Confidential: For Review Only - BMJ · 2019. 7. 31. · Confidential: For Review Only Experience...
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Confidential: For Review OnlyHospital volume and outcomes for acute pulmonary
embolism: analysis from the RIETE registry
Journal: BMJ
Manuscript ID BMJ-2019-049002
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the Author: 26-Jan-2019
Complete List of Authors: Jimenez, David; Ramon y Cajal Hospital and Alcal� de Henares University, Respiratory Department and Medicine Department, IRYCISBikdeli, Behnood; Yale University School of Medicine, Section of Cardiovascular MedicineQuezada, Andres; Hospital Universitario Ramon y CajalMuriel, Alfonso; Ramon y Cajal Hospital, IRYCIS and Alcala de Henares University, Biostatistics Unit; Hospital Universitario Ramon Y Cajal, Unidad de Bioestadistica ClinicaLobo, Jose Luis; Hospital Universitario ArabaDe Miguel, Javier; Hospital General Universitario Gregorio MaranonJara-Palomares, Luis; Medical Surgical Unit of Respiratory Diseases, Hospital Virgen del Rocío, CIBERES, Ruiz-Artacho, Pedro; Clinica Universitaria de NavarraYusen, Roger; Washington University School of Medicine, Monreal, Manuel; Hospital Universitari Germans Trias i Pujol, Internal Medicine
Keywords: Pulmonary embolism, Survival, Experience, Hospital volume
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Hospital volume and outcomes for acute pulmonary embolism: analysis from the RIETE registry
Authors:
David Jiménez, 0000-0002-4571-7721, MD, PhD1, 2*, Behnood Bikdeli, MD,
MS3, 4, 5*, Andrés Quezada, MD1, Alfonso Muriel, PhD6, José Luis Lobo, MD7,
Javier de Miguel, MD, PhD8, Luis Jara-Palomares, MD, PhD9, Pedro Ruiz-
Artacho, MD, PhD10, Roger D. Yusen, MD11, Manuel Monreal, MD, PhD12, for
the RIETE investigators
Affiliation:1 Respiratory Department, Hospital Ramón y Cajal and Instituto Ramón y Cajal de Investigación
Sanitaria IRYCIS, Madrid, Spain2 Medicine Department, Universidad de Alcalá, Madrid, Spain3 Division of Cardiology, Department of Medicine, Columbia University Medical Center, New
York-Presbyterian Hospital. New York, USA.4 Center for Outcomes Research and Evaluation (CORE), Yale University School of Medicine.
New Haven, USA.5 Cardiovascular Research Foundation, New York, USA.6 Biostatistics Department, Ramón y Cajal Hospital and Instituto Ramón y Cajal de Investigación
Sanitaria IRYCIS, CIBERESP, Madrid, Spain.7 Respiratory Department, Hospital Araba, Vitoria, Spain8 Respiratory Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain9 Respiratory Department, Virgen del Rocío Hospital and Instituto de Biomedicina, Sevilla;
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain10 Department of Internal Medicine, Clinica Universidad de Navarra, Madrid, Spain11 Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences,
Washington University School of Medicine, St. Louis, Missouri, USA12 Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona,
Barcelona; Universidad Católica de Murcia, Murcia, Spain
*Both authors contributed equally to the manuscript.
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Correspondence:David Jiménez
Respiratory Department and Medicine Department
Ramón y Cajal Hospital, IRYCIS and Alcalá de Henares University
28034 Madrid, Spain
Phone: +34913368314
e-mail: [email protected]
Running head: Experience and PE
Tables: 4Figures: 2Word count: 2,628
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our worldwide licence referred to above.
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ABSTRACT
Background: Patients with acute symptomatic pulmonary embolism (PE) may
be treated by physicians and institutions with varying levels of experience.
Whether the level of experience affects the PE outcomes remains uncertain.
Methods: We analyzed the data from the Registro Informatizado de la
Enfermedad TromboEmbólica (RIETE) registry between January 1, 2001, and
August 31, 2018. To evaluate the association between annual PE volume and
PE-related mortality, we performed hierarchical multivariable analyses adjusting
for the severity of illness and other differences in the case mix.
Results: The study included 39,720 PE patients from 353 hospitals around the
world. Patients with acute symptomatic PE admitted to high-volume hospitals
(i.e., >40 PEs per year) had a higher burden of comorbidities. Admission to a
hospital in the highest quartile was associated with a 44% reduction in the
adjusted odds of 30-day PE-related mortality compared with admission to
hospitals in the lowest quartile (i.e., <15 PEs per year) (1.3% versus 2.3%;
adjusted odds ratio [OR], 0.56; 95% confidence interval [CI], 0.33 to 0.95; P =
0.03). Results were consistent in all sensitivity analyses. Thirty-day all-cause
mortality was not significantly reduced (adjusted OR, 0.78; 95% CI, 0.50 to
1.22; P = 0.28). Among survivors, there was little change in the odds of
recurrent venous thromboembolism or major bleeding between the low- and
high-volume hospitals.
Conclusions: In patients with acute symptomatic PE, admission to high-volume
hospitals was associated with significant reductions in adjusted 30-day PE-
related mortality. These findings may have implications for management
strategies.
Abstract word count: 246
Key Words: Pulmonary embolism, survival, experience, hospital volume.
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INTRODUCTIONPulmonary embolism (PE) remains a worldwide major health issue (1). PE is
among the most common causes of vascular death after myocardial infarction
and stroke, and is the leading preventable cause of death in hospitalized
patients (2).
The number of patients treated in a hospital is a well-established determinant of
outcomes after different medical and surgical conditions (3-5). For acute
symptomatic PE, however, the contribution of experience to survival is less well
understood (6). Treatment of PE is complex and requires considerable clinical
skills. Patients with PE can present with a wide variety of clinical manifestations
and may develop a number of complications that require timely recognition and
treatment. The optimal treatment for PE patients has markedly evolved over the
past (7-10). Thus, there is a clinical priority to determine whether patients
admitted to hospitals that only occasionally treat PE patients have similar
outcomes to those admitted to hospitals that treat PE patients more frequently.
The Registro Informatizado de la Enfermedad TromboEmbólica (RIETE)
Registry is an ongoing, multicenter, international, prospective registry of
consecutive patients with symptomatic, objectively confirmed, acute venous
thromboembolism (VTE) (11-13). We hypothesized that experience in the
management of acute PE, reflected by hospital case volume, would be
significantly associated with a reduction in 30-day PE-related mortality, after
adjustment of the differences in the patient case mix and hospital status
(university-based or not).
METHODSStudy designFor this study, we used the data from the RIETE registry, which prospectively
collects information on patients with confirmed acute VTE (ClinicalTrials.gov
identifier, NCT02832245). Previous publications have described the design and
conduct of the RIETE registry (14,15). Briefly, at each participating RIETE site,
investigators enrolled consecutive patients with acute VTE. To ensure the
reliability of coding and data entry, trained monitors periodically visited each
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participating hospital and compared the information in a random sample of
hospital charts with the information entered into the RIETE database. RIETE
also uses electronic data monitoring to prevent inconsistent or implausible
values. In fact, previous studies have shown that data from RIETE closely
represents that of multicenter administrative data, further supporting the
representativeness and the validity of the data elements (16).
Patient selectionConfirmatory testing for PE consisted of high probability ventilation-perfusion
(V/Q) scintigraphy (17), positive contrast-enhanced, PE-protocol, helical chest
computerized tomography (CT) [single or multi-detector CT] for PE (18), or
lower limb venous compression ultrasonography positive for proximal deep vein
thrombosis (DVT) in a patient presenting with chest symptoms (19). This study
included patients who were enrolled in RIETE and had a diagnosis of acute
symptomatic PE from January 1, 2001, through August 31, 2018.
