that had good/adequate control of confounding and those with poor control of confounding. The Begg rank correlation method assessed publication bias. All analyses were carried out using statistical software package (Stata; Stata Corp; College Station, TX19; and Meta-DiSc, version 1.4; publicly available at http://www.hrc.es/investigacion/metadisc_en.htm).20

Results Description of Studies Of the 596 articles screened, 28 appeared potentially eligible and were reviewed in depth.4 –7,10 –12,21– 41 Nineteen studies were deemed ineligible4–7,21–35 (Fig 1), and 9 studies met the eligibility criteria.10 –12,36 – 41 Agreement between the two reviewers for study eligibility was very high (␬ ⫽ 0.9). The year of publication of the nine eligible studies ranged from 2003 to 2008 (Table 1). Of the total sample size of 1,366 patients, the individual study samples ranged in size from to 28 to 458 patients. The largest study by Douketis et al39 accounted for 33% of all patients in the metaanalysis, and the two largest studies10,39 accounted for 56% of all patients. Regarding study design, eight studies10 –12, 36 –38, 40, 41 were described as prospective cohort studies, and one study39 utilized a cohort from a randomized controlled trial retrospective database analysis. For the survival (all-cause mortality) analyses, two studies37,40 used the Cox proportional-hazards technique and four studies10,36,39,40 used logistic regression. The studies used tests for measuring levels of either cTnT or cTnI. Most of the studies used a predefined cutoff point to determine abnormal (elevation) vs normal (nonelevation) levels. Three of the studies used the same assay and the same cutoff (⬎ 0.01 ng/mL) for abnormality, and all studies used a cutoff of no more than 0.5 ng/mL. Receiver operating characteristic analysis assessed the optimal cutoff value of cTnT for death and serious adverse event selection in one study.37 In two of the studies,40,41 the mean age of the patients was approximately 53 years, which was younger than the mean age of the other studies and large cohort studies of patients with PE.1,42 Length of follow-up ranged from the in-hospital period11,12,36,38,40 to 3 months.39,41 Reported losses to

Figure 1. Flow chart of the study selection process.

follow-up varied from 0 to 6%. The mortality rates varied from 1%40 to 15%.37 Definitions of Hemodynamic Status and Outcomes The definition of hemodynamic status differed among the studies. Two studies did not provide a definition for the term “normotensive.”38,41 Jime´nez et al10 and Douketis et al39 excluded patients with massive PE associated with hypotension (systolic BP, ⬍ 90 mm Hg), cardiogenic shock, or respiratory failure in whom thrombolytic therapy or surgical thrombectomy might be considered. Kline et al40 excluded patients with systolic BP ⬍ 100 mm Hg. Logeart et al12 excluded patients with hemodynamic impairment, which they defined as shock, systolic BP ⬍ 90 mm Hg, or syncope on hospital admission. Pruszczyk et al36 excluded patients with

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Charlotte, NC; prospective cohort study

Clichy, France; prospective cohort study

Kline et al40/2006

Logeart et al12/2007

All-cause death or adverse events

All-cause death and PE-related death

All-cause death

PE-related death or adverse events

All-cause death or adverse events

Recurrent venous thromboembolism and all-cause death

All-cause death or adverse events

All-cause death, PErelated death, or adverse events

All-cause death or adverse events

Outcome Event

*Values are given as the mean (SD) or mean (range).

Jiménez et al10/2008

Naples, Italy; prospective cohort study

United States; Matisse randomized controlled trial

Douketis et al39/2005

Gallotta et al11/2008

Cosenza, Italy; prospective cohort study

Bova et al38/2005

Amsterdam, the Netherlands; prospective cohort study Madrid, Spain; prospective cohort study

Warsaw, Poland; prospective cohort study

Kostrubiec et al37/2005

Tulevski et al41/2007

Warsaw, Poland; prospective cohort study

Setting and Design

Pruszczyk et al /2003

36

Study/Year

Normotensive patients (60)

