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Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia
Journal of Infection (2013) 66, 27e33
www.elsevierhealth.com/journals/jinf
Risk stratification and prognosis of acute cardiac events in hospitalized adults with communityacquired pneumonia Diego Viasus a,*, Carolina Garcia-Vidal a, Frederic Manresa b,c, a,c Jordi Dorca b,c, Francesc Gudiol a,c, Jordi Carratala Department of Infectious Diseases, Hospital Universitari de Bellvitge e IDIBELL, Feixa Llarga s/n, L’Hospitalet de Llobregat, 08907 Barcelona, Spain b Department of Respiratory Medicine, Hospital Universitari de Bellvitge e IDIBELL, Feixa Llarga s/n, 08907 Barcelona, Spain c Department of Clinical Science, University of Barcelona, Feixa Llarga s/n, 08907 Barcelona, Spain a
Accepted 5 September 2012 Available online 11 September 2012
KEYWORDS Acute cardiac events; Community-acquired pneumonia; Risk factors; Prognosis
Summary Objective: To determine the risk factors and the prognosis of acute cardiac events in patients with community-acquired pneumonia (CAP). Methods: Observational analysis of a prospective cohort of hospitalized adults with CAP (1995e2010). A logistic regression analysis was performed to identify predictors for acute cardiac events and mortality. Results: Of 3921 patients with CAP, 315 (8%) had one or more acute cardiac events during hospitalization (199 new-onset or worsening cardiac arrhythmias, 118 new-onset or worsening congestive heart failure and/or 30 myocardial infarction). In the multivariate analysis, factors associated with these events were age >65 years, chronic heart disease, chronic kidney disease, tachycardia, septic shock, multilobar pneumonia, hypoalbuminemia, and pneumococcal pneumonia. A rule based on these variables had an area under ROC curve of 0.73 (95% CI 0.70e0.76) to predict acute cardiac events. These complications occurred in 2.8% of patients classified in the low-risk (3 points), 9.7% in the intermediate-risk (4e5 points) and 21.2% in the high-risk (6 points) groups (P < .001). The overall case fatality rate was higher in patients who had acute cardiac events (19.4% vs. 6.4%; P < .001). Conclusion: Acute cardiac events occur frequently during hospitalization for CAP and are associated with poor prognosis. A simple rule based on demographic and clinical features may help identify patients at higher risk of these complications. ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ34 932607625; fax: þ34 932607637. E-mail address: [email protected] (D. Viasus). 0163-4453/$36 ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2012.09.003
28
Introduction Community-acquired pneumonia (CAP) is the most common infectious disease requiring hospitalization and a major cause of mortality worldwide.1,2 Recent studies have documented an increased incidence of acute cardiac events (new-onset or worsening cardiac arrhythmias, new-onset or worsening congestive heart failure and/or myocardial infarction) in patients with CAP.3e7 Significantly, although acute cardiac events in this context are associated with poor outcome, these events are underdiagnosed. The mortality rate of patients with CAP and acute cardiac events ranges from 13.9% to 36%.3e5 Nonetheless, information on risk factors for acute cardiac events in CAP is scarce,3,4 and at present there is not clear profile of patients at high risk of suffering these complications. The mechanisms underlying the triggering of acute cardiac events in patients with CAP are diverse and are still to be fully established. They are thought to occur due to increased systemic inflammatory activity, dominant prothrombotic conditions, and vascular endothelium dysfunction during infections. Increased biomechanical stress on coronary arteries, variations in coronary arterial tone, disturbed hemodynamic homeostasis, and altered myocardial metabolic balance have also been described in this scenario.8,9 The aim of the present study was to determine the risk factors for acute cardiac events in a large prospective cohort of non-immunosuppressed adult patients requiring hospitalization for CAP. We also constructed a rule to stratify patients into risk groups for developing these complications.
Materials and methods Setting, patients and study design The study was performed in a 900-bed tertiary university hospital for adults in Barcelona, Spain. All nonimmunocompromised patients hospitalized through the emergency department with CAP between February 1995 and December 2010 were analyzed. Patients with CAP were identified at the emergency department by the attending physicians and/or the study investigators. Data on all patients were prospectively recorded using a computerassisted protocol. The study was approved by the Hospital Ethics Committee and informed consent was obtained from all patients. For the purpose of the present study, patients were divided into two groups: those with acute cardiac events (new-onset or worsening cardiac arrhythmias, new-onset or worsening congestive heart failure and/or myocardial infarction) and those without acute cardiac events during hospital stay.
Clinical assessment and follow-up Patients were seen daily during their hospital stay by one or more of the investigators. Data were collected on
D. Viasus et al. demographic characteristics, comorbidities, causative organisms, antibiotic susceptibilities, biochemical analysis, empirical antibiotic therapy, complications and outcomes, including mortality. Two sets of blood samples were obtained and cultured and, when available, a sputum sample was also evaluated by Gram staining and culture. Urinary antigen detection tests for Streptococcus pneumoniae and Legionella pneumophila were performed if indicated by the attending physician. Paired serum samples during the acute and convalescent phases of infection (separated by a 3e8 week interval) were also obtained for serological studies. Antibiotic therapy was initiated in the emergency department in accordance with the hospital guidelines, which recommend the administration of a b-lactam (ceftriaxone sodium or amoxicillin/clavulanate potassium) with or without macrolide or levofloxacin. Combination therapy was recommended for patients with clinical suspicion of a Legionella species or an atypical pathogen, or in the absence of a demonstrative finding on sputum Gram stain results. Combined amoxicillin/clavulanate was recommended for patients with clinical suspicion of aspiration pneumonia.