Hospital volumeThe exposure variable was the annualized hospital volume, defined as the
mean number of patients with PE per year attended in each hospital during its
participation in the RIETE registry. Accurate case ascertainment is essential for
clinical registries to be valid and representative. We assessed case
ascertainment in the RIETE Registry by linking 16 random Spanish registry
hospitals (four per hospital volume quartile) to the Spanish National Patient
Registry during 2017 (see the Methods section in the Supplementary
Appendix). We examined the association between hospital volume and
outcome after categorizing volume into quartiles, in which the reference
category is the lowest-volume quartile (i.e., <15 patients per year), and with
volume as a continuous variable.
Study outcomesThe primary outcome was 30-day PE-related mortality. The secondary
outcome was 30-day all-cause mortality. We also examined the rates of PE-
related and all-cause mortality within 7 days following the diagnosis of PE. The
RIETE investigators used medical record review to assess vital status. For
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patients who died, further medical record review, and proxy interviews when
necessary, assisted with determination of the date and cause of death. For
deaths confirmed by autopsy or those following a clinically severe PE, either
initially or shortly after an objectively confirmed recurrent event, in the absence
of any alternative diagnosis, the investigators were instructed to judge death as
due to fatal PE. In addition, we examined the rates of nonfatal VTE
recurrences, and nonfatal bleeding events within 30 days following the
diagnosis of PE (see the Methods section in the Supplementary Appendix).
Statistical analysisWe first conducted bivariable analysis comparing the demographic and clinical
characteristics of patients across the quartiles of hospital volume with analysis
of variance for continuous variables and the chi-square test for categorical
variables. We reported the utilization of reperfusion PE therapies, and
appropriate treatment in patients hospitalized to each quartile of hospitals.
To assess the relationship between hospital volume and the outcomes of
interest, we constructed hierarchical multivariable logistic regression models for
the overall cohort. We addressed potential confounding due to the variation in
the case mix by controlling for the severity of illness and additional variables
related to the outcome of patients with acute PE. The following models were
generated sequentially to determine the successive influence of potential
confounders on the relationship between hospital volume and mortality: (1)
unadjusted; (2) adjusted only for age and sex; (3) adjusted for age, sex, and
the following covariates: coexisting conditions (i.e., cancer, immobilization,
chronic lung disease, chronic heart disease), severity of PE (i.e., heart rate,
systolic blood pressure), and laboratory results (i.e., creatinine levels,
hemoglobin levels) at hospital admission; (4) adjusted for age, sex, cancer,
immobilization, chronic lung disease, chronic heart disease, heart rate, systolic
blood pressure, simplified Pulmonary Embolism Severity Index (sPESI) (20),
creatinine levels, and hemoglobin levels (predefined main analysis); and 5)
adjusted for age, sex, cancer, immobilization, chronic lung disease, chronic
heart disease, heart rate, systolic blood pressure, sPESI, creatinine levels,
hemoglobin levels, and hospital status (university-based or not). All these
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models were built at the patient level, with hospital volume as a 4-category
predictor variable. In all models we accounted for clustering of patients within
hospitals and hospitals clustered within countries.
We assessed the sensitivity of our findings by repeating the primary analysis
under varying assumptions about the study population in a sensitivity analysis
for PE-related mortality. Sensitivity analyses comprised the exclusion of outlier
hospitals (those with too few or too many patients), exclusion of patients
younger than 50 years old, exclusion hemodynamically unstable patients, and
exclusion of patients who received reperfusion therapies. Additional analyses
included a falsification-hypothesis analysis in which the cohort was evaluated
for 90-day cancer-, chronic heart disease-, and infection-related mortality. We
also performed alternative event-rate estimation with the use of inverse
probability weighted regression adjustment (see the Supplementary Appendix).
All analyses were conducted using STATA version 13.1 (STATA Corp, College
Station, Texas). All hypothesis tests were two-sided, with a significance level of
0.05.
RESULTSThe study included 39,257 adults with acute PE from 353 participating hospitals
(Figure 1). The linked data showed that the registry captured approximately
84% of the patients with a final diagnosis of PE from each hospital, with little
variation according to hospital volume (Table S1 in the Supplemental
Appendix). Annualized hospital volume ranged from 1 to 112 hospitalized PE
patients per year (median: 7; interquartile range: 4 to 16).
Patients admitted to higher-volume hospitals and those admitted to lower-
volume hospitals differed significantly in preexisting medical conditions, and
relevant clinical, physiologic and laboratory parameters. Patients admitted to
higher-volume hospitals were older, had more comorbid diseases (cancer,
chronic lung disease, congestive heart failure, and recent bleeding), and signs
of clinical severity (high-risk according to the sPESI, tachycardia, hypoxemia
and hypotension), compared with those admitted to lower-volume hospitals
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(Table 1). Regarding in-hospital reperfusion treatments, patients at low-volume
centers were more likely to receive reperfusion therapies (mostly systemic
thrombolysis) (3.9% vs. 3.0%, P <0.001), and less likely to receive an inferior
vena cava (IVC) filter (2.7% vs. 3.3%, P =0.006). Compared to those admitted
to high-volume hospitals, patients at low-volume centers were more likely to
receive management that did not adhere to clinical practice guidelines (17.6%
vs. 14.2%, P <0.001) (Table S2 in the Supplemental Appendix).
The entire cohort had a 30-day all-cause mortality of 5.4% (2,139 of 39,257
patients), and a 30-day PE-related mortality rate of 1.7% (668 of 39,257
patients) (Table 2). As compared with patients in the lowest quartile (quartile 1)
of hospital volume, patients in quartiles 2, 3, and 4 had a reduction in the
adjusted odds of 30-day PE-related death of 34% (P = 0.06), 39% (P = 0.048),
and 44% (P = 0.03), respectively (Table 3 and Table S3). The adjusted risk of
30-day PE-related death was 2.3% for patients in the lowest volume quartile
and 1.3% for patients in the highest volume quartile. In a sensitivity analysis
where hospital volume was kept as a completely continuous variable (between
1-112), there was a consistent gradient for significant reduction in the adjusted
odds of 30-day PE-related mortality rates (P =0.04 for linear trend; Figure 2).
Adjusted 30-day all-cause mortality was 5.2% for patients admitted to hospitals
in the highest quartile and 6.4% for patients admitted to hospitals in the lowest
quartile (odds ratio, 0.78; 95% confidence interval [CI], 0.50 to 1.22; P = 0.28).
Similar findings were observed for 7-day PE- and all-cause mortality. The
adjusted risk of 7-day PE-related death was 1.7% for patients in the lowest
quartile of hospital volume and 1.0% for patients in the highest quartile of
hospital volume, while the adjusted risk of 7-day all-cause mortality was 2.7%
for patients in the lowest volume quartile and 2.1% for patients in the highest
volume quartile.
Among survivors, there was no clear association between hospital volume and
nonfatal recurrence or major bleeding. As compared with the lowest quartile of
hospital volume, higher volume was not associated with a significant reduction
in nonfatal recurrent VTE in quartiles 2, 3, and 4 (odds ratio, 0.82 [0.54-1.23],
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0.74 [0.48-1.14], and 0.76 [0.49-1.19], respectively). There was no significant
difference in the incidence of nonfatal major bleeding events among hospital
volume quartiles (Table 3).
