Acute cardiovascular events in patients with community acquired pneumonia: results from the observational prospective FADOI-ICECAP study

Community acquired pneumonia (CAP) is a frequent and clinically demanding infection [1, 2], and a leading cause of hospitalisation in Internal Medicine wards. The association between CAP and cardiovascular (CV) complications seems to be a frequent event, especially in the elderly population, and recent research has provided insights into the pathogenesis of acute CV events occurring during CAP [3‐6]. Agents causing CAP can induce direct and indirect effects on the CV system. Infections induce a significant inflammatory response with the production and release of several mediators which can determine systemic effects such as activation of coagulation, enhanced platelets aggregation, and myocardial injury [7]. Mediators of the inflammatory response can modify electrophysiological properties of myocardial cells, determining increased vulnerability to cardiac arrhythmias, especially atrial fibrillation (AF) [8]. Moreover S. pneumoniae, the most frequent bacterial agent of CAP, determines cardiotoxicity mainly through the activity of pneumolysin, with direct consequences on myocardial injury [9, 10]. Recently, it has been suggested that CAP patients at risk for early and long-term CV events can be identified by cardiac biomarkers [11].

In the largest available studies [12, 13] roughly one-third of patients admitted for CAP suffered CV events during hospitalisation, and hospitalisation for pneumonia was associated with increased long-term risk of CV complications as well [14]. The occurrence of CV events increased significantly the overall risk of 30-day death, need for Intensive Care Unit (ICU) admission and prolonged hospital stay compared to patients not experiencing such complications. However, the burden of CV complications in CAP patients admitted to Internal Medicine Units, as well as the knowledge of predictors of such events, is still uncertain. Available studies used different designs (retrospective vs prospective), different criteria to define CV complications and were performed in heterogeneous settings such as ICU, Emergency Departments, Pneumology Units, as well as Internal Medicine and the community. Such a heterogeneity makes it difficult to retrieve reliable data regarding CAP patients hospitalised in Internal Medicine Units, which is the setting where most pneumonia patients are currently admitted.

Based on this rationale, the Italian Scientific Society of Hospital Internal Medicine (FADOI) promoted this multicentre prospective study on the Implications of acute Cardiovascular Events in patients hospitalised for Community-Acquired Pneumonia (ICECAP) in order to evaluate, in a large number of Internal Medicine wards, the prevalence and outcome of well-defined acute CV events in patients hospitalised for CAP.

In this large multicentre trial, designed to investigate the prevalence and implications of CV events in patients admitted for CAP to Internal Medicine wards in Italy (ICECAP), we observed a high prevalence of in-hospital CV complications with a significant impact on in-hospital and 30-day outcome.

The prevalence of in-hospital CV events in this study was 23.8%; generally speaking this means that approximately one out of four patients admitted for CAP is expected to suffer from a CV event during hospitalisation for pneumonia. This result confirms previous observations, where a prevalence of CV events during hospitalisation for pneumonia has been reported in the range of 27 to 32.2% [12, 13].

Most of the vascular events detected in our study were of cardiac origin, mainly represented by newly diagnosed decompensated heart failure (15.5%), atrial fibrillation or flutter (8.7%), and acute coronary syndromes (2.7%), while cerebral events occurred in a minority of patients (i.e. less than 1%), as well as the occurrence of advanced degree AV block and ventricular arrhythmias.

Some differences between ICECAP and the two above-mentioned studies exist and should be emphasised. Data from the landmark study by Corrales-Medina et al. [12], referred to a cohort of hospitalised and out-patients dating back to the early 1990’s when troponin and natriuretic peptides were not available, and then not in use for the definition of CV endpoints; therefore, the results could not reflect the current prevalence and significance of CV events occurring during hospitalisation for CAP. The SIXTUS study [13], which is a contemporary and well-designed trial, involved only three hospitals in Italy and Canada. In this perspective, the study population could have some limitations for the generalisability of the observed results.

A significant difference between ICECAP and previous studies addressing the association between CV events and CAP is the definition of some CV endpoints. In ICECAP we used an objective definition of newly diagnosed heart failure that included clinical, instrumental and biohumoral confirmation with NT-proBNP measurement. The difference in definition, with a more strict use of heart failure criteria, is probably the main reason for the lower prevalence of heart failure as a CAP complication in the ICECAP (15.5%) with respect to other studies (20.8 to 23.8%) [12, 13]. Similarly, we decided to consider only new episodes of supraventricular arrhythmias (atrial fibrillation, atrial flutter), and not worsening arrhythmias as considered in previous studies [12, 20]. The decision to use a stricter definition of these endpoints was done in order to identify only those CV events directly related to pneumonia.

The large majority of CV events occurred early during hospitalisation. Specifically, more than half of events occurred within the first 24 h of admission, and 76.8% occurred within 3 days. These results are in line with previous findings, because in the cohort by Corrales-Medina et al. and in the SIXTUS study, CV events occurred within the first day in 55% of patients and within 2 days in 61% of cases, respectively [12, 13]. In our study, the vast majority of CV events occurred within the first 3 days of hospitalisation for CAP, and special attention should be focused in this time window in order to intercept CV complications. This is particularly true for those patients who appeared at higher risk such as those over the age of 75, with a history of coronary artery disease, arterial hypertension, and more severe pneumonia (PSI > 130, pleural effusion). These observations are not unexpected, as all these elements correlate with a higher CV burden and risk of complications, as supported by biological plausibility and results from other studies [12, 13, 21, 22].