Definitions Pneumonia was defined as an acute illness associated with one or more of the following signs and symptoms: new cough with or without sputum production, pleuritic chest pain, dyspnea, fever or hypothermia, altered breath sounds on auscultation, leukocytosis, and the presence of a new infiltrate on a chest radiograph. New-onset or worsening cardiac arrhythmias were considered when they were documented in medical records or electrocardiogram (ECG) of supraventricular arrhythmias and ventricular bigeminy/tachycardia. Ventricular fibrillation was not included in this diagnosis. New-onset or worsening congestive heart failure was considered when patients had Framingham Criteria for congestive heart failure (the simultaneous presence of at least two major criteria or one major criterion in conjunction with two minor criteria).10 Myocardial infarction was defined as the detection of an increase in cardiac biomarkers (creatine kinase fraction MB and/or troponin) with at least one of the following: symptoms of ischemia, electrocardiographic (ECG) changes (new ST-T changes or new left bundle branch block) or development of pathological Q waves in the ECG. Chronic heart disease was defined as evidence in records or treatment for coronary artery disease, arrhythmia, or congestive heart failure, or the presence of valvular heart disease. Chronic pulmonary disease was defined as treatment for asthma, chronic obstructive pulmonary disease (COPD) or the presence of interstitial lung disorders. Chronic kidney disease included preexisting renal disease with documented abnormal serum creatinine levels outside the pneumonia episode (glomerular filtration rate < 60 ml/ min/1.73 m2). Chronic liver failure was defined as a clinical or histologic diagnosis of cirrhosis or another form of chronic liver disease, such as chronic active hepatitis. Cerebrovascular disease was defined as a clinical diagnosis of stroke or transient ischemic attack or stroke documented
Acute cardiac events in CAP by magnetic resonance imaging or computed tomography. Other comorbid disorders included diabetes mellitus (treatment with oral antidiabetic agents or insulin) and neoplastic disease (any leukemia or solid tumor active at the time of presentation or requiring antineoplastic treatment within the past year). Patients in risk classes IV or V of the Pneumonia Severity Index (PSI) were considered to be more severely ill.11 The diagnosis of septic shock was based on the ACCP/SCCM Consensus Conference Committee definitions.12 Pneumococcal pneumonia was diagnosed in patients with one or more cultures positive for S. pneumoniae obtained from blood, normally sterile fluids or sputum, and/or a positive urinary antigen test detection. Only good quality samples of sputum (<10 squamous epithelial cells and >25 leucocytes per field) were accepted for processing. Aspiration pneumonia was diagnosed as described elsewhere.13 Complications were defined as any untoward circumstances occurring during hospitalization. Time to clinical stability was defined as described elsewhere.14 Early and overall case fatality rate were defined as death from any cause within 48 h and during 30 days of admission respectively.
Statistical analysis Continuous variables were presented as mean and standard deviation (SD). All proportions were calculated as percentages of the patients with available data. To detect significant differences between groups, we used the chisquare test or Fisher exact test for categorical variables and the Student t test or ManneWhitney U test for continuous variables, as appropriate. The multivariate logistic regression analysis of factors potentially associated with acute cardiac events included significant variables in the univariate analysis (P < .05) with clinical importance. Continuous variables were recategorized into binary factors using the most discriminant cutoff point (criterion corresponding with highest Youden index). All potential explanatory variables included in the multivariate analyses were subjected to a correlation matrix for analysis of collinearity. Variables with association among each other were not included in the multivariate model. The discriminatory power of the logistic model was evaluated by the area under the receiver operating characteristic (ROC) curve and the goodness-of-fit according to the HosmereLemeshow test. Results of multivariate analyses was reported as odds ratios (OR) and 95% confidence intervals (CI). We also constructed a rule to stratify patients into risk groups for developing acute cardiac events. The logistic regression model coefficients for significant predictors (P < .1) of acute cardiac events were used to assign the value (risk score) of each variable. We then computed the score for each patient reflecting the probability of acute cardiac events and chose the cutoff value that discriminated between low (<5%), intermediate (5e10%), and high (>10%) probability groups. Linear trend analysis was used to account for multiple comparisons. The analyses were performed using SPSS (version 15.0). Statistical significance was set at P < .05. All reported P values are twotailed.
29
Results Of 3921 non-severely immunosuppressed adult patients with CAP requiring hospital admission, 315 (8%, 95% CI 7.2e8.9%) had one or more acute cardiac events (199 newonset or worsening cardiac arrhythmias, 118 new-onset or worsening congestive heart failure and/or 30 myocardial infarction) during hospitalization.
Baseline characteristics The demographic, clinical and laboratory findings at hospital admission of patients with and without acute cardiac events are shown in Table 1. Patients with acute cardiac events were older (95% CI of mean difference 6.0e8.8 years) and were more likely to have comorbid conditions, mainly chronic heart disease, diabetes mellitus, chronic kidney disease and cerebrovascular disease. Among clinical features, patients with acute cardiac events more commonly had dyspnea, altered mental state, tachycardia, tachypnea and septic shock. Regarding laboratory findings, these patients also were more likely to have hypoxemia, hypoalbuminemia, anemia and multilobar pneumonia in chest X-rays. Similarly, pneumococcal pneumonia was most frequently documented among patients with acute cardiac complications. No significant differences in antibiotic therapy were found between study groups (data not shown).
Clinical outcomes The clinical outcomes of patients with and without acute cardiac events are detailed in Table 2. ICU admission and need for mechanical ventilation were more frequent in patients with acute cardiac complications. Similarly, length of hospital stay (95% CI of mean difference 3.7e7.6 days) and time to reach clinical stability (95% CI of mean difference 1.0e3.3 days) were longer in patients with acute cardiac events. In addition, these patients had higher early and overall case fatality rate. ICU admission and overall case fatality rate were significantly more frequent (P < .001) in patients with new-onset or worsening cardiac arrhythmias (27.6% vs 8.2% and 19.6% vs 6.8%, respectively), new-onset or worsening congestive heart failure (22.9% vs 8.7% and 22.9% vs 7%, respectively) and myocardial infarction (40% vs 8.9% and 23.3% vs 7.4%, respectively). After adjusting for confounder factors (age, sex, comorbidities, altered mental status, septic shock, multilobar pneumonia, respiratory failure, hyponatremia, anemia, hypoalbuminemia, tachycardia, tachypnea, and high-risk PSI classes) in a multivariate analysis, acute cardiac events were independently associated with ICU admission (OR 4.76, 95% CI 3.13e7.24) and overall mortality (OR 2.18, 95% CI 1.38e3.42).