To explore the sensitivity of our findings, we repeated the analysis with varying
assumptions about the patient population and hospitals (Table 4). Our results
were not affected by the exclusion of younger patients (i.e., age less than 50
years), hemodynamically unstable patients (i.e. SBP less than 90 mmHg),
patients who received reperfusion therapies, or exclusion of the outlier
hospitals.
We performed a falsification-hypothesis analysis using the outcome of 90-day
cancer-, chronic heart disease-, and infection-related mortality. As compared
with patients in the lowest quartile (quartile 1) of hospital volume, patients in
quartiles 2, 3, and 4 did not have a significant reduction in the adjusted odds of
90-day cancer- (OR, 1.52 [1.06-2.19], 1.57 [1.05-2.33], and 1.52 [1.00-2.31],
respectively), chronic heart disease- (OR, 1.25 [0.65-2.40], 1.05 [0.52-2.09],
and 0.86 [0.42-1.73], respectively), and infection-related mortality (OR, 1.06
[0.61-1.82], 0.86 [0.48-1.55], and 1.34 [0.74-2.44], respectively) (Table S4 in
the Supplementary Appendix). The propensity score analysis confirmed
reduced PE-related mortality for patients admitted to high-volume hospitals,
thereby supporting the primary results (Table S5 in the Supplementary
Appendix).
DISCUSSIONThese data demonstrate an association between an increase in hospital PE
volume and a lower risk-adjusted 30-day PE-related mortality. There was a
consistent dose-response relationship between hospital volume and PE-related
mortality. The results were consistent with use of various adjustment
techniques, across major subgroups of the patient populations and modeling
assumptions, and were less likely to be driven by unmeasured confounding,
represented by the lack of association between hospital PE volume and the
falsification endpoints.
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There are several potential causes of a relationship between hospital PE
volume and outcome among patients with acute PE. High-volume hospitals may
improve outcomes by implementing a broad range of best practices, including
multidisciplinary Pulmonary Embolism Response Teams (PERTs), appropriate
triage of the level of care, and evaluation and delivery of reperfusion therapies
for severe PE (21). Clinicians at high-volume hospitals may also gain
experience in the care of the PE patients, which could translate into improved
rates of survival. More experienced as opposed to less experienced clinicians
may be better at recognizing and treating the complications of PE or may be
better at translating evidence into practice. In addition, our study showed that
clinicians at high-volume hospitals more frequently adhered to evidence-based
guidelines, which has been shown to improve patient outcomes (22).
Few studies have addressed whether hospitals that care for large numbers of
patients with PE have lower short-term mortality than those caring for low
numbers of such patients (6). In a study of 10,354 PE hospitalizations based on
administrative data from 186 Pennsylvania hospitals, Aujesky et al. found that
the hospitals with higher annual volumes (>42 patients per year) of PE cases
had significantly lower in-hospital and 30-day all-cause mortality than the very-
low volume (<10 patients per year) hospitals. Our study’s large sample size, the
availability of rich clinical data that allowed for adjustment for potential
confounders, the availability of cause specific mortality, availability of
falsification endpoints, and the robustness of the findings across multiple
sensitivity analyses provide evidence supporting the concept that patients with
acute symptomatic PE admitted to high-volume hospitals are more likely to
survive than patients admitted to low-volume hospitals.
Our findings have implications on how best to manage patients with acute
symptomatic PE in the future. From the standpoint of health policy, the
existence of an effect of volume is as important as its mechanism, suggesting
field triage, with patients with high suspicion or confirmation of acute severe PE
transported preferentially to high-volume centers with a PERT program
designated for the diagnosis and treatment of these patients. Although the
benefits and effectiveness of PERTs in regard to patient outcomes, quality of
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life, and cost need to be further investigated (23-25), our study’s results support
the implementation of experienced PERTs to improve care of patients with
acute PE. Alternatively, educational strategies could be developed toward
improving the knowledge and clinical expertise of low-volume physicians. This
is particularly important since we observed evidence of both overtreatment and
under-treatment with reperfusion PE therapies in low-volume hospitals (Table S2). For example, use of standardized care maps and admission orders might
improve compliance with recommended treatment protocols among low-volume
hospitals.
Several potential limitations of our study merit consideration. First, despite our
best efforts, the possibility of residual confounding still remains. Nevertheless,
we did adjust for age, sex, comorbidities, severity of PE, and laboratory results,
and we still found a consistent hospital volume-outcome relationship.
Furthermore, the results of sensitivity analyses and falsification-hypothesis
analyses provided evidence of the robustness of the findings. Second, similar to
most studies related to an association between volume and outcomes, our
analysis cannot determine the direction of the association (i.e. causality) (26).
Although high-volume hospitals had better adherence to guideline
recommendations in our study, their good quality of care might have been a
driver in attracting more PE patients, thereby increasing their volume. Additional
qualitative, and mixed-methods research is needed to deeply understand the
reasons for better outcomes in high-volume centers, and the major areas for
improvement in low-volume centers. Finally, since our study cohort was
probably composed of hospitals that were enthusiastic about evidence-based
management of PE, reductions in mortality associated with increases in the
annual volume of cases treated could be more pronounced compared with other
hospitals where vested team of motivated physicians for PE management do
not exist. However, the RIETE registry is the only large-scale, multinational,
observational study of the spectrum of patients diagnosed with a PE, with
continuous recruitment of patients for more than 10 years, and offers a unique
opportunity to look at a large number of patients in various treatment settings,
countries, and continents over a long period of time.
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In conclusion, our results suggest that clinician experience or specific processes
of care common to high-volume centers may be associated with better
outcomes among patients with acute symptomatic PE. Additional research is
needed to determine these care processes and to assess the ability to export
them to low-volume centers, as well as to investigate the feasibility of
regionalizing care through PERTs for select high-risk patients.
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venous thromboembolism is different in surgical and acutely ill medical
patients. Findings from the RIETE registry. J Thromb Haemost 2004; 2:
1892-1898.
14.Riera-Mestre, Jiménez D, Muriel A, et al. Thrombolytic therapy and outcome
of patients with an acute symptomatic pulmonary embolism. J Thromb
Haemost 2012; 10: 751-759.
15.Bikdeli B, Jimenez D, Hawkins M, et al. Rationale, design and methodology
of the computerized registry of patients with venous thromboembolism
(RIETE). Thromb Haemost 2018; 118: 214-224.
16.Guijarro R, de Miguel-Diez L, Jimenez D, et al. Venous thromboembolism in
Spain. Comparison between an administrative database and the RIETE
registry. Eur J Intern Med 2008; 19: 443-446.
17.Remy-Jardin M, Remy J, Wattinne L, Giraud F. Central pulmonary
thromboembolism: diagnosis with spiral volumetric CT with the single-
breath-hold-technique-comparison with pulmonary angiography. Radiology
1992; 185: 381-387.
18.PIOPED investigators. Value of ventilation/perfusion scan in acute
pulmonary embolism: results of the prospective investigation of the
pulmonary embolism diagnosis (PIOPED). JAMA 1990; 263: 2753-2759.
19.Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonography in the
diagnosis of suspected deep venous thrombosis and pulmonary embolism.
Ann Intern Med 1998; 129: 1044-1049.
20.Jiménez D, Aujesky D, Moores L, et al; RIETE Investigators. Simplification
of the pulmonary embolism severity index for prognostication in patients with
acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170: 1383-
1389.
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21.Rosovsky R, Chang Y, Rosenfield K, et al. Pulmonary Embolism Response
Team. Changes in treatment and outcomes after creation of a pulmonary
embolism response team (PERT), a 10-year analysis. J Thromb
Thrombolysis. 2018 Sep 21. doi: 10.1007/s11239-018-1737-8.
