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Relation of Cardiac Complications in the Early Phase of Community-Acquired Pneumonia to Long-Term Mortality and Cardiovascular Events
Am J Cardiol. 2015;116(4):647-51
Community-acquired pneumonia (CAP) is complicated by cardiac events in the early phase of the disease. Aim of this study was to assess if these intrahospital cardiac complications may account for overall mortality and cardiovascular events occurring during a long-term follow-up. Three hundred one consecutive patients admitted to the University-Hospital, Policlinico Umberto I, with community-acquired pneumonia were prospectively recruited and followed up for a median of 17.4 months. Primary end point was the occurrence of death for any cause, and secondary end point was the occurrence of cardiovascular events (cardiovascular death, nonfatal myocardial infarction [MI], and stroke). During the intrahospital stay, 55 patients (18%) experienced a cardiac complication. Of these, 32 had an MI (29 non–ST-elevation MI and 3 ST-elevation MI) and 30 had a new episode of atrial fibrillation (7 nonmutually exclusive events). During the follow-up, 89 patients died (51% of patients with an intrahospital cardiac complication and 26% of patients without, p <0.001) and 73 experienced a cardiovascular event (47% of patients with and 19% of patients without an intrahospital cardiac complication, p <0.001). A Cox regression analysis showed that intrahospital cardiac complications, age, and Pneumonia Severity Index were significantly associated with overall mortality, whereas intrahospital cardiac complications, age, hypertension, and diabetes were significantly associated with cardiovascular events during the follow-up. In conclusion, this prospective study shows that intrahospital cardiac complications in the early phase of pneumonia are associated with an enhanced risk of death and cardiovascular events during long-term follow-up.
Community-acquired pneumonia (CAP) is the most common infection leading to hospitalization in intensive care units and the most common cause of death associated with infectious disease.1 Epidemiologic studies have shown that respiratory tract infections are associated with an increased risk for cardiac complications, including myocardial infarction (MI), cardiovascular death, and cardiac arrhythmia, such as atrial fibrillation, that usually occur in the first few days from pneumonia onset.2 and 3 Occurrence of a cardiac complication in the early phase of pneumonia has a negative impact in the prognosis as documented by a recent prospective study showing an increased risk of low survival at 30 days from hospital admission in patients with pneumonia experiencing cardiac complications.4 It has not been investigated, however, if such complications are also associated with enhanced risk of mortality in a long-term follow-up. Furthermore, even if pneumonia per se seems to predispose to cardiovascular events (CVEs) in a long-term follow-up, predictors of CVE occurrence have not been clarified. Aim of the study was to assess if cardiac complications occurring in the early phase of CAP increase the risk of poor outcomes such as total mortality and CVEs in a follow-up period of ∼2 years.
The study was conducted at the University-Hospital Policlinico Umberto I (Rome, Italy). All patients admitted to medical wards with diagnosis of CAP through the emergency department from January 2011 to December 2014 were consecutively recruited and prospectively followed up. Patients who fulfilled the following criteria were enrolled in the study after giving written informed consent: (1) age ≥18 years; (2) clinical presentation of an acute illness with one or more of the following signs or symptoms suggesting pneumonia: presence of rales, rhonchi, bronchial breath sounds, fever (>38.0°C), tachycardia, chills, dyspnea, coughing (with or without sputum), or chest pain; and (3) presence of new consolidations on chest x-ray. Pneumonia was considered as CAP if it was diagnosed on hospitalization and the patient had not been discharged from an acute care facility within 14 days preceding the clinical presentation.
Patients were excluded from the study if any of the following criteria applied: radiographic evidence of a preexisting infiltrates, immunosuppression (HIV infection, chemotherapy, high dose of immunosuppressive agents, such as prednisone), presence of malignancy, pregnancy or breast feeding, health care-associated pneumonia,5 documented severe allergy to antibiotics, or refusal to sign informed consent.
This study was conducted according to the principles stated in the Declaration of Helsinki. The institutional review board approved this prospective, observational study, which was registered at ClinicalTrials.gov (identifier: NCT01773863).