Interestingly, in ICECAP the occurrence of AKI during hospitalisation was an independent risk factor for the occurrence of CV events. We can speculate that AKI occurring in the context of CAP represents two sides of the same coin. On one side the occurrence of AKI can be the expression of a more severe inflammatory burden. In fact, it has been shown that elevated and imbalanced pro- and anti-inflammatory mediators along with severe endothelial dysfunction and ischemia may induce kidney injury [23]. On the other side, acute renal injury per se determines detrimental effects increasing the risk of CV events [17].

It has been reported that some types of antibiotic treatment can influence the outcome and CV risk in patients hospitalised for pneumonia [24]. In particular, it was suggested that quinolones could increase the risk of arrhythmias [25, 26], but this was not the case in our experience. Indeed, in our study the treatment with quinolones was found to be inversely related to the occurrence of CV events. In our opinion this result is difficult to interpret for several reasons, the more relevant probably being the use of quinolones in association with other antibiotics, and the influence of fluid and electrolyte balance on the occurrence of CV events. All these factors could have affected the occurrence of CV events independently from quinolone use, and finally, we cannot exclude that this observation depends on chance even in the light of what is present in literature and providing neutral or opposite indications.

It is well known that CAP is associated with a relevant risk of mortality during hospital stay and afterwards [27], and previous findings have suggested that CV complications are associated with poor outcome in community-acquired pneumonia [28, 29]. According to the results of our study, the occurrence of CV events in people admitted for CAP has negative consequences on in-hospital and 30-day outcome. The absolute in-hospital and 30-day mortality of patients with CV events were particularly high with respect to those free of events; 12.2% vs 4.7, and 16.3% vs 8.9%, respectively. Remarkably, the occurrence of CV events independently and significantly increased the risk of death at 30 days (HR 1.69, 95% CI 1.14–2.51; p = 0.009) when adjusted for other variables. Only the development of AKI during hospitalisation, dementia, and PSI > 130 points were associated with a substantial risk increase in 30-day mortality. These findings were similar to those reported in the study by Corrales-Medina et al., where the occurrence of a CV event independently increased the probability of 30-day death by a factor of 1.7. These results differ substantially from those reported in the SIXTUS study, where the risk of 30-day mortality attributed to a CV event during hospitalisation increased nearly five-fold.

In addition, CV complications increased significantly the risk of having a longer hospital stay as well as re-hospitalisation at 30 days, with respect to those patients with an uncomplicated course. In the case of occurrence of a CV event, the length of hospital stay increased significantly by an average of 2 days (median 10 days [IQR 7–13] vs 8 days [IQR 6–11]; p = 0.0001), whilst the probability of being readmitted to hospital in the following month increased by a factor of 1.6 (HR 1.62, 95% CI 1.09–2.42; p = 0.02).

A possible limitation of this study can be the lack of standardised management of CAP in the context of participating centres, and the generalisability of observations to other countries where different healthcare organisations (with reference to the role of Internal Medicine) are in place. A second limitation of the study is the exclusion of antimicrobial treatments from statistical analysis of outcome measures. After several considerations, we decided to avoid the inclusion of such variables in regression models. Gathering information for antimicrobial treatment is complex, as an example a single patient can receive multiple antibiotics at different times during the in-hospital course for different reasons, thus obtaining sound information from spurious data can be difficult and possibly misleading. Similarly, another limitation can be that cardiovascular medications were tested as variables at univariate analysis, but not considered for the multivariable model. The reasons supporting this decision were that cardiovascular drugs were registered on admission and prescribed for conditions prior to the hospitalisation for CAP. At univariate analysis, drugs such as ACE-i/ARBs, Beta-blockers and antiplatelets were frequently associated with an increased risk of CV events during hospitalisation for CAP (Supplementary Material Tables 1, 2 and 3). These results seem in contrast with biological plausibility and well-documented scientific evidence proving a protective CV effect of ACE-i/ARBs, Beta-blockers, statins and antiplatelets in many clinical conditions (i.e. surgery, secondary prevention, etc). Indeed, the results of univariate analysis very likely reflect the greater prevalence of CV medications in patients with a history of cardiovascular diseases. In view of these considerations, many potential confounders related to cardiovascular drugs could have induced a bias in the analysis, interpretation and reliability of results, thus we consciously decided not to include cardiovascular medications in the multivariable model.

On the other hand, ICECAP is the largest and contemporary multicentre study offering a comprehensive overview on the prevalence and clinical significance of CV events occurring during hospitalisation for CAP in Internal Medicine Units. The considerable number of centres involved, the clear definition of CV endpoints, and the significant number of patients enrolled at each centre, provide sound results which substantially integrate current evidence in this field and suggest possible practical implications.

In view of the results of this study, which confirm recent observations on the burden of CV complications during hospitalisation for pneumonia, CV events should be regarded as a common and unfavourable complication of CAP. For these reasons, they should be considered together with more classical but less frequent complications, such as pleural empyema and pulmonary abscesses, as common events in the course of pneumonia disease. Direct ECG monitoring or telemetry during the first 3–4 days of admission, in selected patients with a higher baseline CV risk profile (i.e. older age, high baseline CV burden, more severe pneumonia), could be an appropriate strategy to intercept early CV complications that can have detrimental impact on the short- and long-term outcome.