22.Jiménez D, Bikdeli B, Barrios D, et al; RIETE investigators. Management
appropriateness and outcomes of patients with acute pulmonary embolism.
Eur Respir J 2018 May 10;51(5). pii: 1800445. doi:
10.1183/13993003.00445-2018.
23.Kabrhel C, Rosovsky R, Channick R, et al. A multidisciplinary pulmonary
embolism response team: initial 30-month experience with a novel approach
to delivery of care to patients with submassive and massive pulmonary
embolism. Chest 2016; 150: 384-393.
24.Carroll BJ, Pemberton H, Bauer KA, et al. Initiation of a multidisciplinary,
rapid response team to massive and submassive pulmonary embolism. Am
J Cardiol 2017; 120: 1393-1398.
25.Serhal M, Haddadin IS, Heresi GA, et al. Pulmonary embolism response
teams. J Thromb Thrombolysis 2017; 44: 19-29.
26.Luft HS, Hunt SS, Maerki SC. The volume-outcome relationship: practice-
makes perfect or selective-referral patterns? Health Serv Res 1987; 22: 157-
182.
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AcknowledgementsWe express our gratitude to Sanofi Spain for supporting this Registry with an
unrestricted educational grant. We also express our gratitude to Bayer Pharma
AG for supporting this Registry. Bayer Pharma AG’s support was limited to the
part of RIETE outside Spain, which accounts for a 25.29% of the total patients
included in the RIETE Registry. We also thank the RIETE Registry Coordinating
Center, S&H Medical Science Service, for their quality control data, logistic and
administrative support.
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Declaration of interestsD.J. has served as an advisor or consultant for Bayer HealthCare
Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo,
Leo Pharma, Pfizer, ROVI and Sanofi; served as a speaker or a member of a
speakers’ bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim,
Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, ROVI and Sanofi; received
grants for clinical research from Sanofi and ROVI.
B.B. was supported by the National Heart, Lung, and Blood Institute, National
Institutes of Health, through grant number T32 HL007854. The content is solely
the responsibility of the authors and does not necessarily represent the official
views of the NIH. Dr. Bikdeli reports that he serves as a consulting expert (on
behalf of the plaintiff) for a litigation related to inferior vena caval filters.
A.Q. has nothing to disclose.
A.M. has nothing to disclose.
J.L.L. has nothing to disclose.
J. M. has nothing to disclose.
L.J-P. has served as an advisor or consultant for Actelion Pharmaceuticals,
Bayer HealthCare Pharmaceuticals, Leo Pharma, Menarini, Pfizer, and ROVI.
P.R-A. has served as an advisor or consultant for Leo Pharma and Pfizer;
served as a speaker or a member of a speakers’ bureau for Bayer HealthCare
Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi
Sankyo, Leo Pharma, ROVI and Sanofi.
R.Y. has received research funding from Bayer HealthCare Pharmaceuticals,
Inc., Portola, Inc., Pfizer, Inc. and Bristol-Meyers Squibb in the past 3 years. He
has served as a consultant for Bayer HealthCare, Inc., Bristol-Meyers Squibb
Glaxo-Smithkline, Janssen, Johnson & Johnson, Ortho Pharmaceuticals, Inc.,
Organon, Inc., Pfizer, Inc., Portola, Inc., Sanofi-Aventis, SCIOS, Inc. in the past
3 years.
M.M. has served as an advisor or consultant for Bayer HealthCare
Pharmaceuticals, Daiichi Sankyo, Leo Pharma, and Sanofi; served as a
speaker or a member of a speakers’ bureau for Bayer HealthCare
Pharmaceuticals, Daiichi Sankyo, Leo Pharma and Sanofi; received grants for
clinical research from Sanofi and Bayer.
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Author contributionsStudy concept and design: Jimenez, Bikdeli, Quezada, Monreal
Acquisition of data; analysis and interpretation of data; statistical analysis:
Jimenez, Bikdeli, Quezada, Muriel, Lobo, de Miguel, Jara-Palomares, Ruiz-
Artacho, Yusen, Monreal
Drafting of the manuscript: Jimenez, Bikdeli, Quezada, Yusen, Monreal
Critical revision of the manuscript for important intellectual content: Jimenez,
Bikdeli, Quezada, Muriel, Lobo, de Miguel, Jara-Palomares, Ruiz-Artacho,
Yusen, Monreal
Study supervision: Jimenez, Monreal
The corresponding author, David Jiménez, had full access to all the data in the
study and had final responsibility for the decision to submit for publication.
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Figure 1. STROBE study cohort flow diagram
Figure 2. Relationship between hospital volume and PE-related mortality
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Table 1. Baseline characteristics in patients with acute pulmonary embolism by hospital volume
Characteristic Quartile 1(<15
patients/yr)
Quartile 2(15-25
patients/yr)
Quartile 3(>25-40
patients/yr)
Quartile 4(>40
patients/yr)
P value for trend
Hospitals
No. of hospitals 253 52 28 20
No. of beds (mean + SD) 520 (428) 605 (361) 831 (516) 861 (342)
No. (%) of teaching hospitals 88 (35) 16 (31) 18 (64) 13 (65)
Patients
No. (%) of patients 8,596 8,130 9,750 12,781
Age, years (mean + SD) 65.6 (17.6) 67.2 (16.9) 68.0 (16.4) 67.7 (16.7) <0.001
Age > 80 years, n (%) 2,024 (23.5) 2,160 (26.6) 2,670 (27.4) 3,440 (26.9) <0.001
Male gender, n (%) 4,050 (47.1) 3,756 (46.2) 4,593 (47.1) 5,968 (46.7) 0.58
Weight, kilograms (mean + SD) 76.5 (16.0) 75.9 (16.3) 76.8 (16.2) 75.4 (16.4) <0.001
History of VTE, n (%) 5,069 (61.9) 5,339 (67.8) 6,488 (68.4) 8,931 (71.1) <0.001
Cancer, n (%) † 1,751 (20.4) 1,861 (22.9) 1,875 (19.2) 3,287 (25.7) <0.001
Recent surgery, n (%) ‡ 1,010 (11.7) 898 (11.0) 1,186 (12.2) 1,504 (11.8) 0.14
Immobilization for > 4 days, n (%) § 2,038 (23.7) 1,894 (23.3) 2,040 (20.9) 2,852 (22.3) <0.001
Chronic lung disease, n (%) 1,162 (13.5) 1,142 (14.0) 1,340 (13.7) 1,918 (15.0) 0.008
Chronic heart disease, n (%) 705 (8.2) 718 (8.8) 808 (8.3) 1,293 (10.1) <0.001
Recent major bleeding, n (%) 209 (2.4) 196 (2.4) 188 (1.9) 349 (2.7) 0.002
Pulse, beats (mean + SD) 93.0 (19.7) 91.9 (20.0) 91.8 (20.0) 93.5 (20.2) <0.001
Pulse > 110 beats/min, n (%) 1,744 (21.4) 1,492 (19.5) 1,903 (19.7) 2,819 (22.3) <0.001
Systolic blood pressure, mmHg
(mean + SD)
128.3 (23.7) 130.6 (23.1) 130.3 (24.3) 128.6 (24.5) <0.001
Systolic blood pressure < 100 mm
Hg, n (%)
651 (7.6) 537 (6.6) 724 (7.4) 1,217 (9.5) <0.001
Arterial oxyhemoglobin saturation
(SaO2) < 90%, n (%)
1,971 (38.5) 1,639 (33.9) 1,947 (32.3) 3,015 (38.4) <0.001
sPESI (20)
Low-risk, n (%) 2,755 (32.0) 2,502 (30.8) 3,193 (32.7) 3,586 (28.1) -
High-risk, n (%) 5,841 (68.0) 5,628 (69.2) 6,557 (67.3) 9,195 (71.9) <0.001
Abnormal creatinine levels
(> 2 mg/dL)
1,505 (18.2) 1,542 (20.1) 1,971 (20.6) 2,381 (18.9) <0.001
Hemoglobin, g/dL (mean + SD) 13.0 (2.1) 13.0 (2.1) 13.1 (2.0) 13.0 (2.0) <0.001
Inappropriate management ¶ 1,512 (17.6) 1,251 (15.4) 1,453 (14.9) 1,821 (14.2) <0.001
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Reperfusion therapies, n (%) 334 (3.9) 206 (2.5) 326 (3.3) 383 (3.0) <0.001
IVC filter insertion, n (%) 230 (2.7) 224 (2.8) 255 (2.6) 423 (3.3) 0.006
Abbreviations: SD, standard deviation; VTE, venous thromboembolism; sPESI, simplified Pulmonary
Embolism Severity Index; IVC, inferior vena cava.
