Abstract
Acute pericarditis is an inflammatory disease associated with a non-negligible risk of acute complications and future recurrence. The exact incidence of pericarditis recurrence in patients with a first uncomplicated clinical course is however unknown. We sought to evaluate the incidence and clinical predictors of recurrence after a first episode of acute uncomplicated pericarditis in a large urban hospital in the USA. We conducted a retrospective review, through electronic health records, to complete a database that includes patients admitted with a first episode of acute pericarditis and then selected only those with uncomplicated course (without in-hospital death, large pericardial effusion [>20 mm] or tamponade, constriction, or incessant pericarditis) at the VCU Medical Center (Richmond, VA) between 2009 and 2018. A total of 240 patients met acute pericarditis criteria: 164 (68%) patients had an uncomplicated course (median age was 50 [interquartile range 32 to 62] years, 43% females). The median follow-up time was 186 [19-467] days. Pericarditis was idiopathic in 84 patients (51%). Fifteen (9%) patients had at least one episode of recurrent pericarditis. Compared with those without recurrence, patients with recurrent pericarditis were younger (37 [25-59] vs 51 [34-62], p=0.034), had a higher prevalence of subacute/delayed presentation (2 [13%] vs 1 [1%], p=0.023) and less frequently received colchicine (6 [40%] vs 100 [67%], p=0.036). At multivariate logistic regression analysis subacute presentation and younger age remained predictor of recurrence at follow-up. In conclusion, 9% of patients with an acute pericarditis experienced a recurrence over a 6-month median follow-up despite an initial uncomplicated course. Younger age and subacute presentation were associated to a significantly higher risk of recurrence.
Keywords: acute pericarditis, recurrence, subacute presentation, uncomplicated
Acute pericarditis is an inflammatory disease that is responsible for up to 4% of emergency room admissions for chest pain (1). Although most patients have a favorable prognosis, acute pericarditis is associated with a non-negligible risk of acute and chronic complications and reduced quality of life (1-3). The most common complication is recurrent pericarditis, defined as the occurrence of symptoms and signs of acute pericarditis after a symptom-free interval of at least four-six weeks. Recurrent pericarditis may occur in up to 30% of cases at follow-up, usually within 18 months, and especially among those patients not acutely treated with colchicine (1-7). However, the incidence and predictors of pericarditis recurrence in patients with a first uncomplicated episode of acute pericarditis is unknown. In this study we sought to evaluate the incidence and clinical predictors of recurrence after a first episode of acute uncomplicated pericarditis in a large urban hospital in the United States of America (USA).
METHODS
We conducted a retrospective review through an informatics engine-based search of electronic health records to create a database that includes patients admitted with a first episode of acute pericarditis at the Virginia Commonwealth University Medical Center (Richmond, VA) between 2009 and 2018. The method of the search has been previously described in detail (6). According to the last European Society of Cardiology guidelines, the diagnosis of acute pericarditis requires at least two of the four following criteria: 1) pericardial chest pain; 2) pericardial rubs; 3) new ST-elevation or PR depression on electrocardiography (ECG); 4) new or worsening pericardial effusion (8). We then selected only the patients with an uncomplicated course (defined as absence of in-hospital death, large pericardial effusion [>20 mm] or tamponade, constriction during the index hospitalization or incessant pericarditis). Incessant pericarditis was defined as persistence of symptoms for greater than 4 weeks (regardless of anti-inflammatory treatment) without a sustained remission or recurrence of symptoms after a symptom-free interval of less than six weeks after the acute episode (9). Recurrent pericarditis at follow-up was defined as the occurrence of symptoms and signs of acute pericarditis after a symptom-free interval of least six weeks. Patients with subacute/delayed presentation were defined as symptoms over several days without a clear-cut acute onset but for less than 4 weeks. An analysis on the entire cohort of patients with acute pericarditis has been published elsewhere (6). The rate of pericarditis recurrence between patients with uncomplicated and complicated clinical course was also performed.