Data on demographic characteristics and co-morbidities were collected. Severity of illness at presentation was quantified by the Pneumonia Severity Index (PSI), a validated prediction score for 30-day mortality in patients with CAP.6 Type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, and chronic obstructive pulmonary disease were defined as previously described.7 and 8 Persistent, permanent, and paroxysmal atrial fibrillation were defined as previously reported.9 Baseline treatments were defined according to the patients' pharmacologic history.
Immediately after diagnosis of CAP, routine blood laboratory tests including serum high-sensitivity cardiac troponin T (hs-cTnT) and arterial blood gas test were performed. Thereafter, serum hs-cTnT was repeated at least every 12 hours, and a 12-lead electrocardiography was repeated every 24 hours. New intrahospital atrial fibrillation was recognized on the basis of the analysis of electrocardiogram.
MI was diagnosed according to the Third Universal Definition of Myocardial Infarction. ST-elevation myocardial infarction (STEMI) and non-STEMI were defined as previously reported.10 After discharge, all patients were followed up for a minimum of 6 and a maximum of 60 months.
The primary study outcome was the occurrence of death for any cause at long-term follow-up. Secondary outcome was the occurrence of a CVE, that is, the first occurrence of cardiovascular death, nonfatal ischemic stroke, and nonfatal MI10 during the follow-up. Cardiovascular death included fatal MI, fatal stroke, sudden death, death due to cardiogenic shock in patients with the New York Heart Association IV heart failure, death related to cardiovascular investigation/procedure/operation, death due to other specified cardiovascular causes, and presumed cardiovascular deaths (i.e., those for which a noncardiovascular cause had not been clearly established). The occurrence of stroke was determined on the basis of clinical manifestations and was confirmed by computed tomography.11
Follow-up data were obtained by review of hospital databases, medical records, death certificates, or telephone interviews. Adjudication of the events was performed by a central adjudication committee (CC and FB) who did not participate to the patients' recruitment and follow-up and was unaware of the clinical and laboratory characteristics of any patient.
Categorical variables were reported as counts (percentage), and continuous variables were expressed as mean ± SD or median and interquartile range. Differences between percentages were assessed by the chi-square test or Fisher's exact test. Normal distribution of parameters was assessed by the Kolmogorov-Smirnov test. Student's unpaired t test and analysis of variance were used for normally distributed continuous variables. Appropriate nonparametric tests (Mann-Whitney and Kruskal-Wallis tests) were used for all the other variables.
After dividing the population in 2 groups according to the presence of an intrahospital CVE, the cumulative incidence was estimated using a Kaplan-Meier product-limit estimator. Survival curves were formally compared using the log-rank test. Cox proportional hazards analysis was used to calculate the adjusted relative hazards of outcome events by each clinical variable.
Stochastic level of entry into the model was set at a p value = 0.10, and interaction terms were explored for all the variables in the final model. Only p values <0.05 were regarded as statistically significant. All tests were 2 tailed, and analyses were performed using computer software packages (SPSS-19.0; IBM, New York).
We recruited 301 patients hospitalized for CAP (187 men and 114 women; age 71.8 ± 15.7 years). Most of the patients had arterial hypertension (70%). T2DM was present in 26%, chronic obstructive pulmonary disease in 34%, dyslipidemia in 24%, and a history of stroke in 12%. A history of paroxysmal atrial fibrillation was present in 14% of patients, whereas 12% were affected by chronic (persistent or permanent) atrial fibrillation and 13% had severe chronic kidney disease (i.e., a glomerular filtration rate <30 ml/min). Of the entire population, 108 (36%) were treated with 100 mg/day aspirin, 94 (31%) with statins, and 39 (13%) with oral anticoagulation.
During the intrahospital stay, 55 patients (18%) experienced a cardiac complication: 32 had an MI (29 non-STEMI and 3 STEMI) and 30 had a new recognized atrial fibrillation (7 experienced both atrial fibrillation and MI). Demographic and clinical characteristics of patients experiencing or not a cardiac complication are reported in Table 1.