† Active or under treatment in the last year.
‡ In the previous month.
§ Immobilized patients defined as non-surgical patients who had been immobilized (i.e., total bed rest with
bathroom privileges) for ≥4 days in the month prior to PE diagnosis.
¶ Definition of inappropriate management is provided in the Supplemental Appendix.
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Table 2. Observed rates of mortality and nonfatal outcomes by volume
Overall-no./total no. (%) Quartile 1(<15 patients/yr)
Quartile 2(15-25 patients/yr)
Quartile 3(>25-40 patients/yr)
Quartile 4(>40 patients/yr)
Mortality
30-day PE-related mortality 201/8,596
(2.3)
125/8,130
(1.5)
148/9,750
(1.5)
194/12,781
(1.5)
30-day all-cause mortality 525/8,596
(6.1)
433/8,130
(5.3)
459/9,750
(4.7)
722/12,781
(5.6)
7-day PE-related mortality 153/8,596
(1.8)
91/8,130
(1.1)
110/9,750
(1.1)
154/12,781
(1.2)
7-day all-cause mortality 236/8,596
(2.7)
169/8,130
(2.1)
191/9,750
(2.0)
291/12,781
(2.3)
Nonfatal complications
30-day VTE recurrences 94/8,596
(1.1)
69/8,130
(0.8)
75/9,750
(0.8)
125/12,781
(1.0)
30-day major bleeding 299/8,596
(3.5)
270/8,130
(3.3)
352/9,750
(3.6)
496/12,781
(3.9)
Abbreviations: PE, pulmonary embolism; VTE, venous thromboembolism.
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Table 3. Adjusted rates of mortality and nonfatal outcomes by volume*
Variable Quartile 1(<15 patients/yr)
Quartile 2(15-25 patients/yr)
Quartile 3(>25-40 patients/yr)
Quartile 4(>40 patients/yr)
Odds ratio (95% CI) †
30-day PE-related mortality 1.0 0.66 (0.43-1.01) 0.61 (0.38-0.99) 0.56 (0.33-0.95)
30-day all-cause mortality 1.0 0.68 (0.48-0.97) 0.73 (0.19-1.10) 0.78 (0.50-1.22)
7-day PE-related mortality 1.0 0.65 (0.41-1.02) 0.68 (0.42-1.11) 0.60 (0.35-1.03)
7-day all-cause mortality 1.0 0.72 (0.48-1.07) 0.72 (0.46-1.12) 0.76 (0.47-1.24)
30-day nonfatal VTE recurrences 1.0 0.82 (0.54-1.23) 0.74 (0.48-1.14) 0.76 (0.49-1.19)
30-day nonfatal major bleeding 1.0 0.92 (0.70-1.20) 0.90 (0.66-1.22) 1.07 (0.77-1.47)
Adjusted percent (95% CI) ‡
30-day PE-related mortality 2.3 (1.8-2.8) 1.5 (1.0-2.1) 1.4 (0.9-2.0) 1.3 (0.7-1.9)
30-day all-cause mortality 6.4 (5.4-7.3) 4.7 (3.5-5.8) 4.9 (3.5-6.4) 5.2 (3.4-7.0)
7-day PE-related mortality 1.7 (1.3-2.1) 1.1 (0.7-1.5) 1.2 (0.7-1.6) 1.0 (0.6-1.5)
7-day all-cause mortality 2.7 (2.1-3.2) 2.0 (1.4-2.6) 2.0 (1.3-2.7) 2.1 (1.3-2.9)
30-day nonfatal VTE recurrences 1.1 (0.8-1.4) 0.9 (0.5-1.1) 0.8 (0.5-1.1) 0.8 (0.5-1.2)
30-day nonfatal major bleeding 3.6 (3.1-4.2) 3.2 (2.5-3.9) 3.8 (2.9-4.7) 3.9 (2.8-4.9)
Abbreviations: CI, confidence interval; PE, pulmonary embolism; VTE, venous thromboembolism.
* Adjusted for age, sex, cancer, immobilization, chronic lung disease, chronic heart disease, heart rate, systolic blood pressure, sPESI, creatinine
levels, and hemoglobin levels at hospital admission. Confidence intervals (CI) and P values take into account clustering according to center.
† Event rates were compared across quartiles of patient volume according to adjusted odds ratios (with 95 percent confidence intervals); the lowest
quartile of hospital volume served as the reference group.
‡ Adjusted percents were determined with the main model evaluating hospital volume categorized into quartiles.
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Table 4. Sensitivity analysis for PE-related mortality rates*
Model No. of patients No. of hospitals Odds ratio (95% CI)
Main model 39,270 353 0.56 (0.33-0.95)
Excluding outlier hospitals† 33,142 231 0.53 (0.28-0.97)
Excluding hospitals with an annualized volume less
than 5 patients per year
36,585 256 0.57 (0.33-0.98)
Excluding hospitals with an annualized volume more
than 80 patients per year
34,295 344 0.50 (0.28-0.91)
Excluding younger patients‡ 30,770 345 0.51 (0.30-0.87)
Excluding unstable patients§ 35,916 348 0.59 (0.35-1.03)
Excluding patients who received reperfusion
therapies¶
35,962 345 0.53 (0.30-0.91)
* Odds ratios and 95 percent confidence intervals (CIs) are presented comparing the highest quartile of hospital volume
(>40 patients per year) with the lowest quartile of hospital volume (<15 patients per year). Models were adjusted for
age, sex, cancer, immobilization, chronic lung disease, chronic heart disease, heart rate, systolic blood pressure,
sPESI, creatinine levels, and hemoglobin levels at hospital admission. Confidence intervals take into account clustering
according to center.
† Hospitals that were outliers in terms of volume were excluded because their annualized volume was less than 5 or
greater than 80 patients per year.
‡ Age less than 50 years old.
§ Systolic blood pressure less than 90 mmHg
¶ Systemic thrombolysis, catheter-directed therapy, or surgical embolectomy.
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Figure 1.
Abbreviations: VTE, venous thromboembolism; RIETE, Registro Informatizado de la
Enfermedad TromboEmbólica; PE, pulmonary embolism; DVT, deep vein thrombosis.
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Figure 2.
Hospital volume is defined as the number of patients admitted per year. The adjusted odds of death are
presented relative to the lowest-volume institution.
