risk of heart failure following community acquired pneumonia… · heart failure from 6 hospitals...
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Risk of Heart Failure Following Community Acquired
Pneumonia: A Prospective Controlled Study with 10-Years of Follow-up
Journal: BMJ
Manuscript ID BMJ.2016.035000
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the Author: 11-Aug-2016
Complete List of Authors: Eurich, Dean; University of Alberta, School of Public Health Marrie, Thomas; Dalhousie University, Minhas-Sandhu, Jashu; University of Alberta, Majumdar, Sumit; University of Alberta, Medicine
Keywords: Pneumonia, heart failure, prospective cohort, mortality
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Risk of Heart Failure Following Community Acquired Pneumonia: A Prospective
Controlled Study with 10-Years of Follow-up
Dean T. Eurich, Professor1,2 [email protected]; Thomas J. Marrie, Professor3 [email protected]; Jasjeet K Minhas-Sandhu, Research Associate2 [email protected]; Sumit R. Majumdar, Professor1,2,4 [email protected]
1 School of Public Health, University of Alberta, Edmonton, Alberta, Canada, T6G 2G3; 2ACHORD, 2-040 Li Ka Shing Center, University of Alberta, Edmonton, Alberta, Canada, T6G 2E1;3Department of Medicine, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7; 4Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2B7;
Corresponding Author and address to which reprints should be addressed:
Dean T. Eurich, 2-040 Li Ka Shing Center for Health Research Innovation, University of Alberta, Edmonton, Alberta, Canada, T6G 2E1; Phone 780-492-6333; fax 780-492-7455; email: [email protected];
Abstract: 256; Text: 2724
Key Words: Pneumonia, Heart Failure,
Running Title: Heart Failure Following Pneumonia
What this paper adds:
Section 1: What is already known on this subject
CAP has been associated with new-onset heart failure; however, the true attributable risk of CAP on heart failure incidence relative to a control population is unknown, particularly over the long-term.
Section 2: What this study adds
Our data suggests that the ten-year risk of developing incident HF following a CAP event is very high. Indeed, for every twenty patients presenting with CAP, we would expect to see one additional case of heart failure compared to patients accessing the health system without pneumonia.
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Abstract
Objective: CAP has been associated with new-onset heart failure; however, the true
attributable risk of CAP on heart failure incidence relative to a control population is
unknown, particularly over the long-term.
Design: Cohort study
Setting and Participants: Between 2000-2002, 4988 adults with CAP and no history of
heart failure from 6 hospitals and 7 Emergency Departments in Edmonton (Alberta,
Canada) were prospectively recruited and matched on age, sex, and site of treatment with
up to 5 non-pneumonia controls without prevalent heart failure (n=29,402).
Main Outcome Measure: Risk of incident heart failure hospitalization or a combined
endpoint of heart failure or death through to 2012 were evaluated using multivariable
Cox proportional hazards analyses.
Results: Average age was 55 years [35% ≥ 65 years], 2649 (53%) were male, and the
majority were managed as outpatients (63%). Over a median of 9.9 years, (592) 12% of
CAP patients had incident heart failure compared with (1712) 7% of controls (adjusted
hazard ratio (aHR) 1.61, 95%CI 1.44 to 1.81, p<0.001). CAP patients were also more
likely to achieve the combined endpoint of heart-failure or all-cause mortality than the
controls (41% vs 26%; aHR=1.53, 95% CI=1.44 to 1.63, p<0.001). The increased risk for
CAP patients was observed in both the short-term (i.e., 90 days, p=0.015) and
intermediate term (i.e., 1 year, p<0.001) following acute illness. Results were consistent
based on inpatient or outpatient treatment and robust to several sensitivity analyses.
Conclusion. Our results demonstrate that CAP patients are at high risk for the future
development of heart failure and this should be considered when formulating post-
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discharge care plans and preventive strategies.