Inpatients and outpatients were both included. Patients’ demographic data, clinical characteristics, laboratory data, treatments received, and adverse outcomes were collected. All data, including ECG and echocardiographic data, were reviewed by at least two cardiologists before entry into the final database. Disagreements on findings or readings were resolved through discussion. Levels of C-reactive protein have not been reported as data were available only for a minority of the patients.
Continuous data were reported as median and interquartile range, and data were compared with the Mann-Whitney U test. Categorical variables were expressed as numbers and percentages (%) and compared using χ2 test or Fisher exact test, as appropriate. Clinically relevant variables were put in a logistic univariate model and tested for statistical significance. Those meeting statistical significance in the univariate model (p < 0.1, two-tailed) were incorporated in the multivariate logistic regression model to identify independent variables associated with the pericarditis recurrence. For the univariate and multivariate analysis, the measure of uncertainty was expressed as an odds ratio (OR) and 95% confidence interval (CI). All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0 for Mac (IBM).
The study was approved by the local Institutional Review Board and complied with the Declaration of Helsinki.
RESULTS
A total of 240 patients met acute pericarditis criteria. Among them, 164 (68%) patients had an uncomplicated course and 76 (32%) had an acute complicated clinical course. In patients with an uncomplicated clinical course the median age was 50 [interquartile range 32 to 62] years, 43% were females, and 48% Black. Pericarditis was considered idiopathic in 84 patients (51%), and 58 patients (35%) had post-cardiac surgery injury pericarditis. All patients were discharged free of symptoms. The median follow-up time was 186 [19-467] days. Fifteen (9%) patients experienced at least one episode of recurrent pericarditis after 164 [91-371] days (vs. 22 [29%] of patients with an acute complicated episode; p<0.001) (Figure). When compared to those without recurrence, patients with recurrent pericarditis were younger (37 [25-59] vs 51 [34-62], p=0.034), had a higher prevalence of subacute/delayed presentation (2 [13%] vs 1 [1%], p=0.023) and were less frequently treated with colchicine (6 [40%] vs 100 [67%], p=0.036). There were no differences between the two groups regarding use of non-steroidal anti-inflammatory drugs (NSAIDs) (13 [87%]vs 113 [76%], p=0.524) and oral corticosteroids (0 [0%] vs 15 [10%], p=0.365). There were no other clinical (including the etiology of pericarditis) or laboratory significant differences between those with and without pericarditis recurrence at follow-up (Table 1).
Figure:
Schematic representation of the prevalence of recurrent pericarditis in patients hospitalized for a first episode of acute pericarditis comparing those with and without a complicated clinical course.
Table 1:
Characteristics of the population according to pericarditis recurrence
| Pericarditis recurrence | |||
|---|---|---|---|
| Variable | Yes (n=15) | No (n=149) | P value |
| Demographics | |||
| Women | 8 (53%) | 62 (42%) | 0.382 |
| Age, y (median, IQR) | 37 [25-59] | 51 [34-62] | 0.032 |
| Body mass index (median, IQR) (Kg/m2) | 22.9 [21-35] | 28.4 [24 -32] | 0.069 |
| White | 6 (40%) | 72 (48%) | 0.523 |
| Black | 9 (60%) | 76 (51%) | 0.523 |
|
| |||
| Medical history | |||