Baseline characteristics of patients in relation to cardiac complications occurrence during the intra-hospital stay
|Variable||Intra-hospital cardiac complication||p value|
|Age (years)||70.0 ± 16.5||79.7 ± 8.6||<0.001|
|Men||62% (n=152)||64% (n=35)||0.803|
|Preexisting comorbid conditions|
|Paroxysmal atrial fibrillation||9%||38%||<0.001|
|Chronic atrial fibrillation||13%||9%||0.408|
|Chronic obstructive pulmonary disease||35%||35%||0.978|
|Type 2 diabetes mellitus||27%||27%||0.968|
|Severe chronic kidney disease||12%||16%||0.379|
|Pneumonia Severity Index score||86.4 ± 30.2||111.8 ± 27.7||<0.001|
|Hs-cTnT (μg/L)||0.014 [0.010-0.034]||0.083 [0.028-0.298]||<0.001|
|Oral anticoagulants use||13%||13%||0.905|
All patients were followed for a median time of 17.4 months (range 6 to 60 months) yielding a total of 560 person-years of observation. During the follow-up, 90 patients died.
Patients who died during the follow-up were older (80.7 ± 31.5 vs 68.1 ± 16.4; p <0.001) and had a higher prevalence of diabetes (35% vs 23%; p = 0.027), hypertension (83% vs 65%; p = 0.002), severe chronic kidney disease (19% vs 10%; p = 0.047), and history of stroke (19 vs 9%, p = 0.009). Furthermore, they had a higher PSI score (106 ± 25 vs 85 ± 31; p = 0.007) and higher levels of baseline hs-cTnT (0.052 [0.022 to 0.115] vs 0.014 [0.010 to 0.038] μg/L; p <0.001). Finally, death occurred more frequently in patients who experienced a cardiac complication (32% vs 13%, p <0.001) during the hospitalization for CAP (Figure 1). A Cox regression analysis showed that intrahospital cardiac complications, together with age and PSI, independently predicted overall mortality, after adjusting for possible confounding factors (Table 2).
Kaplan-Meier estimates of time to primary outcome events (death for any cause) in patients with or without intrahospital cardiac complications.
Adjusted hazard ratios (HR), based on a Cox proportional hazards model, of total mortality according to selected variables
|Intra-hospital cardiac complication||1.759||0.019||1.099||2.816|
|Pneumonia Severity Index score||1.010∗||0.012||1.002||1.020|
∗ HR for an increasing unit change in the independent factor.
After adjusting for history of stroke, type 2 diabetes mellitus, hypertension, severe chronic kidney disease and baseline hs-cTnT.
The secondary aim of our study was to examine the occurrence of cardiovascular events during the follow-up. Seventy-three patients experienced a cardiovascular event, such as cardiovascular death (n = 49), nonfatal MI (n = 6), or stroke (n = 8); 47% of cardiovascular events occurred in patients with and 19% in patients without an intrahospital cardiac complication, p <0.001 (Figure 2). A Cox regression analysis showed that independent predictors of cardiovascular events during follow-up were age, hypertension, T2DM, intrahospital baseline values of hs-cTnT, and intrahospital cardiac complications (Table 3).
Kaplan-Meier estimates of time to secondary outcome events (cardiovascular events) in patients with or without intrahospital cardiac complications.
Adjusted hazard ratios (HR), based on a Cox proportional hazards model, of cardiovascular events during the follow-up according to selected variables
|Intra-hospital cardiac complication||2.100||0.005||1.249||3.531|
|Type 2 diabetes mellitus||1.924||0.009||1.175||3.148|
|Intra-hospital baseline hs-cTnT||1.815∗||<0.001||1.261||2.610|
∗ HR for an increasing unit change in the independent factor.
After adjusting for history of stroke, severe chronic kidney disease and Pneumonia Severity Index score.
This study shows that cardiac complications occurring during the acute phase of hospitalization are associated with an enhanced risk of total mortality and CVEs in a follow-up of 2 years. Recent studies demonstrated that the early phase of pneumonia is complicated by cardiac events including acute coronary syndromes and arrhythmias, such as AF.4, 12, and 13 Consistently with these reports, ∼20% of our population experienced MI and/or AF in the early phase of acute disease. Although the association between intrahospital cardiac complications and mortality at 30 days has been already reported,4 there are no data linking early cardiac complication with long-term mortality. During a median follow-up of 17.4 months, total mortality rate of our population was ∼30%. This long-term mortality rate is consistent with previous reports showing that hospitalization for pneumonia is associated with a mortality risk ranging from 15% to 30% per year.14 and 15 Cardiac complications occurring in the early phase of pneumonia may provide an explanation for this finding; thus, ∼50% of patients who died during the follow-up had intrahospital cardiac complications. This extends the concept that intrahospital cardiac complications increase the risk of mortality not only after a short-term4 but also after a long-term follow-up. We found other predictors of long-term mortality, such as age and PSI, indicating that low survival is more frequent in older patients with severe pneumonia.