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Introduction
Community acquired pneumonia (CAP) is a common condition associated with
substantial morbidity and mortality irrespective of age.1 CAP remains the seventh
leading cause of death in the United States, accounts for an estimated $9 billion in direct
health care costs and 600 000 admissions to hospital each year.2-4 Although often
considered an acute event, the long-term risks of CAP are substantial (>50% mortality
over 5 years and near twofold higher risk of subsequent CAP than non-CAP controls).1
Moreover, despite major advances in risk stratification and management, downstream
sequelae in survivors of pneumonia have not substantively improved over the last
decade.5
There is increasing attention between the link of CAP and subsequent
cardiovascular diseases (CVD). Several studies have reported a significant short-term
risk in major CVD following acute respiratory infections, although the longer-term
impact of CAP on CVD is less certain.6 One cardiovascular complication that seems to
be highly prevalent in patients with CAP is heart failure (HF).7-22 The mechanism by
which CAP may influence heart failure is multidimensional. Acute infections can result
in reduced myocardial function (e.g. septic shock), increased oxygen consumption,
tachycardia, and circulatory problems which may all lead to increased cardiac workload
and risk of heart failure.23-25
Overall, studies have reported incident HF rates of 1.4% in outpatient CAP
populations to as high as 24% among CAP inpatients.6-20 Key study limitations have been
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highly selected samples (cohorts derived from trial participants or from hospitalized
patients from a single medical center),6 7 9-15 17-20 inclusion of existing HF exacerbation
with new onset incident HF,6 7 9 11-20, small sample sizes (<500),7 12 13 15 16 short follow-
ups (e.g. in-hospital events only),6 7 9 11-16 20 and relatively small number of events.7 12 13 15
16 18 Moreover, the majority of studies have only focused on hospitalized patients 7 9 11-20
and none have been able to distinguish the true attributable risk associated with CAP on
HF events relative to a control population without pneumonia or prevalent HF.
Thus, it remains unclear if CAP truly increases the risk of incident HF relative to
non-CAP patients in the short or longer-term. We therefore assembled a representative
population-based cohort of patients with pneumonia and age-sex matched population
controls without pneumonia, to better understand the natural history of an episode of
pneumonia and its relative impact with respect to short and long-term incidence of HF.
Methods
Cases – Pneumonia patients.
This prospective population-based clinical registry has been extensively described in
previous publications.1 All patients >17 years of age with CAP admitted from 2000-2002
to any of the six hospitals or 7 Emergency Departments in Edmonton, Alberta, Canada,
which serves a population of approximately 1 million people, were enrolled in a clinical
registry. Subjects who had tuberculosis or cystic fibrosis, were immunocompromised
(e.g., >10mg/day prednisone equivalents), or were pregnant were excluded. All cases had
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to have radiographic confirmation of pneumonia by treating physicians and at least two
signs or symptoms of CAP (cough; pleuritic chest pain; shortness of breath; temperature
>38°C; and crackles or bronchial breath sounds). All patients were treated according to a
validated clinical CAP pathway which outlined preferred processes of care. 26 All data
were prospectively collected by trained research nurses from presentation to discharge
using standardized abstract forms. These data included demographic information,
physician-confirmed clinical and laboratory data, and prescription medication use within
the week prior to admission. Ethics approval for the study was granted by the Health
Research Ethics Board at the University of Alberta.
Matched Controls – Non-pneumonia patients.
Each CAP subject was frequency matched with up to five age (5 year age bands) and sex
matched controls. Controls were required to be alive at the time of the CAP case,
presenting at same site of care (same hospital for inpatients or same Emergency
Department for outpatients) as the case within the same month and year for a non-
pneumonia related diagnosis, and have no history of CAP in the 1 year prior based on
International Classification of Disease 9th Revision Clinical Modification codes 480-487
or ICD 10 codes J10-J18.