Patients with submassive PE participating in a randomized trial with fondaparinux sodium (458) Normotensive ED and hospital inpatients (181)

cTnT, ⬎ 0.01 ng/ mL

cTnI, ⬎ 0.5 ng/mL

cTnI, ⬎ 0.03 ng/mL

cTnI, ⬎ 0.1 ng/mL

cTnT, ⬎ 0.01 ng/ mL

cTnI, ⬎ 0.06 ng/mL

Normotensive outpatients (90)

Normotensive outpatients (28) No cardiac or pulmonary medical history Hemodynamically stable outpatients (318)

Hemodynamically stable outpatients (67)

Normotensive outpatients (100)

cTnT, ⬎ 0.07 ng/ mL

cTnT, ⬎ 0.1 ng/mL

Normotensive outpatients (64)

Population (No.)

cTnT, ⬎ 0.01 ng/ mL

Troponin Cutoff for Positive Test Result Sex

72% female

57% female

57% female

40% female

58% female

57% female

65% female

65% female

Table 1—Characteristics of the Studies

67 (18)

72 (14)

53 (18)

53 (17)

63 (19–92)

65 (18)

62 (18)

61 (17)

Age, yr*

In-hospital period

30 d

90 d

In-hospital period

In-hospital period and 6 mo

3 mo

In-hospital period and 3 mo

40 d

In-hospital period

Follow-up

Elevated troponin was significantly associated with the likelihood of in-hospital death

cTnI level was an independent predictor of PE-related death

After adjustment, there was no significant difference in outcome between positive and negative troponin test groups Patients with positive troponin test results had higher risks of in-hospital events compared with patients with negative troponin test results Mortality was significantly higher in patients with positive troponin test result

25% mortality rate for positive troponin test group vs 0% for negative troponin test group After adjustment, patients with a positive troponin test result had significantly greater risk of overall mortality compared with those with a negative troponin test (HR, 9.2; 95% CI, 3.3–26.1) 27% mortality rate for positive troponin test group vs 3% for negative troponin test group Crude all-cause mortality rate was 4.1-fold (95% CI, 1.4– 11.8) greater in patients with a positive troponin test

Study Results

systolic BP at hospital admission of ⬍ 90 mm Hg, those requiring catecholamine infusion or ventilatory support, and those who had undergone cardiopulmonary resuscitation. Kostrubiec et al37 excluded patients who presented with systolic BP ⬍ 90 mm Hg. Gallotta et al11 excluded patients with shock or systolic BP ⬍ 90 mm Hg, or severe tachyarrhythmias or bradyarrhythmias. In most studies, the primary outcome was allcause mortality. PE-related death was the primary outcome in three studies.10,32,36 For the purpose of this metaanalysis, we only analyzed all-cause mortality for all studies. Quality Assessment of Included Studies Regarding study quality assessment criteria (Table 2), the study participation was adequate and the baseline study sample was adequately described in six of the studies.10 –12,37,39,40 In the studies of Pruszczyk et al36 and Bova et al,38 it was unclear whether only outpatients were eligible, and there was no information about the period of recruitment. Tulevski et al41 did not specify study eligibility criteria, and the source population was not adequately described for key characteristics. Only three studies10,40,41 provided adequate information about patients lost to follow-up, whereas the other six studies11,12,36 –39 did not. All studies adequately measured troponin levels, although the assays and the cutoffs for high/low levels varied, as described earlier and in Table 1. An independent blinded committee assessed the outcome criteria in one study.10 Important potential confounders were appropriately accounted for in six studies.10,11,36,37,39,40 The use of appropriate statistical analyses in six stud-