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Confidential: For Review OnlySupplementary Appendix
Hospital volume and outcomes for acute pulmonary embolism: analysis from the RIETE registry
Authors:
David Jiménez, MD, PhD1, 2*, Behnood Bikdeli, MD, MS3, 4, 5*, Andrés Quezada,
MD1, Alfonso Muriel, PhD6, José Luis Lobo, MD7, Javier de Miguel, MD, PhD8,
Luis Jara-Palomares, MD, PhD9, Pedro Ruiz-Artacho, MD, PhD10, Roger D.
Yusen, MD11, Manuel Monreal, MD, PhD12, for the RIETE investigators
Correspondence:David Jiménez
Respiratory Department and Medicine Department
Ramón y Cajal Hospital, IRYCIS and Alcalá de Henares University
28034 Madrid, Spain
Phone: +34913368314
e-mail: [email protected]
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Confidential: For Review OnlyTable of Contents
A. InvestigatorsA1. Contribution to the study
A2. Members of the RIETE registry
B. MethodsB1. Inclusion criteria for RIETE
B2. Exclusion criteria for RIETE
B3. Data collected in RIETE
B4. Ascertainment of PE cases
B5. Definition of inappropriate management
B6. Definition of recurrent VTE and major bleeding
B7. Propensity score analysis
C. ResultsTable S1. Ascertainment of PE cases
Table S2. Inappropriate management of acute PE
Table S3. Multivariable logistic regression models
Table S4. Sensitivity analyses of falsification endpoints
Table S5. Propensity score analysis
D. References
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Confidential: For Review OnlyA. Investigators:
A1. Contribution to the studyStudy concept and design: Jimenez, Bikdeli, Quezada, Monreal
Acquisition of data; analysis and interpretation of data; statistical analysis: Jimenez, Bikdeli, Quezada, Muriel, Lobo, de Miguel, Jara-Palomares,
Ruiz-Artacho, Yusen, Monreal
Drafting of the manuscript: Jimenez, Bikdeli, Quezada, Yusen, Monreal
Critical revision of the manuscript for important intellectual content: Jimenez, Bikdeli, Quezada, Muriel, Lobo, de Miguel, Jara-Palomares, Ruiz-
Artacho, Yusen, Monreal
Study supervision: Jimenez, Monreal
The corresponding author, David Jiménez, had full access to all the data in the
study and had final responsibility for the decision to submit for publication.
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Confidential: For Review OnlyA2. Members of the RIETE registryCoordinator of the RIETE Registry: Dr. Manuel Monreal (Spain)
RIETE Steering Committee Members:Dr. Paolo Prandoni (Italy)
Dr. Benjamin Brenner (Israel)
Dr. Dominique Farge-Bancel (France)
RIETE National Coordinators: Dr. Raquel Barba (Spain)
Dr. Pierpaolo Di Micco (Italy)
Dr. Laurent Bertoletti (France)
Dr. Sebastian Schellong (Germany)
Dr. Inna Tzoran (Israel)
Dr. Abilio Reis (Portugal)
Dr. Marijan Bosevski (R.Macedonia)
Dr. Henri Bounameaux (Switzerland)
Dr. Radovan Malý (Czech Republic)
Dr. Peter Verhamme (Belgium)
Dr. Joseph A. Caprini (USA)
Dr. Hanh My Bui (Vietnam)
RIETE Registry Coordinating Center: S&H Medical Science Service
Members of the RIETE Group:
SPAIN: Adarraga MD, Agud M, Aibar MA, Alcalde-Manero M, Amado C,
Arcelus JI, Ballaz A, Barba R, Barbagelata C, Barrón M, Barrón-Andrés B,
Blanco-Molina A, Camon AM, Cañas I, Carrasco C, Castro J, Cerdà P, de
Ancos C, de Miguel J, del Toro J, Demelo P, Díaz-Peromingo JA, Díaz-Simón
R, Elías-Hernández T, Falgá C, Farfán AI, Fernández-Capitán C, Fernández-
Criado MC, Fidalgo MA, Font C, Font L, Furest I, García MA, García-Bragado
F, García-Morillo M, García-Raso A, Gavín O, Gayol MC, Gil-Díaz A, Gómez V,
Gómez-Cuervo C, González-Martínez J, Grau E, Gutiérrez J, Hernández-
Blasco LM, Iglesias M, Jara-Palomares L, Jaras MJ, Jiménez D, Joya MD, Jou
I, Lalueza A, Lima J, Llamas P, Lobo JL, López-Jiménez L, López-Miguel P,
López-Núñez JJ, López-Reyes R, López-Sáez JB, Lorente MA, Lorenzo A,
Lumbierres M, Madridano O, Maestre A, Marchena PJ, Martín del Pozo M,
Martínez-García MA, Mella C, Mellado M, Monreal M, Morales MV, Nieto MA,
Nieto JA, Núñez MJ, Olivares MC, Ortega-Michel C, Otalora S, Otero R,
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Confidential: For Review OnlyPanadero-Macía M, Pedrajas JM, Pellejero G, Pérez-Ductor C, Pérez-Rus G,
Peris ML, Porras JA, Riera-Mestre A, Rivas A, Rodríguez-Cobo A, Rodríguez-
Hernández A, Rubio CM, Ruiz-Artacho P, Ruiz-Ruiz J, Ruiz-Sada P, Sahuquillo
JC, Sala-Sainz MC, Salazar V, Salgueiro G, Sampériz A, Sánchez-Cámara S,
Sánchez-Muñoz-Torrero JF, Sancho T, Soler S, Suriñach JM, Tolosa C, Torres
MI, Uresandi F, Valle R, Vela JR, Vidal G, Villares P, ARGENTINA: Gutiérrez
P, Vázquez FJ, Vilaseca A, BELGIUM: Vanassche T, Vandenbriele C,
Verhamme P, BRAZIL: Yoo HHB, CZECH REPUBLIC: Hirmerova J, Malý R, ECUADOR: Salgado E, FRANCE: Benzidia I, Bertoletti L, Bura-Riviere A,
Debourdeau P, Falvo N, Farge-Bancel D, Helfer H, Hij A, Mahé I, Moustafa F, GERMANY: Schellong S, ISRAEL: Braester A, Brenner B, Tzoran I, IRAN: Sharif-Kashani B, ITALY: Barillari G, Bilora F, Bortoluzzi C, Brandolin B,
Ciammaichella M, Dentali F, Di Micco P, Imbalzano E, Landolfi R, Maida R,
Mastroiacovo D, Mumoli N, Pace F, Pallotti G, Pesavento R, Prandoni P,
Quintavalla R, Rocci A, Siniscalchi C, Tufano A, Visonà A, Zalunardo B, LATVIA: Gibietis V, Kigitovica D, Skride A, REPUBLIC OF MACEDONIA: Bosevski M, SWITZERLAND: Bounameaux H, Mazzolai L, USA: Bikdeli B,
Caprini J, VIETNAM: Bui HM.
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Confidential: For Review OnlyB. Methods:
B1. Inclusion criteria for RIETE (1)Acute objectively confirmed DVT or acute objectively confirmed PEa, b
Availability of data for at least 54 core variables and minimum of 3-month follow-
up
Abbreviations: RIETE, Registro Informatizado Enfermedad TromboEmbolica; DVT, deep vein
thrombosis; PE, pulmonary embolism.a Not mutually exclusive (i.e. patients may have both DVT and PE but will not be double
counted).b In more recent years, those with superficial vein thrombosis, splanchnic vein thrombosis (i.e.
thrombosis involves thrombosis in the mesenteric, splenic or portal veins), retinal vein
thrombosis and cerebral vein thrombosis have been separately enrolled.