| Hypertension | 8 (53%) | 74 (50%) | 0.786 |
| Diabetes mellitus | 2 (13%) | 33 (22%) | 0.427 |
| Dyslipidemi | 2 (13%) | 48 (32%) | 0.154 |
| Coronary artery disease | 3 (20%) | 35 (24%) | 1 |
| Chronic heart failure | 2 (13%) | 32 (22%) | 0.739 |
| Stroke/transiet ischemic attack | 1 (7%) | 10 (7%) | 1 |
| Atrial fibrillation | 3 (20%) | 40 (27%) | 0.761 |
| Myocardial infarction | 1 (7%) | 26 (17%) | 0.469 |
| Autoimmune disease | 0 | 11 (7%) | 0.601 |
| Tuberculosis | 0 | 2 (1%) | 1 |
| Chest radiation | 0 | 5 (3%) | 1 |
| Neoplastic diseases | 2 (13%) | 17 (11%) | 0.686 |
| Severe chronic kidney disease | 3 (20%) | 23 (15%) | 0.710 |
| Chest trauma | 0 | 2 (1%) | 1 |
|
| |||
| Recent cardiac procedure | 0.666 | ||
| Percutanous coronary intervention | 0 | 4 (2%) | |
| Pacemaker/cardiac ablation | 2 (13%) | 16 (11%) | |
| Cardiac surgery | 0 | 10 (7%) | |
|
| |||
| Previous therapies | |||
| Immunosuppressive therapy | 0 | 11 (7%) | 0.601 |
| High-dose corticosteroids | 0 | 4 (3%) | 1 |
| Oral anticoagulation | 0 | 22 (13%) | 0.226 |
|
| |||
| Etiology | |||
| Idiopathic | 10 (67%) | 74 (50%) | 0.209 |
| Postcardiac surgery injury | 3 (30%) | 55 (37%) | 0.191 |
|
| |||
| Clinical presentation | |||
| Fever | 0 | 13 (9%) | 0.366 |
| Subacute presentation | 2 (13%) | 1 (1%) | 0.023 |
| Chest pain | 14 (93%) | 142 (95%) | 1 |
|
| |||
| Cardiac examination | |||
| Pericardial rub | 3 (20%) | 32 (22%) | 1 |
| Pulsus paradoxus | 0 | 2 (1%) | 1 |
|
| |||
| ECG | |||
| PR depression | 2 (13%) | 48 (32%) | 0.229 |
| ST elevation | 8 (53%) | 73 (49%) | 0.781 |
| T wave inversion | 2 (13%) | 37 (25%) | 0.520 |
|
| |||
| Laboratory | |||
| White blood cell count (No. ×103/mL) (median, IQR) | 7.9 [6.45-11.7] | 8.8 [6.3-12.6] | 0.727 |
| Neutrophils (No. ×103/mL) (median, IQR) | 5.6 [4.3-8.5] | 6.7 [3.8-9.7] | 0.765 |
| Lymphocyte (No. ×103/mL) (median, IQR) | 1.4 [1.2-1.9] | 1.6 [1-2.1] | 0.952 |
| Hemoglobin (g/dL) (median, IQR) | 12.8 [11.4-14.2] | 12.4 [10.7-14.1] | 0.517 |
| Creatinine (mg/dL) (median, IQR) | 0.77 [0.65-0.94] | 0.9 [0.65-0.94] | 0.089 |
| Troponin ≥ 0.20 (ng/mL) | 1 (7%) | 39 (26%) | 0.169 |
|
| |||
| In hospital therapy and discharge | |||
| Nonsteroidal anti-inflammatory drugs | 13 (87%) | 113 (76%) | 0.524 |
| Colchicine | 6 (40%) | 100 (67%) | 0.036 |
| Corticosteroids | 0 | 15 (10%) | 0.365 |
|
| |||
| Days of follow-up | 273 [161-611] | 173 [15-441] | 0.137 |
Abbreviations: ECG: electrocardiogram; IQR: interquartile range,
At univariate analysis younger age (OR 0.963, CI [0.933-994], p=0.018), subacute presentation (OR 22.462, CI [1.906-264.640], p=0.013) and lower use of colchicine therapy (OR 0.327, CI [0.110-0.970], p=0.044) were associated with an increased risk of recurrence at follow-up. At multivariate logistic regression analysis, younger age (OR 0.965, CI [0.934-0.997], p=0.034) and subacute presentation (OR 15.113, CI [1.077-211.977], p= 0.044) remained positive predictors of recurrent pericarditis (Table 2).
Table 2:
Variables associated with pericarditis recurrence by univariate and multivariate logistic regression analysis.
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
|
| ||||
| OR (95% C.I.) | p | OR (95% C.I.) | p | |
| Age | 0.963 [0.933-994] | 0.018 | 0.965 [0.934-0.997] | 0.034 |
| Sex (male) | 1.604 [0.553-4.654] | 0.385 | ||
| Subacute presentation | 22.462 [1.906-264.640] | 0.013 | 15.113 [1.077-211.977] | 0.044 |
| Colchicine therapy | 0.327 [0.110-0.970] | 0.044 | 0.370 [0.118-1.160] | 0.088 |
Abbreviations: OR: odds ratio; CI: confidence interval.