Risk factors for acute cardiac events The results of multivariate logistic regression analysis for factors potentially associated with acute cardiac events in patients with CAP are summarized in Table 3. Factors
30 Table 1
D. Viasus et al. Characteristics of CAP patients with and without acute cardiac events.
Category, characteristic
Acute cardiac events (n Z 315)
Without acute cardiac events (n Z 3606)
P
Demographic data Age, mean SD, years Male sex Current/former smoker Influenza vaccine (season) Pneumococcal vaccine, 5 years Comorbid conditions Chronic pulmonary disease Chronic heart disease Diabetes mellitus Chronic kidney disease Chronic liver failure Neoplastic disease Cerebrovascular disease
73.1 221 52 162 54 280 81 149 86 40 23 27 34
(11.4) (70.2) (16.2) (60.7) (20.8) (88.9) (25.7) (47.5) (27.3) (12.7) (7.3) (8.6) (10.8)
65.7 2464 974 1571 509 2698 1018 772 733 223 220 309 266
(17.3) (68.4) (27.2) (48.4) (16.1) (74.8) (28.2) (21.4) (20.3) (6.2) (6.1) (8.6) (7.4)
<.001 .51 <.001 <.001 .05 <.001 <.34 <.001 .003 <.001 .39 .99 .02
Clinical features at presentation Temperature, mean SD, C Tachycardia (100 beats$min1) Tachypnea (24 breaths$min1) Arthromyalgias Pleuritic chest pain Altered mental state Septic shock
37.7 163 241 46 130 61 43
(1.0) (58.2) (82.3) (14.6) (41.4) (19.4) (13.7)
37.9 1447 2087 737 1496 509 243
(1.0) (49.7) (64.3) (20.5) (41.7) (14.2) (6.8)
.001 .006 <.001 <.01 .92 .01 <.001
251 .5 195 175 27 32 130 56
(62.3) (61.9) (62.9) (10.9) (10.3) (41.4) (17.8)
276.3 2115 1441 251 246 1154 616
(60.2) (58.8) (43.8) (10.1) (6.9) (32.3) (17.2)
<.001 .28 <.001 .66 .02 <.001 .76
129 16 13 15 266
(41) (5.1) (4.1) (4.8) (84.7)
1217 200 190 267 2034
(33.7) (5.5) (5.3) (7.4) (56.6)
.01 .72 .38 .08 <.001
Laboratory and radiographic findings PaO2/FiO2, mean SD Leucocytosis (leucocytes 12 109/L) Hypoalbuminemia (albumin < 30 g/L) Hyponatremia (sodium < 130 mEq/L) Anemia (hematocrit < 30%) Multilobar pneumonia Pleural effusion Etiology Streptococcus pneumoniae Legionella pneumophila Hemophilus influenzae Aspiration pneumonia High-risk PSI classesa
Note. PSI, pneumonia severity index; SD, standard deviation. a Patients were stratified into the following risk classes according to the PSI score: low risk (90 points, classes I, II, and III) and high risk (>90 points, classes IV and V).
Table 2
Outcomes of CAP patients with and without acute cardiac events.
ICU admission Need for mechanical ventilation Time to clinical stability, mean (SD), days Length of hospital stay, mean (SD), days Early case fatality rate (48 h) Overall case fatality rate (30 days) Note. ICU, intensive care unit; SD, standard deviation.
Acute cardiac events (n Z 315)
Without acute cardiac events (n Z 3606)
P
80 55 6.6 15.7 17 61
278 161 4.4 9.9 66 232
<.001 <.001 <.001 <.001 <.001 <.001
(25.4) (17.6) (6.4) (16.9) (5.4) (19.4)
(7.7) (4.5) (3.9) (8) (1.8) (6.4)
Acute cardiac events in CAP Table 3
31
Factors associated with acute cardiac events in CAP patients: multivariate analysis.
Age (>65 years) Chronic heart disease Diabetes mellitus Chronic kidney disease Cerebrovascular disease Altered mental status Septic shock Tachycardia (100 beats$min1) Anemia (hematocrit < 30%) Hypoalbuminemia (albumin < 30 g/L) Multilobar pneumonia Pneumococcal pneumonia
OR
95% CI
P
1.78 3.05 1.16 1.49 1.04 0.98 1.70 1.61 1.22 2.33 1.36 1.39
(1.28e2.47) (2.28e4.08) (0.84e1.59) (0.96e2.30) (0.68e1.60) (0.67e1.41) (1.03e2.56) (1.21e2.13) (0.77e1.96) (1.74e3.12) (1.03e1.81) (1.05e1.38)
.001 <.001 .35 .07 .83 .98 .01 .001 .38 <.001 .03 .02
Note. CAP, community-acquired pneumonia; CI, confidence interval; OR, odds ratio.
associated with acute cardiac events were age >65 years, chronic heart disease, tachycardia (cardiac rate 100), septic shock, multilobar pneumonia, hypoalbuminemia (albumin 30 gr/L), and pneumococcal pneumonia. The goodness-of-fit of the model was 0.66 and the area under ROC curve was 0.74 (95% CI 0.71e0.77). Factors associated with arrhythmias in univariate analysis were age >65 years, chronic heart disease, chronic kidney disease, altered mental state, tachycardia, septic shock, hypoalbuminemia, and pneumococcal pneumonia. Factors related with heart failure were age >65 years, chronic heart disease, chronic kidney disease, diabetes mellitus, septic shock, hypoalbuminemia, and multilobar pneumonia. Factors for myocardial infarction were age >65 years, male sex, chronic heart disease, chronic kidney disease, diabetes mellitus, tachycardia, septic shock, hypoalbuminemia, and multilobar pneumonia.
Score derivation Results from the multivariate analysis were used to develop the clinical prediction rule (including variables with P < .1). According to the regression coefficients, we assigned 1 point to each parameter, except for chronic heart disease (3 points) and hypoalbuminemia (2 points) (Table 4). A rule based on these variables had an area under ROC curve of 0.73 (95% CI 0.70e0.76) to predict acute cardiac events. These complications occurred in 2.8% of patients classified into the low-risk group (3 points), 9.7% in intermediaterisk group (4e5 points) and 21.2% in high-risk group (6 points) (chi-square for trend P < .001) (Fig. 1). Areas under ROC curve of the rule to predict new-onset or worsening cardiac arrhythmias, new-onset or worsening congestive heart failure and myocardial infarction were 0.71 (95% CI 0.67e0.74), 0.76 (95% CI 0.71e0.81) and 0.71 (0.67e0.64) respectively.