Cardiovascular event incidence after hospital discharge, which was the secondary end point of the study, was 14% per year. This finding is comparable with that previously reported by Corrales-Medina et al,14 who observed, in a similar population of hospitalized patients for pneumonia, an event rate of 17.9% at 1 year. In our population, patients who experienced a cardiac complication during the hospitalization for pneumonia were at about twice the risk of developing a long-term cardiovascular event during the follow-up, indicating that intrahospital cardiac complications increase the risk of long-term recurrence. The role of intrahospital cardiac complications as predictors of CVE recurrence was further corroborated by the independent association between hs-troponins and CVE in the follow-up. The association between hs-troponins and fatal and nonfatal CVE is in keeping with previous reports showing that hs-troponins are predictors of low survival.16
Mechanisms accounting for intrahospital cardiac complications consequent to CAP may be only speculative at the moment. Platelet activation may play a role by favoring plaque instability and thrombosis as also suggested by an observational study showing that patients with CAP on aspirin have lower intrahospital cardiac complication compared with non-aspirin users.17 and 18 Furthermore, pneumonia can cause coronary vasoconstriction by mechanisms involving interaction among bacteria, platelet, and endothelial function.18 and 19
Our findings provide an explanation for high long-term mortality rate in patients hospitalized for pneumonia.14 and 15 In this context, our previous observation of cardiac complications in the early phase of pneumonia may be of particular relevance12 as an accurate and early diagnosis helps identifying patients at high risk of mortality and/or CVE recurrence. Heart failure is another intrahospital complication, which is associated with poor outcome and should also be considered among the cardiac complications worsening CAP prognosis.4 Lack of Holter monitoring is a limitation of the study, and hence, we could have underestimated the real incidence of intrahospital AF.
Our previous and present studies have been done in the same geographic area and in Caucasian patients; therefore, a multicenter study with other ethnic groups should be done to support our findings. We do not have information on where and how patients with CAP with intrahospital cardiac complications have been followed up after hospital discharge. Because of the high mortality rate observed in this subset of patients with CAP, appropriate monitoring and treatment of this patients' category are mandatory.
This work was supported by a grant from the Sapienza University of Rome, Rome, Italy (“Ricerche Universitarie” 2013, n. C26A13W5JX) to Prof. F. Violi. All the authors have no conflicts of interest to disclose.
SIXTUS Study Group
Simona Battaglia, MD, Elisa Biliotti, MD, Cinzia M. Calabrese, MD, Marco Casciaro, MD, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Maurizio De Angelis, MD, Infectious and Tropical Diseases Unit, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; Paolo De Marzio, MD, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Rozenn Esvan, MD, Infectious and Tropical Diseases Unit, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; Lucia Fazi, MD, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Lucia F. Sulekova, MD, Cristiana Franchi, MD, Infectious and Tropical Diseases Unit, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; Laura Giordo, MS, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Stefania Grieco, MD, Infectious and Tropical Diseases Unit, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; Elisa Manzini, MS, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Paolo Marinelli, MD, Michela Mordenti, MD, Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy; Sergio Morelli, MD, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Paolo Palange, MD, Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy; Daniele Pastori, MD, Pasquale Pignatelli, MD, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Marco R. Capparuccia, MD, Infectious and Tropical Diseases Unit, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; Giulio F. Romiti, MS, Elisabetta Rossi, MD, Eleonora Ruscio, MS, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; Alessandro Russo, MD, Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy; Luisa Solimando, MS, Stefano Trapè, MS, and Filippo Toriello, MS, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.
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a Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
b Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
c Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
d Infectious and Tropical Diseases Unit, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
∗ Corresponding author: Tel: (+39) 0-64461933; fax: (+39) 0-649970103.
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