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Confidential: For Review OnlyB2. Exclusion criteria for RIETE (1)Enrolment in any treatment trial (VTE or other conditions) in a blinded fashion
Previous enrolment in the registry
Lack or withdrawal of patient consent
Abbreviations: RIETE, Registro Informatizado Enfermedad TromboEmbolica; VTE, venous
thromboembolism.
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Confidential: For Review OnlyB3. Data collected in RIETEPatients enrolled in RIETE had data collected from around the time of VTE
diagnosis that included but were not limited to: age; gender; body weight;
presence of coexisting conditions such as chronic heart or lung disease; recent
major bleeding (<30 days prior to the index VTE event); presence of risk factors
for PE including active cancer (defined as newly diagnosed cancer or cancer
undergoing treatment [i.e. surgery, chemotherapy, radiotherapy, hormonal, or
supportive therapy]), recent immobility (defined as non-surgical patients
assigned to bed rest with bathroom privileges for ≥4 days in the 2-months prior
to VTE diagnosis), surgery (defined as those who had undergone major surgery
in the 2 months prior to VTE); clinical signs and symptoms on admission,
including heart rate, systolic blood pressure and arterial oxyhemoglobin
saturation; and laboratory results at hospital admission that included
hemoglobin, platelet count and serum creatinine.
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Confidential: For Review OnlyB4. Ascertainment of PE casesWe randomly chose four Spanish hospitals per hospital volume quartile. The
completeness of case ascertainment by registry hospitals was determined by
comparing the number of symptomatic PE cases entered into the registry with
the number of symptomatic PE cases reported to the Spanish National Patient
Registry (SNPR) during 2017, thus the Spanish National Patient Registry was
regarded as the gold standard. To quantify completeness, we calculated the
percent difference between the number of cases entered in the registry relative
to the number of cases in the Spanish National Patient Registry:
Percent difference (%) = ([registry −SNPR] /SNPR) ×100.
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Confidential: For Review OnlyB5. Definition of inappropriate managementInappropriate management was defined as any of the following:
1. Use of intravenous unfractionated heparin (UFH) in a patient i) without severe
renal failure (i.e., creatinine clearance < 30 mL/min), ii) without severe obesity
(i.e., body weight > 120 kilograms), and iii) without unstable PE (defined as
cardiogenic shock, systolic blood pressure < 90 mmHg, or use of inotropic or
vasopressor support) (2); or use of low-molecular-weight heparin (LMWH) in a
patient i) with severe renal failure, ii) severe obesity, or iii) unstable PE (3).
2. Use of thrombolytic therapy in a hemodynamically stable patient who did not
deteriorate soon after diagnosis (2, 4); or no use of thrombolytic therapy in a
hemodynamically unstable patient without major contraindications owing to
bleeding risk (2, 4, 5).
3. Insertion of an inferior vena cava (IVC) filter in a patient without a
contraindication to anticoagulant therapy (2, 4, 5); or no insertion of an inferior
vena cava filter in a patient with a contraindication to anticoagulant therapy (4-
6).
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Confidential: For Review OnlyB6. Definition of recurrent VTE and major bleedingRecurrent symptomatic VTE was defined as a recurrent PE, or a new or a
recurrent distal or proximal lower extremity DVT, within 1 month after study
entry with acute PE. For the recurrent PE diagnosis, we required the presence
of a new perfusion defect involving 75% or more of a lung segment on V/Q
scintigraphy, or a new intraluminal filling defect or an extension of a previous
filling defect on PE-protocol chest CT (6). For a new or recurrent DVT, we
required the appearance of a new noncompressible vein segment, or a 4-mm or
more increase in the diameter of a thrombus on complete compression
ultrasound (7).
We defined major bleeding episodes as those that required a transfusion of at
least 2 units of blood, were retroperitoneal, spinal or intracranial, or were fatal
(8).
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Confidential: For Review OnlyB7. Propensity score analysisWe used inverse probability weighted regression adjustment (IPWRA) that was
based on propensity score to construct a weighted cohort of patients who
differed with respect to the volume of the hospital where they were managed
but were similar with respect to other measured characteristics (9, 10). To
calculate the inverse probability of weights, we estimated each patient’s
propensity to be treated in the corresponding volume hospital quartile, using a
multinomial logistic regression model that included predictor variables that had
been selected on the basis of their a priori possibility of confounding the
relationship between hospital volume and outcome (age, sex, cancer,
immobilization, chronic lung disease, chronic heart disease, heart rate, systolic
blood pressure, sPESI, creatinine levels, and hemoglobin levels). Inverse
probability weighted regression adjustment that was based on the propensity
score was then used as the primary tool to adjust for differences between the
low-volume (quartile 1) and high-volume (quartile 4) groups. This approach,
which was implemented to create balance, involved weighting each patient in a
high-volume hospital by the inverse of the probability that he or she would
belong to a high-volume hospital and weighting each patient who belonged to a
low-volume hospital by the inverse of the probability that he or she would
belong to a low-volume hospital (11).
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Confidential: For Review OnlyC. Results:
Table S1. Ascertainment of PE cases
Hospital PE cases in RIETE 2017 PE cases in SNPR 2017 Percent difference
Quartile 4 (>40 patients/yr)
Total 357 422 -15.4
Hospital 1 47 57 -17.5
Hospital 2 70 88 -20.4
Hospital 3 98 111 -11.7
Hospital 4 142 166 -14.5
Quartile 3 (>25-40 patients/yr)
Total 140 170 -17.6
Hospital 5 29 31 -6.5
Hospital 6 33 45 -26.7
Hospital 7 38 47 -19.1
Hospital 8 40 47 -14.9
Quartile 2 (15-25 patients/yr)
Total 78 93 -16.1
Hospital 9 16 19 15.8
Hospital 10 18 20 -10.0
Hospital 11 21 25 -16.0
Hospital 12 23 29 -20.7
Quartile 1 (<15 patients/yr)
Total 27 33 -18.2
Hospital 13 10 12 -16.7
Hospital 14 7 9 -22.2
Hospital 15 6 6 0
Hospital 16 4 6 -33.3
Abbreviations: PE, pulmonary embolism; RIETE, Registro Informatizado Enfermedad
TromboEmbolica; SNPR, Spanish National Patient Registry.
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Confidential: For Review OnlyTable S2. Inappropriate management of acute PE
Variable Hospital volume quartiles
Q1(<15 patients/yr)
Q2(15-25 patients/yr)
Q3(>25-40 patients/yr)
Q4(>40 patients/yr)
Anticoagulant therapyNo UFH in a patient with severe renal
insufficiency, severe obesity, unstable
PE, n/N (%)
187/1,633
(11.5%)
164/1,544
(10.6%)
135/1,907
(7.1%)
119/2,812
(4.2%)
UFH in a patient without severe renal
insufficiency, severe obesity, unstable
PE, n/N (%)
206/6,963
(3.0%)
178/6,586
(2.7%)
188/7,843
(2.4%)
209/9,969
(2.1%)
Reperfusion therapyNo reperfusion in an unstable patient, n/N
(%)
461/587
(78.5%)
366/472
(77.5%)
487/686
(71.0%)
680/963
(70.6%)
Reperfusion in a stable patient, n/N (%) 208/8,009
(2.6%)
100/7,658
(1.3%)
127/9,064
(1.4%)
100/11,818
(0.8%)
Inferior vena cava filterNo filter in a patient with contraindication
to anticoagulation, n/N (%)
526/637
(82.6%)
383/502
(76.3%)
634/783
(81.0%)
938/1,239
(75.7%)
Filter in a patient without contraindication
to anticoagulation, n/N (%)
119/7,959
(1.5%)
105/7,628
(1.4%)
106/8,967
(1.2%)
122/11,542
(1.1%)
Inappropriate management, n (%) 1,512(17.6%)
1,251(15.4%)
1,453(14.9%)
1,821(14.2%)
Abbreviations: PE, pulmonary embolism; UFH, unfractionated heparin.