Discussion In this large prospective cohort study of nonimmunocompromised patients hospitalized for CAP, the presence of age >65 years, chronic heart disease, tachycardia (cardiac rate 100), septic shock, multilobar pneumonia,
hypoalbuminemia (albumin 30 gr/L), and pneumococcal pneumonia were identified by multivariate analysis as independent predictors of acute cardiac events. In addition, a simple, practical clinical score was generated to stratify the risk of acute cardiac events in these patients. After adjustment for potential confounders, we documented that acute cardiac events were independently associated with poor outcomes. In addition, each one new-onset or worsening cardiac arrhythmias, new-onset or worsening congestive heart failure and myocardial infarction was associated with higher risk for ICU admission and mortality. This finding is in line with other studies that have identified a link between acute cardiac events and worst prognosis in CAP,3e5 and highlights the importance of identifying the profile of patients at risk of suffering these events. Information on risk factors for acute cardiac events in patients with CAP is scarce.3,4 Recently, Corrales-Medina et al3 reported that older age, nursing home residence, history of heart failure, prior cardiac arrhythmias, previously diagnosed coronary artery disease, arterial hypertension, respiratory rate >30 breaths per minute, blood pH < 7.35, blood urea nitrogen >30 mg/dL, serum sodium <130 mmol/L, hematocrit <30%, pleural effusion on presenting chest x-ray, and inpatient care were factors independently associated with the diagnosis of these complications. However, authors did not analyze the impact of causative microorganisms, nor did they define specific risk groups. Similarly, in another study,4 factors significantly associated with acute myocardial infarction were age, previous acute myocardial infarction, COPD and chronic renal disease. Age, diabetes mellitus and prior myocardial infarction were also associated with increased risk of atrial fibrillation. Nevertheless, this study had some limitations, including its retrospective design and the use of ICD-10 codes to identify cases of CAP and vascular events. Our study identifies factors associated with acute cardiac events in patients with CAP and stratifies them according to the risk for developing these complications. These factors are markers of increased cardiovascular risk (age >65 years, chronic heart disease, chronic kidney disease),15 and more severe pneumonia at hospital admission (tachycardia, septic shock, multilobar pneumonia).11 Significantly, nearly 50% of patients with acute cardiac
32
D. Viasus et al.
Table 4 Prediction rule for acute cardiac events in hospitalized patients with CAP. Variable
Points
Chronic heart disease Hypoalbuminemia (albumin < 30 g/L) Age (>65 years) Chronic kidney disease Septic shock Tachycardia (100 beats$min1) Multilobar pneumonia Pneumococcal pneumonia
3 2 1 1 1 1 1 1
Note. CAP, community-acquired pneumonia.
events did not have a medical history of comorbid chronic heart disease. Therefore, acute cardiac events also should also be considered in CAP patients without this underlying disease. We found that pneumococcal pneumonia was also an independent factor associated with acute cardiac events. Previously, another study reported a higher incidence of myocardial infarction among patients with pneumococcal pneumonia.7 Interestingly, it has recently been suggested that inflammatory response in CAP may depend, at least in part, of the causative microorganism. In this regard, the lowest inflammatory expression has been found in cases of unknown etiology, although one of the microorganisms with the highest increase in cytokines was S. pneumonia.16 It should be noted that increased systemic inflammatory activity has been related to triggering of acute cardiac events in patients with CAP.8,9 This is also applicable to patients with severe pneumonia, which has also been associated with greater elevation of inflammatory biomarkers.17,18 Significantly, hypoalbuminemia was associated with acute cardiac events in this study. In most cases, hypoalbuminemia was related to malnutrition or sepsis and was not the consequence of hemodilution, since no differences were found in the frequency of hyponatremia and pleural effusion between the study groups. Our findings concur with previous reports that found
hypoalbuminemia to be a frequent and major cause of the incidence and exacerbation of heart failure19e21 and ischemic cardiac disease.21 Our predictive model discriminates between three patient subgroups. The low-risk and moderate-risk groups had rates of positive events of 0e4.4% and 9.5e9.9% respectively, and the high-risk group a rate between 18.7% and 34.6%. To apply the scoring system, demographic and clinical variables are available at presentation for almost all patients and are easy to obtain. The accuracy of the method is good but not excellent, as the statistical analysis demonstrates for internal validation (AUC 0.73). The moderate and high-risk groups identify nearly 85% of patients with acute cardiac events, so clinical suspicion of these complications should be maintained in those patients at low-risk. The potential benefit of stratification of patients at risk for acute cardiac events is that diagnostic tools, monitoring and preventive strategies, such as bblockers or conservative fluid strategies, could be useful. In this regard, it has been suggested that b-blocker use during perioperative period may reduce myocardial ischemia and longer-term cardiovascular complications, although findings have been inconsistent across studies.22,23 The strengths of this study are the large number of patients included, its prospective design, and the comprehensive clinical and microbiologic data gathered. In addition, the independent variables were recollected and defined from the time the study began. Nevertheless, the definition of acute myocardial infarction was modified with the inclusion of troponin as a marker of myocardial damage in 2001.24 Finally, this is the first study to attempt to identify and stratify patients at increased risk for acute cardiac events in this context. On the other hand, there are some limitations that should be acknowledged. The study was conducted at single center and the present scoring tool should be validated in further investigations. Furthermore, no information about the timing of onset of acute cardiac events and long-term outcomes were recorded. Finally, we did not evaluate the usefulness of biomarkers to identify patients at risk of cardiac events. In conclusion, acute cardiac events are frequent in hospitalized patients with CAP and are associated with high morbidity and poor prognosis. The risk of acute cardiac events can be estimated at bedside by evaluating simple demographic and clinical factors. The prediction rule allows for the stratification of patients according to the risk of acute cardiac events, and identifies subgroups of high-risk patients for whom diagnostic tools, monitoring and preventive strategies may have value.
Acknowledgments
Figure 1 Risk groups for acute cardiac events in hospitalized patients with CAP.
Financial support: This work was supported by the the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III e co-financed by the European Regional Development Fund “A way to achieve Europe” ERDF, Spanish Network for Research in Infectious Diseases (REIPI RD06/ n Sanitaria de la 0008) and the Fondo de Investigacio Seguridad Social (grant 07/0864 and 11/01106). Dr. Viasus is the recipient of a research grant from the Institut Biome dica de Bellvitge (IDIBELL). Dr Garciad’Investigacio
Acute cardiac events in CAP
33
Vidal is the recipient of a Juan de la Cierva research grant from the Instituto de Salud Carlos III, Madrid, Spain.
Role of the funding sources The funding sources had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
13.
14.
Competing interests 15.
All authors declare that they have no conflicting interests that are relevant to this article.