Outcomes
The primary outcome of interest was incident HF, which we defined as any heart-failure
related hospitalization following the initial CAP event (or matched control index event)
through to March 31st, 2012. Hospitalizations with any diagnostic code of HF were
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identified using the International Classification of Diseases, Ninth and Tenth Revision
Clinical Modification codes (ICD-9-CM 428.x; ICD-10-CM I50) and ascertained by
linking patients to comprehensive provincial healthcare administrative databases and vital
statistics file.27 The quality and validity of the provincial administrative databases are
routinely checked both provincially and federally with processes to resolve data issues
where identified. Secondarily, we evaluated the risk of incident HF in the short-term (90
days post index discharge) and intermediate term (1 year post index discharge
composite). We also evaluated a composite endpoint of “incident HF or all-cause
mortality” over the follow-up period.
Statistical Analysis
As we were most interested in new-onset heart failure post discharge, we excluded all
prevalent heart failure patients defined as any ICD-9-DM or ICD-10-CM codes for heart
failure occurring prior to or during their initial CAP or matched control visit (minimum
of 3 years prior). Furthermore, we restricted our cohort to only those cases and controls
that survived their initial index hospitalization or ED visit. Time to heart-failure related
hospitalization from the index CAP event (or matched control event) were described
using Kaplan-Meier curves.
Multivariate Cox proportional hazard regression accounting for the matched nature of
this data were used to evaluate the outcomes for CAP patients relative to controls and
presented as hazard ratios (HR) and 95% confidence intervals (CI). No violations of
proportional hazards assumptions were found via log-log plots and Schoenfeld residuals.
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Censoring occurred at departure from Alberta Health or March 31, 2012, providing a
maximum follow-up of about 11 years. Repeat events were not considered; only time to
first event was evaluated.
To ensure differences in outcomes were not driven by differences in comorbidity, all
analyses were adjusted using the 31 co-existing conditions as defined by the Elixhauser
index. The Elixhauser index conditions were calculated based on diagnostic codes within
the three years prior to the index event for cases and matched controls. Adjustments were
also made for socioeconomic status (based on government level of support provided) and
Aboriginal status, as well as the number of physician visits in the one year prior to the
index event as an additional marker of disease burden. In addition, age was included in
the models to control for any residual confounding not accounted for in the matching
process. In addition, all analyses were stratified by site of care (inpatient and outpatient)
for initial visit to ensure results were consistent among inpatients and outpatients. All
analyses were conducted using SAS V9.4 (City, State, SAS Institute Inc.).
Sensitivity Analysis
First, as the primary analysis excluded patients with new-onset heart failure during their
initial index event visit, we expanded the endpoint to include heart failure events that
occurred within the initial CAP or matched control visit. Thus, the endpoint considered
any incident heart-failure diagnosis during the index hospitalization or any subsequent
heart-failure related hospitalization as having incident heart-failure. Second, we expanded
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our outcome definition to include not only heart-failure related hospitalizations post
discharge but also included heart failure-related ED visits. For this analysis, only time to
first ED or hospitalization visit for heart failure was considered. Third, given the
relatively high rates of mortality in this older population, we re-ran our primary analyses
using a competing risk framework.28 Fourth, we specifically evaluated new-onset HF in
patients with a history of myocardial infarction or in those who experienced a myocardial
infarction during their initial index event. Finally, we specifically evaluated the risk of
new-onset HF in patients with Streptococcus pneumoniae bacteremia.15
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Results
Of the 6874 CAP patients in the cohort, 314 (5%) died in hospital, 857 (12%) had
prevalent heart failure, and 309 (5%) had a heart failure code occurring within their initial
CAP visit and were excluded from our primary analyses. Of the remaining 5394 CAP
patients, 4988 were successfully matched with at least one control (n=23060; 3676 [74%]
with 5 controls). Of the 406 unmatched CAP patients, 22 (0.5%) could not be linked to
administrative databases and 384 (7%) did not have suitable controls (Supplemental
Figure). The median follow-up was 9.9 years (IQR=4.8), with maximum follow-up being
11.4 years. CAP patients were 55 years old (SD=20) with 1762 (35%) over 65 years old,
and were mostly treated on an outpatient basis (63%). While cases and controls were
evenly distributed by sex (p=0.60), controls were slightly younger (53 vs 55 years,
p<0.001) and had fewer comorbidities (Table 1).