ies10,11,36,37,39,40 limited the potential for the incorporation of and presentation of invalid results, whereas the other three studies did not perform any predictive statistics. End Point Overall, 27.6% of normotensive patients with acute symptomatic PE had elevated troponin levels. Sixty of the 377 patients with elevated troponin levels died (15.9%; 95% CI, 12.2 to 19.6) compared with 34 of 989 with normal troponin levels (3.4%; 95% CI, 2.3 to 4.6). Summary receiver operating characteristic analysis showed a relationship between the sensitivity and specificity of troponin to predict overall mortality (Fig 2). Pooled results showed that elevated troponin levels, compared with nonelevated levels, were associated with a 4.26-fold increased odds of overall mortality (95% CI, 2.13 to 8.50; heterogeneity ␹2 ⫽ 12.64; degrees of freedom ⫽ 8; p ⫽ 0.125) [Fig 3] during short-term follow-up. The pooled estimate was dominated by the three larger studies,10,39,40 which together provided about threequarters of the total number of patients, and these studies had the most conservative (nonextreme) results. Five of the nine studies did not have statistically significant findings, although all studies showed the same trend. The result was consistent for either troponin I (OR, 2.65; 95% CI, 1.26 to 5.56) or troponin T (OR, 8.60; 95% CI, 2.72 to 27.22), and for high-quality studies (OR, 3.18; 95% CI, 1.56 to 6.45) or low-quality studies (OR, 15.29; 95% CI, 3.32 to 70.37). There was no evidence of publication bias using the Begg rank correlation method. The metaanalysis showed the following: (1) a slight increase in the rate of elevation of troponin levels in

Table 2—Quality Assessment of Studies Included in the Systematic Review Study Follow-up Described Participation and Adequate

Study/Year Pruszczyk et al36/2003 Kostrubiec et al37/2005

Unclear Adequate

Unclear Unclear

Bova et al38/2005 Douketis et al39/2005 Kline et al40/2006 Logeart et al12/2006 Tulevski et al41/2007

Unclear Adequate Adequate Adequate Unclear

Jiménez et al10/2008 Gallotta et al11/2008

Adequate Adequate

Troponin Measurement

Outcome Defined and Described Appropriately

Control of Confounding*

Analysis Described Appropriately

Yes Yes

Adequate Good

Yes Yes

Unclear Unclear Yes Unclear Yes

Adequate No predefined cutoff point Adequate Adequate Adequate Adequate Adequate

Yes Yes Yes No No

No Yes Yes No No

Yes Yes

Adequate Adequate

Yes Yes

Poor Good Good Poor Poor; not main objective of article Good Good

Yes Yes

*Control of confounding was classified as poor if little or no attempt was made to measure or control for known basic confounders (ie, age, sex, comorbidities, anticoagulant treatment, or prognostic indices). Adequate control considered at least age and comorbidities, and good control considered the majority of the confounders. 978

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Figure 2. Correlation between different levels of elevated troponins and death in patients with PE.

patients who died, compared with the rate of elevated troponin levels in patients who survived (positive LR, 2.26; 95% CI, 1.67 to 3.07) [Fig 4]; and (2) a slight decrease in the rate of nonelevated troponin levels in patients who died, compared with the rate of nonelevated troponin in patients who survived (negative LR, 0.59; 95% CI, 0.39 to 0.88) [Fig 5] during the short-term follow-up. These nonextreme

LRs do not significantly change the odds of death based on an elevated troponin level or the odds of survival based on a nonelevated troponin level. Comment In this metaanalysis of nine studies, which included 1,366 normotensive patients with acute symptomatic PE, patients with elevated troponin

Figure 3. OR of short-term death based on elevated troponin test results in normotensive patients with acute PE: random-effects metaanalysis of nine studies. www.chestjournal.org

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Figure 4. Positive LR for troponin test results and short-term death in normotensive patients with acute symptomatic PE: random-effects metaanalysis of nine studies. (Positive LR equals the rate of troponin level elevation in patients who died divided by the rate of troponin level elevation in patients who survived).