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www.elsevierhealth.com/journals/jinf
Risk stratification and prognosis of acute cardiac events in hospitalized adults with communityacquired pneumonia Diego Viasus a,*, Carolina Garcia-Vidal a, Frederic Manresa b,c, a,c Jordi Dorca b,c, Francesc Gudiol a,c, Jordi Carratala Department of Infectious Diseases, Hospital Universitari de Bellvitge e IDIBELL, Feixa Llarga s/n, L’Hospitalet de Llobregat, 08907 Barcelona, Spain b Department of Respiratory Medicine, Hospital Universitari de Bellvitge e IDIBELL, Feixa Llarga s/n, 08907 Barcelona, Spain c Department of Clinical Science, University of Barcelona, Feixa Llarga s/n, 08907 Barcelona, Spain a
Accepted 5 September 2012 Available online 11 September 2012
KEYWORDS Acute cardiac events; Community-acquired pneumonia; Risk factors; Prognosis
Summary Objective: To determine the risk factors and the prognosis of acute cardiac events in patients with community-acquired pneumonia (CAP). Methods: Observational analysis of a prospective cohort of hospitalized adults with CAP (1995e2010). A logistic regression analysis was performed to identify predictors for acute cardiac events and mortality. Results: Of 3921 patients with CAP, 315 (8%) had one or more acute cardiac events during hospitalization (199 new-onset or worsening cardiac arrhythmias, 118 new-onset or worsening congestive heart failure and/or 30 myocardial infarction). In the multivariate analysis, factors associated with these events were age >65 years, chronic heart disease, chronic kidney disease, tachycardia, septic shock, multilobar pneumonia, hypoalbuminemia, and pneumococcal pneumonia. A rule based on these variables had an area under ROC curve of 0.73 (95% CI 0.70e0.76) to predict acute cardiac events. These complications occurred in 2.8% of patients classified in the low-risk (3 points), 9.7% in the intermediate-risk (4e5 points) and 21.2% in the high-risk (6 points) groups (P < .001). The overall case fatality rate was higher in patients who had acute cardiac events (19.4% vs. 6.4%; P < .001). Conclusion: Acute cardiac events occur frequently during hospitalization for CAP and are associated with poor prognosis. A simple rule based on demographic and clinical features may help identify patients at higher risk of these complications. ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ34 932607625; fax: þ34 932607637. E-mail address: [email protected] (D. Viasus). 0163-4453/$36 ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2012.09.003
28
Introduction Community-acquired pneumonia (CAP) is the most common infectious disease requiring hospitalization and a major cause of mortality worldwide.1,2 Recent studies have documented an increased incidence of acute cardiac events (new-onset or worsening cardiac arrhythmias, new-onset or worsening congestive heart failure and/or myocardial infarction) in patients with CAP.3e7 Significantly, although acute cardiac events in this context are associated with poor outcome, these events are underdiagnosed. The mortality rate of patients with CAP and acute cardiac events ranges from 13.9% to 36%.3e5 Nonetheless, information on risk factors for acute cardiac events in CAP is scarce,3,4 and at present there is not clear profile of patients at high risk of suffering these complications. The mechanisms underlying the triggering of acute cardiac events in patients with CAP are diverse and are still to be fully established. They are thought to occur due to increased systemic inflammatory activity, dominant prothrombotic conditions, and vascular endothelium dysfunction during infections. Increased biomechanical stress on coronary arteries, variations in coronary arterial tone, disturbed hemodynamic homeostasis, and altered myocardial metabolic balance have also been described in this scenario.8,9 The aim of the present study was to determine the risk factors for acute cardiac events in a large prospective cohort of non-immunosuppressed adult patients requiring hospitalization for CAP. We also constructed a rule to stratify patients into risk groups for developing these complications.
Materials and methods Setting, patients and study design The study was performed in a 900-bed tertiary university hospital for adults in Barcelona, Spain. All nonimmunocompromised patients hospitalized through the emergency department with CAP between February 1995 and December 2010 were analyzed. Patients with CAP were identified at the emergency department by the attending physicians and/or the study investigators. Data on all patients were prospectively recorded using a computerassisted protocol. The study was approved by the Hospital Ethics Committee and informed consent was obtained from all patients. For the purpose of the present study, patients were divided into two groups: those with acute cardiac events (new-onset or worsening cardiac arrhythmias, new-onset or worsening congestive heart failure and/or myocardial infarction) and those without acute cardiac events during hospital stay.
Clinical assessment and follow-up Patients were seen daily during their hospital stay by one or more of the investigators. Data were collected on
D. Viasus et al. demographic characteristics, comorbidities, causative organisms, antibiotic susceptibilities, biochemical analysis, empirical antibiotic therapy, complications and outcomes, including mortality. Two sets of blood samples were obtained and cultured and, when available, a sputum sample was also evaluated by Gram staining and culture. Urinary antigen detection tests for Streptococcus pneumoniae and Legionella pneumophila were performed if indicated by the attending physician. Paired serum samples during the acute and convalescent phases of infection (separated by a 3e8 week interval) were also obtained for serological studies. Antibiotic therapy was initiated in the emergency department in accordance with the hospital guidelines, which recommend the administration of a b-lactam (ceftriaxone sodium or amoxicillin/clavulanate potassium) with or without macrolide or levofloxacin. Combination therapy was recommended for patients with clinical suspicion of a Legionella species or an atypical pathogen, or in the absence of a demonstrative finding on sputum Gram stain results. Combined amoxicillin/clavulanate was recommended for patients with clinical suspicion of aspiration pneumonia.