The primary endpoint of incident heart-failure occurred in 592 (12%) of CAP cases
compared to 1712 (7%) of controls (p<0.001); this translates into HF rates of 1.7 per 100
person years vs 0.9 per 100 person years respectively (p<0.001) (Figure 1). After
adjustment, CAP patients had a higher rate of incident heart-failure relative to the
matched controls (adjusted hazard ratio (aHR)=1.61, 95% confidence interval (CI)=1.44
to 1.81, p<0.001)(Table 2). Moreover, compared to controls, CAP patients were also
more likely to have an incident heart-failure hospitalization within 90 days post index
discharge (1.4% vs 0.6%; aHR=1.52, 95% CI=1.08 to 2.13, p=0.015) and also a higher
risk at 1 year (3.3% vs. 1.43%; aHR=1.86, 95% CI=1.50 to 2.32, p<0.001. Results were
also consistent when stratified by site of care (inpatient vs outpatient) (Table 2).
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Over the entire follow-up, 1917 (38%) CAP cases and 5509 (24%) controls died from
any-cause (p<0.001) ); this translates into mortality rates of 5.2 per 100 person years vs
2.9 per 100 person years respectively (p<0.001). A substantial number of both cases and
controls experienced the composite endpoint of incident heart-failure or all-cause
mortality with 2035 (41%) of cases and 6041 (26%) of controls having the composite
endpoint. After adjustment, CAP patients were also more likely to achieve the combined
endpoint of incident heart-failure or all-cause mortality than the control patients
(aHR=1.53, 95% CI=1.44 to 1.63, p<0.001) (Table 2). Again, increased risk of the
composite endpoint was observed for both inpatients and outpatients relative to controls
(Table 2).
Sensitivity Analyses
Sensitivity analyses were robust and showed similar results to the primary analyses
(Figure 2). After expanding the endpoint to include incident heart failure occurring within
the initial index visit, compared to their matched controls, CAP patients were still at an
increased risk of incident heart-failure related events compared to their matched controls
(777 (15%) vs 2220 (8.9%); vs aHR=1.82, 95%CI=1.65 to 2.01, p<0.001). Second, after
including incident heart failure-related emergency department visits into the outcome,
patients with CAP were still more likely to have heart failure hospitalizations (706 (14%)
vs 2 022 (8.8%) vs aHR=1.62, 95%CI=1.45 to 1.80, p<0.001). Third, our results were
similar when re-evaluated using a competing risk framework (aHR 1.37, 95%CI=1.25 to
1.51, p<0.001). Finally, compared to their matched controls (n=460), patients with
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pneumococcal bacteremia (n=98) were at significant risk of incident heart failure (13
(13.3%) vs 34 (7.4%)13%; aHR 2.4, 95%CI=1.08 to 5.3).
Discussion
In this large, population-based cohort study of CAP patients, we have highlighted the
significant increased risk of incident HF after an episode of CAP. Our data suggests that
the ten-year risk of developing incident HF following a CAP event is approximately 12%.
Further, compared to age-sex matched controls, there was over a 50% relative increase in
the risk of incident HF. This increased risk of HF following a CAP event is conferred
relatively early following discharge (within 90 days) and in many patients the occurrence
of “new” HF and CAP occur simultaneously during the same acute episode of illness.