DISCUSSION
We herein report the outcomes of patients hospitalized for a first uncomplicated episode of acute pericarditis in a large urban hospital in the USA: 9% of patients experience a pericarditis recurrence in the following 6 months, with subacute presentation and younger age being independent predictors. Subacute presentation was defined as symptoms occurring over several days without a clear-cut acute onset. Patients with subacute presentation had already been reported to be at higher risk of developing adverse outcomes after acute pericarditis (2). These patients may be more likely to show up later for medical evaluation during the course of the disease, leading to a delay in the anti-inflammatory treatment, potentially increasing pericardium inflammation and the future complication rate (2). We also found that younger patients are more prone to pericarditis recurrence. The potential explanations for the higher rate of pericarditis recurrences observed in younger patients are not clear and may include the stronger immune and/or inflammatory response, higher heart rate, incomplete adherence to exercise restriction, medication non-adherence or early medication therapy discontinuation (10). Our findings are in line with previous evidence showing a higher risk of recurrences in younger patients (11-13). In recent prospective study including 240 patients hospitalized with diagnosis of acute pericarditis, younger age was also the strongest predictor of pericarditis recurrence (12).
Furthermore, we found that patients with recurrent pericarditis at follow-up had less frequently received colchicine during the first acute episode. In fact, while the majority of patients experienced a prompt resolution of symptoms and inflammation when treated with NSAIDs alone, the combination with colchicine therapy showed to improve the symptoms and decrease the rate of recurrent pericarditis (5,14). In particular, 16% of those not receiving colchicine experienced a recurrence at follow-up. The use of colchicine was not associated to a lower risk of recurrence in the multivariate model, likely due to be limited by the reduced number of events of at follow-up. The high recurrence rate in patients not on colchicine may have implications for treatment in patients unable to receive colchicine.
The strengths of our study include the diagnostic accuracy guaranteed by a chart-level review as each case of pericarditis was confirmed according to the guidelines criteria. This is of relevant importance considering the inaccuracy of ICD codes alone to correctly identify pericarditis cases. Furthermore, this is the first study from “real-world” data reporting the prevalence and predictors of recurrent pericarditis in patients hospitalized for a first uncomplicated acute pericarditis episode using very selective inclusion criteria.
However, this study has also some limitations including the small sample size, the long recruitment time, the single center design and the retrospective nature of this observation limiting the power to detect difference. The small number of patients with subacute presentation as well as the wide CI values may suggest that multivariable modelling is of limited value given the only few events. Furthermore, the relation between inflammatory markers and risk of recurrence was not explored due to missing data. Prospective studies with larger sample sizes are needed to draw definite conclusions.
In conclusion, our study highlights that even patients with an acute uncomplicated episode of acute pericarditis are at risk of future recurrence.
Funding/Support:
This study was supported in part by a grant from Kiniksa Pharmaceuticals Ltd. to Dr. Gal and Dr. Abbate, and by the Bio-informatics Core of the Institutional CTSA award No. UL1TR002649 from the National Center for Advancing Translational Sciences (T.S.G.). Dr. Abbate received support from the ‘Sapienza Visiting Professor Programme 2020” of the Sapienza Università di Roma, Italy. Research funding for this work was also generously provided by Drs. Claudia and Richard Balderston.
Conflict of interests:
Dr. Abbate has served as a consultant for Astra Zeneca, Effetti, Implicit Biosciences, Kiniksa, Janssen, Merck, Novartis, Olatec, and Serpin pharma. Dr. Vecchià received a travel grant from Kiniksa Pharmaceuticals Ltd. to attend the 2019 AHA Scientific Sessions. Dr. Bonaventura received a travel grant from Kiniksa Pharmaceuticals Ltd. to attend the 2019 AHA Scientific Sessions.
Footnotes
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Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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