Definitions Pneumonia was defined as an acute illness associated with one or more of the following signs and symptoms: new cough with or without sputum production, pleuritic chest pain, dyspnea, fever or hypothermia, altered breath sounds on auscultation, leukocytosis, and the presence of a new infiltrate on a chest radiograph. New-onset or worsening cardiac arrhythmias were considered when they were documented in medical records or electrocardiogram (ECG) of supraventricular arrhythmias and ventricular bigeminy/tachycardia. Ventricular fibrillation was not included in this diagnosis. New-onset or worsening congestive heart failure was considered when patients had Framingham Criteria for congestive heart failure (the simultaneous presence of at least two major criteria or one major criterion in conjunction with two minor criteria).10 Myocardial infarction was defined as the detection of an increase in cardiac biomarkers (creatine kinase fraction MB and/or troponin) with at least one of the following: symptoms of ischemia, electrocardiographic (ECG) changes (new ST-T changes or new left bundle branch block) or development of pathological Q waves in the ECG. Chronic heart disease was defined as evidence in records or treatment for coronary artery disease, arrhythmia, or congestive heart failure, or the presence of valvular heart disease. Chronic pulmonary disease was defined as treatment for asthma, chronic obstructive pulmonary disease (COPD) or the presence of interstitial lung disorders. Chronic kidney disease included preexisting renal disease with documented abnormal serum creatinine levels outside the pneumonia episode (glomerular filtration rate < 60 ml/ min/1.73 m2). Chronic liver failure was defined as a clinical or histologic diagnosis of cirrhosis or another form of chronic liver disease, such as chronic active hepatitis. Cerebrovascular disease was defined as a clinical diagnosis of stroke or transient ischemic attack or stroke documented
Acute cardiac events in CAP by magnetic resonance imaging or computed tomography. Other comorbid disorders included diabetes mellitus (treatment with oral antidiabetic agents or insulin) and neoplastic disease (any leukemia or solid tumor active at the time of presentation or requiring antineoplastic treatment within the past year). Patients in risk classes IV or V of the Pneumonia Severity Index (PSI) were considered to be more severely ill.11 The diagnosis of septic shock was based on the ACCP/SCCM Consensus Conference Committee definitions.12 Pneumococcal pneumonia was diagnosed in patients with one or more cultures positive for S. pneumoniae obtained from blood, normally sterile fluids or sputum, and/or a positive urinary antigen test detection. Only good quality samples of sputum (<10 squamous epithelial cells and >25 leucocytes per field) were accepted for processing. Aspiration pneumonia was diagnosed as described elsewhere.13 Complications were defined as any untoward circumstances occurring during hospitalization. Time to clinical stability was defined as described elsewhere.14 Early and overall case fatality rate were defined as death from any cause within 48 h and during 30 days of admission respectively.
Statistical analysis Continuous variables were presented as mean and standard deviation (SD). All proportions were calculated as percentages of the patients with available data. To detect significant differences between groups, we used the chisquare test or Fisher exact test for categorical variables and the Student t test or ManneWhitney U test for continuous variables, as appropriate. The multivariate logistic regression analysis of factors potentially associated with acute cardiac events included significant variables in the univariate analysis (P < .05) with clinical importance. Continuous variables were recategorized into binary factors using the most discriminant cutoff point (criterion corresponding with highest Youden index). All potential explanatory variables included in the multivariate analyses were subjected to a correlation matrix for analysis of collinearity. Variables with association among each other were not included in the multivariate model. The discriminatory power of the logistic model was evaluated by the area under the receiver operating characteristic (ROC) curve and the goodness-of-fit according to the HosmereLemeshow test. Results of multivariate analyses was reported as odds ratios (OR) and 95% confidence intervals (CI). We also constructed a rule to stratify patients into risk groups for developing acute cardiac events. The logistic regression model coefficients for significant predictors (P < .1) of acute cardiac events were used to assign the value (risk score) of each variable. We then computed the score for each patient reflecting the probability of acute cardiac events and chose the cutoff value that discriminated between low (<5%), intermediate (5e10%), and high (>10%) probability groups. Linear trend analysis was used to account for multiple comparisons. The analyses were performed using SPSS (version 15.0). Statistical significance was set at P < .05. All reported P values are twotailed.
29
Results Of 3921 non-severely immunosuppressed adult patients with CAP requiring hospital admission, 315 (8%, 95% CI 7.2e8.9%) had one or more acute cardiac events (199 newonset or worsening cardiac arrhythmias, 118 new-onset or worsening congestive heart failure and/or 30 myocardial infarction) during hospitalization.
Baseline characteristics The demographic, clinical and laboratory findings at hospital admission of patients with and without acute cardiac events are shown in Table 1. Patients with acute cardiac events were older (95% CI of mean difference 6.0e8.8 years) and were more likely to have comorbid conditions, mainly chronic heart disease, diabetes mellitus, chronic kidney disease and cerebrovascular disease. Among clinical features, patients with acute cardiac events more commonly had dyspnea, altered mental state, tachycardia, tachypnea and septic shock. Regarding laboratory findings, these patients also were more likely to have hypoxemia, hypoalbuminemia, anemia and multilobar pneumonia in chest X-rays. Similarly, pneumococcal pneumonia was most frequently documented among patients with acute cardiac complications. No significant differences in antibiotic therapy were found between study groups (data not shown).
Clinical outcomes The clinical outcomes of patients with and without acute cardiac events are detailed in Table 2. ICU admission and need for mechanical ventilation were more frequent in patients with acute cardiac complications. Similarly, length of hospital stay (95% CI of mean difference 3.7e7.6 days) and time to reach clinical stability (95% CI of mean difference 1.0e3.3 days) were longer in patients with acute cardiac events. In addition, these patients had higher early and overall case fatality rate. ICU admission and overall case fatality rate were significantly more frequent (P < .001) in patients with new-onset or worsening cardiac arrhythmias (27.6% vs 8.2% and 19.6% vs 6.8%, respectively), new-onset or worsening congestive heart failure (22.9% vs 8.7% and 22.9% vs 7%, respectively) and myocardial infarction (40% vs 8.9% and 23.3% vs 7.4%, respectively). After adjusting for confounder factors (age, sex, comorbidities, altered mental status, septic shock, multilobar pneumonia, respiratory failure, hyponatremia, anemia, hypoalbuminemia, tachycardia, tachypnea, and high-risk PSI classes) in a multivariate analysis, acute cardiac events were independently associated with ICU admission (OR 4.76, 95% CI 3.13e7.24) and overall mortality (OR 2.18, 95% CI 1.38e3.42).