To our knowledge, this is the longest outcomes study of CAP patients and HF reported to
date. Only one other previous study evaluated the longer-term risk of HF following an
episode of CAP. In a highly select study evaluating the effect of clarithromycin on
cardiovascular events, Schembri et al observed 3% of patients with CAP developed new
or worsening HF within one year. This is consistent with our results at one year where we
also observed 3% of CAP patients having a HF hospitalization, although among
inpatients our results were slightly higher whereby 6% were hospitalized for HF within 1
year. Our results are less consistent with a previous meta-analysis that suggested an
overall short-term risk of 14.1% among CAP inpatients.21 Although 18% of inpatients
will develop HF over the longer term, substantially fewer patients develop HF in the
short term. Indeed, by 90 days of discharge only 1.4% of patients developed HF (2%
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among inpatients) and only approximately 5% had HF when in-hospital heart failure
events were included. The discrepancy in results is likely fully explained by the fact
previous studies were conducted in highly select populations with small sample sizes and
events, and often included patients with prevalent HF.6 7 9-20 Moreover, no previous study
has been conducted relative to a control population. Indeed, although age-sex matched
controls also have significant long-term risk of HF, CAP confers a much higher risk of
HF, resulting in an absolute risk of HF of associated with CAP of 5% relative to controls.
Our study also builds on the evidence for patients with CAP managed as outpatients.
Only a single previous study has evaluated the impact of CAP on HF in patients managed
on an outpatient basis. In 907 outpatients, the PORT investigators observed an incident
rate of HF of 1.4% within 30 days.10 Conversely, within 90 days only 1% of outpatients
had incident HF in our study (with 8% developing HF over the entire follow-up). Again,
the PORT study was fairly restrictive in the spectrum of patients included in their study
and unlike our study was not population based.
The putative role of CAP on HF, and cardiac disease in general, is still evolving. CAP
raises systematic oxidative stress and inflammatory markers (e.g. circulatory cytokines),
in both the short and long term, leading increased risk of thrombogenesis, destabilization
of atherosclerotic plaques and endothelial dysfunction potentially leading to increased
rates of ischemic heart disease, atrial fibrillation, and reduced ventricular function.6 15 29
Furthermore, this increased host response to infection has been shown to occur even in
those with less severe infections and persistent long after a patient clinically recovers
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from the acute infection itself.25 Whether CAP truly causes HF per se or whether HF is
simply the endgame in the cardiac cascade triggered by acute CAP is not fully
elucidated. Other factors, which are common to both CAP and HF, are also likely at play
including advanced age, reduced renal function, and the presence of other major
comorbidities (e.g., atherosclerosis, diabetes, hypertension), and collectively all likely
contribute to the elevated risk of HF in CAP patients.6 A major limitation of our study is
we could not examine these potential mechanisms and etiologies of HF related to CAP.
Additional limitations include the fact that our study did not include certain high risk
patient groups, most notably those who are immunocompromised. Although this would
not be expected to lead directly to heart failure, immunocompromise is associated with
frailty and potentially sicker patients who may be at increased risk of complications and
chronic diseases including heart failure. Second, our diagnosis of incident heart failure
was based on administrative data as opposed to clinical data. However, heart failure
codes in administrative data have previously been shown to be highly valid with high
positive and negative predictive values as compared to medical records.30 Importantly,
both our CAP cases and controls used the same method to identify incident heart failure
and no differential bias would be expected. Last, due to the administrative coding, we are
unable to assess the degree of severity of heart failure in either of our cohorts. Moreover,
we were unable to account for some clinical differences (e.g., blood pressure) that may
have influenced heart failure events between the groups. We did adjust our models,
however, for a well-known and validated comorbidity index that would have captured
physician diagnosed hypertension. Despite these limitations, our study has several major
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strengths including the large population based sample, the use of controls to fully
evaluate the potential incremental risk of CAP on HF, and long-term follow-up data.
In conclusion, our results demonstrate that CAP patients are at very high risk for the
future development of heart failure. Indeed, for every twenty patients presenting with
CAP for either inpatient or outpatient management, we would expect to see one
additional case of heart failure compared to patients accessing the health system without
pneumonia. Whether CAP is simply a marker of a high risk population or contributes to
the underlying mechanism for the development of cardiovascular diseases and heart
failure is strongly debated.6 21 Regardless, our results clearly show the high risk nature of
these patients which will assist front-line clinicians in formulating post-discharge care
plans and preventive strategies.