levels had a fourfold increased risk of short-term death compared with patients with nonelevated levels. Other studies of cohorts that consisted of both normotensive and unstable patients with acute PE showed similar results6,23 and support these findings. Regardless of the varying assays employed or the cutoffs used to define an elevated troponin level, the studies showed relatively consistent results. Risk stratification algorithms for patients presenting with acute PE could incorporate troponin level assessment.5,42 Ideally, high troponin levels would identify hemodynamically stable patients who may benefit from thrombolytic treatment, and low troponin levels would identify patients who are at low risk of death or PE-related complications. Such low-risk patients might be the most appropriate patients to

consider for full or partial out-of-hospital treatment of acute PE. Unfortunately, troponin by itself does not appear clinically to change significantly the pretest-to-posttest probabilities (ie, positive and negative LRs are not extreme) of risk in either scenario. For patients with acute symptomatic PE, a high troponin level in itself should not significantly drive the decision to administer thrombolytic therapy, and a low troponin level should not significantly drive the decision to treat at home. The evidence does not support the use of troponin levels for such decision making. These metaanalytic results support the data from individual studies26,27 that showed that elevated troponin level has higher predictive value when used in combination with other tests (eg, echocardiography)

Figure 5. Negative LR for troponin test results and short-term death in normotensive patients with acute symptomatic PE: random-effects metaanalysis of nine studies. (Negative LR equals the rate of nonelevated troponin levels in patients who died divided by the rate of nonelevated troponin levels in patients who survived). 980

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to identify patients who are at high risk for death after PE. We suggest that troponin measurement combined with other tools (eg, clinical prognostic scores and echocardiography) might better determine eligibility of patients for out-of-hospital treatment of acute PE.43 Limitations of each of the included studies may have introduced significant biases into the estimates of the prognostic value of troponin levels this metaanalysis. Some of the studies did not clearly describe the referral patterns, and they may have not included consecutive patients. Also, some of the studies did not adjust for other important prognostic factors or types of treatment that could have been prescribed based on troponin levels. A previous metaanalysis9 and a recent large cohort study10 have provided conflicting conclusions about the benefits of troponin measurement for risk stratification of patients with acute symptomatic PE. The metaanalysis9 suggested that elevated troponin levels identify patients with acute PE at high risk of short-term death, whereas the cohort study10 suggested that troponin testing does not identify patients with stable PE who are at very low risk of fatal medical outcomes. Unlike the previous metaanalysis,9 the current metaanalysis focused only on normotensive patients and it included three additional studies with 475 more patients. Because most of the included studies in both metaanalyses did not report whether or not an independent blinded committee assessed the outcome criteria, we aimed to minimize diagnostic suspicion bias by only assessing the outcome of all-cause mortality. The total sample size, the proportion of patients with an elevated troponin level, and the death rate all allowed for reasonable estimates of risk. The varied settings and patient characteristics improved the generalizability of the study. The prognostic value of troponin was consistent among high-quality and low-quality studies, and for both cTnI and cTnT. Moreover, the results of this metaanalysis showed a statistically significant correlation between different levels of elevated troponins and death in patients with PE. In conclusion, the prognostic value of troponin levels in normotensive patients in whom acute PE had been diagnosed depends greatly on the cutoff points used, and the usefulness of basing therapeutic decision making solely on troponin levels does not appear warranted. Troponin levels are likely to be most useful when used in combination with echocardiographic or CT scan evidence of right ventricular strain and with clinical prognostic scores. If the combination of troponin measurement with those prognostic tools improves our ability to predict outwww.chestjournal.org

comes, we may be able to better determine eligibility for thrombolytic therapy and for out-of-hospital treatment of acute PE. Acknowledgments Author contributions: Drs. Jime´nez, Uresandi, Otero, Lobo, Monreal, Martí, and Yusen contributed to the study concept and design. Drs. Jime´nez, Zamora, Muriel, Monreal, Aujesky, and Yusen contributed to the acquisition of data, analysis and interpretation of data, and statistical analysis. Drs. Jime´nez, Martí, Monreal, and Yusen contributed to the drafting of the manuscript. Drs. Jime´nez, Uresandi, Monreal, Aujesky, and Yusen contributed to the critical revision of the manuscript for important intellectual content. Drs. Jime´nez and Yusen contributed to the study supervision. Dr. Jime´nez, the corresponding author, had full access to all the data in the study and had final responsibility for the decision to submit for publication. Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: We thank Vittorio Palmieri for his unpublished data that were included in this analysis.

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