Risk factors for acute cardiac events The results of multivariate logistic regression analysis for factors potentially associated with acute cardiac events in patients with CAP are summarized in Table 3. Factors
30 Table 1
D. Viasus et al. Characteristics of CAP patients with and without acute cardiac events.
Category, characteristic
Acute cardiac events (n Z 315)
Without acute cardiac events (n Z 3606)
P
Demographic data Age, mean SD, years Male sex Current/former smoker Influenza vaccine (season) Pneumococcal vaccine, 5 years Comorbid conditions Chronic pulmonary disease Chronic heart disease Diabetes mellitus Chronic kidney disease Chronic liver failure Neoplastic disease Cerebrovascular disease
73.1 221 52 162 54 280 81 149 86 40 23 27 34
(11.4) (70.2) (16.2) (60.7) (20.8) (88.9) (25.7) (47.5) (27.3) (12.7) (7.3) (8.6) (10.8)
65.7 2464 974 1571 509 2698 1018 772 733 223 220 309 266
(17.3) (68.4) (27.2) (48.4) (16.1) (74.8) (28.2) (21.4) (20.3) (6.2) (6.1) (8.6) (7.4)
<.001 .51 <.001 <.001 .05 <.001 <.34 <.001 .003 <.001 .39 .99 .02
Clinical features at presentation Temperature, mean SD, C Tachycardia (100 beats$min1) Tachypnea (24 breaths$min1) Arthromyalgias Pleuritic chest pain Altered mental state Septic shock
37.7 163 241 46 130 61 43
(1.0) (58.2) (82.3) (14.6) (41.4) (19.4) (13.7)
37.9 1447 2087 737 1496 509 243
(1.0) (49.7) (64.3) (20.5) (41.7) (14.2) (6.8)
.001 .006 <.001 <.01 .92 .01 <.001
251 .5 195 175 27 32 130 56
(62.3) (61.9) (62.9) (10.9) (10.3) (41.4) (17.8)
276.3 2115 1441 251 246 1154 616
(60.2) (58.8) (43.8) (10.1) (6.9) (32.3) (17.2)
<.001 .28 <.001 .66 .02 <.001 .76
129 16 13 15 266
(41) (5.1) (4.1) (4.8) (84.7)
1217 200 190 267 2034
(33.7) (5.5) (5.3) (7.4) (56.6)
.01 .72 .38 .08 <.001
Laboratory and radiographic findings PaO2/FiO2, mean SD Leucocytosis (leucocytes 12 109/L) Hypoalbuminemia (albumin < 30 g/L) Hyponatremia (sodium < 130 mEq/L) Anemia (hematocrit < 30%) Multilobar pneumonia Pleural effusion Etiology Streptococcus pneumoniae Legionella pneumophila Hemophilus influenzae Aspiration pneumonia High-risk PSI classesa
Note. PSI, pneumonia severity index; SD, standard deviation. a Patients were stratified into the following risk classes according to the PSI score: low risk (90 points, classes I, II, and III) and high risk (>90 points, classes IV and V).
Table 2
Outcomes of CAP patients with and without acute cardiac events.
ICU admission Need for mechanical ventilation Time to clinical stability, mean (SD), days Length of hospital stay, mean (SD), days Early case fatality rate (48 h) Overall case fatality rate (30 days) Note. ICU, intensive care unit; SD, standard deviation.
Acute cardiac events (n Z 315)
Without acute cardiac events (n Z 3606)
P
80 55 6.6 15.7 17 61
278 161 4.4 9.9 66 232
<.001 <.001 <.001 <.001 <.001 <.001
(25.4) (17.6) (6.4) (16.9) (5.4) (19.4)
(7.7) (4.5) (3.9) (8) (1.8) (6.4)
Acute cardiac events in CAP Table 3
31
Factors associated with acute cardiac events in CAP patients: multivariate analysis.
Age (>65 years) Chronic heart disease Diabetes mellitus Chronic kidney disease Cerebrovascular disease Altered mental status Septic shock Tachycardia (100 beats$min1) Anemia (hematocrit < 30%) Hypoalbuminemia (albumin < 30 g/L) Multilobar pneumonia Pneumococcal pneumonia
OR
95% CI
P
1.78 3.05 1.16 1.49 1.04 0.98 1.70 1.61 1.22 2.33 1.36 1.39
(1.28e2.47) (2.28e4.08) (0.84e1.59) (0.96e2.30) (0.68e1.60) (0.67e1.41) (1.03e2.56) (1.21e2.13) (0.77e1.96) (1.74e3.12) (1.03e1.81) (1.05e1.38)
.001 <.001 .35 .07 .83 .98 .01 .001 .38 <.001 .03 .02
Note. CAP, community-acquired pneumonia; CI, confidence interval; OR, odds ratio.
associated with acute cardiac events were age >65 years, chronic heart disease, tachycardia (cardiac rate 100), septic shock, multilobar pneumonia, hypoalbuminemia (albumin 30 gr/L), and pneumococcal pneumonia. The goodness-of-fit of the model was 0.66 and the area under ROC curve was 0.74 (95% CI 0.71e0.77). Factors associated with arrhythmias in univariate analysis were age >65 years, chronic heart disease, chronic kidney disease, altered mental state, tachycardia, septic shock, hypoalbuminemia, and pneumococcal pneumonia. Factors related with heart failure were age >65 years, chronic heart disease, chronic kidney disease, diabetes mellitus, septic shock, hypoalbuminemia, and multilobar pneumonia. Factors for myocardial infarction were age >65 years, male sex, chronic heart disease, chronic kidney disease, diabetes mellitus, tachycardia, septic shock, hypoalbuminemia, and multilobar pneumonia.
Score derivation Results from the multivariate analysis were used to develop the clinical prediction rule (including variables with P < .1). According to the regression coefficients, we assigned 1 point to each parameter, except for chronic heart disease (3 points) and hypoalbuminemia (2 points) (Table 4). A rule based on these variables had an area under ROC curve of 0.73 (95% CI 0.70e0.76) to predict acute cardiac events. These complications occurred in 2.8% of patients classified into the low-risk group (3 points), 9.7% in intermediaterisk group (4e5 points) and 21.2% in high-risk group (6 points) (chi-square for trend P < .001) (Fig. 1). Areas under ROC curve of the rule to predict new-onset or worsening cardiac arrhythmias, new-onset or worsening congestive heart failure and myocardial infarction were 0.71 (95% CI 0.67e0.74), 0.76 (95% CI 0.71e0.81) and 0.71 (0.67e0.64) respectively.