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Competing Interests:
All authors have completed the ICMJE uniform disclosure form at
www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the
submitted work; no financial relationships with any organisations that might have an
interest in the submitted work in the previous three years; no other relationships or
activities that could appear to have influenced the submitted work.
Details of contributions
DTE & JMS were responsible for the study design, statistical analysis and interpretation
of data, drafting the manuscript. All authors contributed to the study design,
interpretation of data and critical revision of manuscript. All authors, external and
internal, had full access to all of the data (including statistical reports and tables) in the
study and can take responsibility for the integrity of the data and the accuracy of the data
analysis. DTE affirms that the manuscript is an honest, accurate, and transparent account
of the study being reported; that no important aspects of the study have been omitted; and
that any discrepancies from the study as planned (and, if relevant, registered) have been
explained.
Funding
DTE receives salary support through a Canada Research Chair Award from the
Government of Canada. SRM holds the Endowed Chair in Patient Health Management
from the Faculties of Medicine and Dentistry and Pharmacy and Pharmaceutical
Sciences, all at the University of Alberta. Grants-in-aid from Capital Health, and
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unrestricted grants from Abbott Canada, Pfizer Canada, and Janssen-Ortho Canada have
been issued to TJM. All authors declare that DTE, TJM, JMS, and SRM have no non-
financial interests that may be relevant to the submitted work. The study sponsors played
no role in study design or conduct; collection, analysis, interpretation of data; writing of
the report; or in the decision to submit the paper for publication.
Data Sharing: No additional data available.
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Table 1 – Baseline Characteristics of Cases and Controls
N=28 048 Control
(n=23 060)
Case
(n=4 988)
p-value
N (%) or Mean (SD)
Age (SD) 53 (20) 55 (20) <0.001
Age Categories Under 25 26-45 46-65 66-80 Over 80
1919 (8)
7403 (32) 6684 (30) 4901 (21) 2153 (9)
373 (8)
1482 (30) 1371 (27) 1118 (22) 644 (13)
<0.001
Sex - Male 12152 (53) 2649 (53)
Welfare 1524 (6) 542 (11) <0.001 Aboriginal 807 (4) 320 (6) <0.001
Location of Treatment Outpatient Inpatient
15092 (65) 7968 (35)
3163 (63) 1825 (37)
1.00
MD visits in 1 year prior to index (SD) 11 (12) 12 (14) <0.001
Average length of follow-up in years 8.3 (4) 7.4 (4) <0.001
Median length of follow-up in years 10 (IQR=4.1) 9.6 (IQR=6.7)
Charlson Index 0.46 (1) 0.73 (2) <0.001
Elixhauser index Cardiac arrhythmia Valvular disease Pulmonary circulation disorders Peripheral vascular disorders Hypertension uncomplicated Other neurological disorders COPD Diabetes uncomplicated Diabetes complicated Hypothyroidism Renal failure Liver disease Solid tumor without metastasis Rheumatoid arthritis/collagen Obesity Fluid and electrolyte disorders Alcohol abuse Drug abuse Psychoses Depression
921 (4) 289 (1) 108 (1) 428 (2)
2303 (10) 556 (2)
1186 (5) 892 (4) 269 (1) 559 (2) 222 (1) 347 (2) 908 (4) 234 (1) 495 (2)
2096 (9) 816 (4) 551 (2) 393 (2)
1179 (5)
309 (6) 82 (2) 73 (2)
131 (3) 601 (12) 263 (5)
796 (16) 275 (6) 80 (2)
194 (4) 83 (2)
150 (3) 193 (4) 96 (2)
156 (3) 629 (13) 324 (7) 225 (5) 98 (2)
365 (7)
<0.001 0.029
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.012
<0.001 <0.001 <0.001
0.82 <0.001 <0.001 <0.001 <0.001 <0.001 0.203
<0.001
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Table 2 – Risk of Heart Failure and /or Death Among Cases and Controls
N=28 048 Control
(n=23 060)
Case
(n=4 988)
Adjusted Hazard
Ratio with 95%