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Confidential: For Review OnlyTable S3. Multivariable logistic regression models*
Variable Quartile 1(<15 patients/yr)
Quartile 2(15-25 patients/yr)
Quartile 3(>25-40 patients/yr)
Quartile 4(>40 patients/yr)
Model 1 (unadjusted)
Odds ratio (95% CI)
30-day PE-related mortality 1.0 0.68 (0.43-1.09) 0.63 (0.37-1.09) 0.67 (0.37-1.23)
30-day all-cause mortality 1.0 0.78 (0.53-1.14) 0.81 (0.51-1.28) 0.94 (0.56-1.59)
7-day PE-related mortality 1.0 0.65 (0.41-1.06) 0.70 (0.40-1.21) 0.71 (0.38-1.31)
7-day all-cause mortality 1.0 0.77 (0.50-1.20) 0.80 (0.49-1.33) 0.89 (0.51-1.57)
30-day nonfatal VTE recurrences 1.0 0.78 (0.51-1.18) 0.71 (0.45-1.12) 0.82 (0.51-1.32)
30-day nonfatal major bleeding 1.0 0.97 (0.74-1.28) 0.95 (0.68-1.31) 1.16 (0.82 -1.63)
Model 2 (adjusted for age and sex)
Odds ratio (95% CI)
30-day PE-related mortality 1.0 0.65 (0.41-1.02) 0.59 (0.35-1.01) 0.62 (0.34-1.11)
30-day all-cause mortality 1.0 0.74 (0.51-1.06) 0.73 (0.47-1.13) 0.87 (0.52-1.44)
7-day PE-related mortality 1.0 0.62 (0.38-1.00) 0.68 (0.40-1.17) 0.64 (0.35-1.17)
7-day all-cause mortality 1.0 0.73 (0.48-1.11) 0.73 (0.44-1.19) 0.82 (0.48-1.42)
30-day nonfatal VTE recurrences 1.0 0.79 (0.52-1.20) 0.68 (0.43-1.08) 0.84 (0.52-1.35)
30-day nonfatal major bleeding 1.0 0.95 (0.72-1.25) 0.90 (0.65-1.24) 1.11 (0.79-1.55)
Model 3 (adjusted for age, sex, cancer, immobilization, chronic lung disease, chronic heart disease, heart rate, systolic blood pressure, creatinine levels, and hemoglobin levels)Odds ratio (95% CI)
30-day PE-related mortality 1.0 0.65 (0.42-1.01) 0.61 (0.38-1.00) 0.56 (0.33-0.96)
30-day all-cause mortality 1.0 0.68 (0.48-0.97) 0.74 (0.49-1.11) 0.78 (0.49-1.23)
7-day PE-related mortality 1.0 0.65 (0.41-1.02) 0.68 (0.42-1.11) 0.61 (0.35-1.04)
7-day all-cause mortality 1.0 0.72 (0.48-1.07) 0.72 (0.46-1.12) 0.76 (0.47-1.25)
30-day nonfatal VTE recurrences 1.0 0.82 (0.54-1.23) 0.74 (0.48-1.14) 0.76 (0.49-1.19)
30-day nonfatal major bleeding 1.0 0.91 (0.70-1.20) 0.90 (0.66-1.23) 1.07 (0.77-1.48)
Model 4 (adjusted for age, sex, cancer, immobilization, chronic lung disease, chronic heart disease, heart rate, systolic blood pressure, sPESI, creatinine levels, and hemoglobin levels)Odds ratio (95% CI)
30-day PE-related mortality 1.0 0.66 (0.43-1.01) 0.61 (0.38-0.99) 0.56 (0.33-0.95)
30-day all-cause mortality 1.0 0.68 (0.48-0.97) 0.73 (0.19-1.10) 0.78 (0.50-1.22)
7-day PE-related mortality 1.0 0.65 (0.41-1.02) 0.68 (0.42-1.11) 0.60 (0.35-1.03)
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Confidential: For Review Only 7-day all-cause mortality 1.0 0.72 (0.48-1.07) 0.72 (0.46-1.12) 0.76 (0.47-1.24)
30-day nonfatal VTE recurrences 1.0 0.82 (0.54-1.23) 0.74 (0.48-1.14) 0.76 (0.49-1.19)
30-day nonfatal major bleeding 1.0 0.92 (0.70-1.20) 0.90 (0.66-1.22) 1.07 (0.77-1.47)
Model 5 (adjusted for age, sex, cancer, immobilization, chronic lung disease, chronic heart disease, heart rate, systolic blood pressure, sPESI, creatinine levels, hemoglobin levels, and hospital status)Odds ratio (95% CI)
30-day PE-related mortality 1.0 0.66 (0.43-1.01) 0.60 (0.37-0.98) 0.54 (0.32-0.93)
30-day all-cause mortality 1.0 0.68 (0.48-0.97) 0.72 (0.48-1.09) 0.77 (0.48-1.21)
7-day PE-related mortality 1.0 0.64 (0.41-1.02) 0.65 (0.40-1.07) 0.57 (0.33-0.98)
7-day all-cause mortality 1.0 0.72 (0.48-1.07) 0.69 (0.44-1.09) 0.73 (0.44-1.20)
30-day nonfatal VTE recurrences 1.0 0.80 (0.53-1.20) 0.67 (0.44-1.02) 0.66 (0.42-1.03)
30-day nonfatal major bleeding 1.0 0.91 (0.70-1.20) 0.89 (0.66-1.22) 1.05 (0.75-1.46)
Abbreviations: CI, confidence interval; PE, pulmonary embolism; VTE, venous
thromboembolism.
* All these models accounted for clustering of patients within hospitals and hospitals clustered
within countries.
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Confidential: For Review OnlyTable S4. Sensitivity analyses of falsification endpoints*
Variable Quartile 1(<15 patients/yr)
Quartile 2(15-25 patients/yr)
Quartile 3(>25-40 patients/yr)
Quartile 4(>40 patients/yr)
Odds ratio (95% CI)
90-day cancer-related mortality 1.0 1.52 (1.06-2.19) 1.57 (1.05-2.33) 1.52 (1.00-2.31)
90-day chronic heart disease-related mortality 1.0 1.25 (0.65-2.40) 1.05 (0.52-2.09) 0.86 (0.42-1.73)
90-day infection-related mortality 1.0 1.06 (0.61-1.82) 0.86 (0.48-1.55) 1.34 (0.74-2.44)
Abbreviations: CI, confidence interval.
* Adjusted for age, sex, cancer, immobilization, chronic lung disease, chronic heart disease, heart rate,
systolic blood pressure, sPESI, creatinine levels, and hemoglobin levels at hospital admission. Confidence
intervals (CI) and P values take into account clustering according to center.
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Confidential: For Review OnlyTable S5. Propensity score analysis
30-day outcome RR 95% CI P value
PE-related death 0.60 0.37-0.90 0.046
Death 0.84 0.58-1.20 0.33
Recurrent VTE 0.82 0.46-1.45 0.50
Major bleeding 1.03 0.80-1.36 0.78
Abbreviations: RR, relative risk; CI, confidence interval; PE, pulmonary embolism; VTE, venous
thromboembolism.
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Confidential: For Review OnlyD. References:1. Bikdeli B, Jimenez D, Hawkins M, et al. Rationale, design and methodology
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