Discussion In this large prospective cohort study of nonimmunocompromised patients hospitalized for CAP, the presence of age >65 years, chronic heart disease, tachycardia (cardiac rate 100), septic shock, multilobar pneumonia,
hypoalbuminemia (albumin 30 gr/L), and pneumococcal pneumonia were identified by multivariate analysis as independent predictors of acute cardiac events. In addition, a simple, practical clinical score was generated to stratify the risk of acute cardiac events in these patients. After adjustment for potential confounders, we documented that acute cardiac events were independently associated with poor outcomes. In addition, each one new-onset or worsening cardiac arrhythmias, new-onset or worsening congestive heart failure and myocardial infarction was associated with higher risk for ICU admission and mortality. This finding is in line with other studies that have identified a link between acute cardiac events and worst prognosis in CAP,3e5 and highlights the importance of identifying the profile of patients at risk of suffering these events. Information on risk factors for acute cardiac events in patients with CAP is scarce.3,4 Recently, Corrales-Medina et al3 reported that older age, nursing home residence, history of heart failure, prior cardiac arrhythmias, previously diagnosed coronary artery disease, arterial hypertension, respiratory rate >30 breaths per minute, blood pH < 7.35, blood urea nitrogen >30 mg/dL, serum sodium <130 mmol/L, hematocrit <30%, pleural effusion on presenting chest x-ray, and inpatient care were factors independently associated with the diagnosis of these complications. However, authors did not analyze the impact of causative microorganisms, nor did they define specific risk groups. Similarly, in another study,4 factors significantly associated with acute myocardial infarction were age, previous acute myocardial infarction, COPD and chronic renal disease. Age, diabetes mellitus and prior myocardial infarction were also associated with increased risk of atrial fibrillation. Nevertheless, this study had some limitations, including its retrospective design and the use of ICD-10 codes to identify cases of CAP and vascular events. Our study identifies factors associated with acute cardiac events in patients with CAP and stratifies them according to the risk for developing these complications. These factors are markers of increased cardiovascular risk (age >65 years, chronic heart disease, chronic kidney disease),15 and more severe pneumonia at hospital admission (tachycardia, septic shock, multilobar pneumonia).11 Significantly, nearly 50% of patients with acute cardiac
32
D. Viasus et al.
Table 4 Prediction rule for acute cardiac events in hospitalized patients with CAP. Variable
Points
Chronic heart disease Hypoalbuminemia (albumin < 30 g/L) Age (>65 years) Chronic kidney disease Septic shock Tachycardia (100 beats$min1) Multilobar pneumonia Pneumococcal pneumonia
3 2 1 1 1 1 1 1
Note. CAP, community-acquired pneumonia.
events did not have a medical history of comorbid chronic heart disease. Therefore, acute cardiac events also should also be considered in CAP patients without this underlying disease. We found that pneumococcal pneumonia was also an independent factor associated with acute cardiac events. Previously, another study reported a higher incidence of myocardial infarction among patients with pneumococcal pneumonia.7 Interestingly, it has recently been suggested that inflammatory response in CAP may depend, at least in part, of the causative microorganism. In this regard, the lowest inflammatory expression has been found in cases of unknown etiology, although one of the microorganisms with the highest increase in cytokines was S. pneumonia.16 It should be noted that increased systemic inflammatory activity has been related to triggering of acute cardiac events in patients with CAP.8,9 This is also applicable to patients with severe pneumonia, which has also been associated with greater elevation of inflammatory biomarkers.17,18 Significantly, hypoalbuminemia was associated with acute cardiac events in this study. In most cases, hypoalbuminemia was related to malnutrition or sepsis and was not the consequence of hemodilution, since no differences were found in the frequency of hyponatremia and pleural effusion between the study groups. Our findings concur with previous reports that found
hypoalbuminemia to be a frequent and major cause of the incidence and exacerbation of heart failure19e21 and ischemic cardiac disease.21 Our predictive model discriminates between three patient subgroups. The low-risk and moderate-risk groups had rates of positive events of 0e4.4% and 9.5e9.9% respectively, and the high-risk group a rate between 18.7% and 34.6%. To apply the scoring system, demographic and clinical variables are available at presentation for almost all patients and are easy to obtain. The accuracy of the method is good but not excellent, as the statistical analysis demonstrates for internal validation (AUC 0.73). The moderate and high-risk groups identify nearly 85% of patients with acute cardiac events, so clinical suspicion of these complications should be maintained in those patients at low-risk. The potential benefit of stratification of patients at risk for acute cardiac events is that diagnostic tools, monitoring and preventive strategies, such as bblockers or conservative fluid strategies, could be useful. In this regard, it has been suggested that b-blocker use during perioperative period may reduce myocardial ischemia and longer-term cardiovascular complications, although findings have been inconsistent across studies.22,23 The strengths of this study are the large number of patients included, its prospective design, and the comprehensive clinical and microbiologic data gathered. In addition, the independent variables were recollected and defined from the time the study began. Nevertheless, the definition of acute myocardial infarction was modified with the inclusion of troponin as a marker of myocardial damage in 2001.24 Finally, this is the first study to attempt to identify and stratify patients at increased risk for acute cardiac events in this context. On the other hand, there are some limitations that should be acknowledged. The study was conducted at single center and the present scoring tool should be validated in further investigations. Furthermore, no information about the timing of onset of acute cardiac events and long-term outcomes were recorded. Finally, we did not evaluate the usefulness of biomarkers to identify patients at risk of cardiac events. In conclusion, acute cardiac events are frequent in hospitalized patients with CAP and are associated with high morbidity and poor prognosis. The risk of acute cardiac events can be estimated at bedside by evaluating simple demographic and clinical factors. The prediction rule allows for the stratification of patients according to the risk of acute cardiac events, and identifies subgroups of high-risk patients for whom diagnostic tools, monitoring and preventive strategies may have value.
Acknowledgments
Figure 1 Risk groups for acute cardiac events in hospitalized patients with CAP.
Financial support: This work was supported by the the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III e co-financed by the European Regional Development Fund “A way to achieve Europe” ERDF, Spanish Network for Research in Infectious Diseases (REIPI RD06/ n Sanitaria de la 0008) and the Fondo de Investigacio Seguridad Social (grant 07/0864 and 11/01106). Dr. Viasus is the recipient of a research grant from the Institut Biome dica de Bellvitge (IDIBELL). Dr Garciad’Investigacio
Acute cardiac events in CAP
33
Vidal is the recipient of a Juan de la Cierva research grant from the Instituto de Salud Carlos III, Madrid, Spain.
Role of the funding sources The funding sources had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
13.
14.
Competing interests 15.
All authors declare that they have no conflicting interests that are relevant to this article.
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