Confidence
interval
p-value
Primary Analysis (n, %)
Incident HF
Combined
Inpatients
Outpatients
1712 (7)
875 (11)
837 (5.6)
592 (12)
334 (18)
258 (8.2)
1.61 (1.44 to 1.81)
1.94 (1.64 to 2.29)
1.33 (1.12 to 1.57)
<0.001
<0.001
<0.001
Secondary Analyses (n, %)
Incident HF
within 90 days
Combined
Inpatients
Outpatients
145 (0.6)
80 (1)
65 (0.4)
68 (1.4)
41 (2)
27 (0.9)
1.52 (1.08 to 2.13)
1.45 (0.90 to 2.34)
1.38 (0.79 to 2.39)
<0.001
0.1
0.3
Incident HF
within 1 year
Combined
Inpatients
Outpatients
321 (1.4)
181 (2)
140 (1)
164 (3.3)
106 (6)
58 (2)
1.86 (1.5 to 2.32)
1.96 (1.46 to 2.64)
1.54 (1.08 to 2.20)
<0.001
<0.001
0.019
Incident HF or
All-cause Mortality
Combined
Inpatients
6041 (26%)
3172 (40)
2035 (41%)
1178 (65)
1.53 (1.44 to 1.63)
1.77 (1.62 to 1.93)
<0.001
<0.001
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Outpatients 2869 (19) 857 (27) 1.34 (1.23 to 1.47) <0.001
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Figure 1. Cumulative Incidence of Heart Failure
Legend
CAP Case
Control
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Figure 2. Adjusted Hazard Ratios for CAP Patients Relative to Controls Incident
HF
1.61
1.82
1.62
1.37
2.40
0.5 1.5 2.5 3.5 4.5 5.5HR:
Reduced Risk Increased Risk
Incident HF
Main Analyses
Competing Risk Analysis with Death
Inclusion of HF During Index Event
Sensitivty Analyses
Inclusion of Emergency Department HF
Events
Pneumococcal Bacteremia
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Roles: All authors contributed to the conception and design, DTE, SRM, JMS, TJM contributed to the analysis and interpretation of data. DTE, JMS drafted the article, all authors revised it critically for important intellectual content, and all authors provided final approval of the version to be published. DTE and JMS had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Role of Funding
DTE receives salary support through a Canada Research Chair Award. SRM holds an Endowed Chair in Patient Health Management supported by the Faculties of Medicine and Dentistry and Pharmacy and Pharmaceutical Sciences at the University of Alberta. Grants-in-aid from Capital Health, and unrestricted grants from Abbott Canada, Pfizer Canada, and Janssen-Ortho Canada have been issued to TJM. All authors declare that DTE, TJM, JMS, and SRM have no non-financial interests that may be relevant to the submitted work. The study sponsors played no role in study design or conduct; collection, analysis, interpretation of data; writing of the report; or in the decision to submit the paper for publication.
Exclusive License
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence (http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%202013.doc) to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution and convert or allow conversion into any format including without limitation audio, iii) create any other derivative work(s) based in whole or part on the on the Contribution, iv) to exploit all subsidiary rights to exploit all subsidiary rights that currently exist or as may exist in the future in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above. All research articles will be made available on an Open Access basis (with authors being asked to pay an open access fee—see http://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/copyright-open-access-and-permission-reuse). The terms of such Open Access shall be governed by a Creative Commons licence—details as to which Creative Commons licence will apply to the research article are set out in our worldwide licence referred to above.
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29. Van Eeden S, Leipsic J, Paul Man SF, et al. The relationship between lung inflammation and cardiovascular disease. Am J Respir Crit Care Med 2012;186(1):11-6. doi: 10.1164/rccm.201203-0455PP
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