Confidential: For Review Only - BMJ · 2019. 7. 31. · Confidential: For Review Only Experience and PE BMJ 4 ABSTRACT Background: Patients with acute symptomatic pulmonary embolism

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

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review Only

Experience and PE

BMJ

1

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.

Page 1 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

2

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

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

Page 2 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

mailto:[email protected]


Experience and PE

BMJ

3

our worldwide licence referred to above.

Page 3 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

4

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.

Page 4 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

5

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

Page 5 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

6

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

Page 6 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

7

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

Page 7 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

8

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

Page 8 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

9

(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],

Page 9 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

10

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.

Page 10 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

11

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

Page 11 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

12

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.

Page 12 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

13

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.

Page 13 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

14

REFERENCES1. Bĕlohlávek J, Dytrych V, Linhart A. Pulmonary embolism, part I:

Epidemiology, risk factors and risk stratification, pathophysiology, clinical

presentation, diagnosis and nonthrombotic pulmonary embolism. Exp Clin

Cardiol 2013; 18: 129-138.

2. Heit JA. The epidemiology of venous thromboembolism in the community.

Arterioscler Thromb Vasc Biol 2008; 28: 370-372.

3. Kumbhani DJ, Fonarow GC, Heidenreich PA, et al. Association between

hospital volume, processes of care, and outcomes in patients admitted with

heart failure: insights from get with the guidelines-heart failure. Circulation

2018; 137: 1661-1670.

4. Tu JV, Austin PC, Chan BTB. Relationship between annual volume of

patients treated by admitting physician and mortality after acute myocardial

infarction. JAMA 2001; 285: 3116-3122.

5. Ko DT, Dattani ND, Austin PC, et al. Emergency department volume and

outcomes for patients after chest pain assessment. Circ Cardiovasc Qual

Outcomes 2018; 11: e004683.

6. Aujesky D, Mor MK, Geng M, Fine MJ, Renaud B, Ibrahim SA. Hospital

volume and patient outcomes in pulmonary embolism. CMAJ 2008; 178: 27-

33.

7. Meyer G, Vicaut E, Danays T, et al; PEITHO Investigators. Fibrinolysis for

patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;

370: 1402-1411.

8. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; “MOPETT”

Investigators. Moderate pulmonary embolism treated with thrombolytics

(from the ‘MOPETT’ trial). Am J Cardiol 2013; 111: 273-277.

9. Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of

ultrasound-assisted catheter-directed thrombolysis for acute intermediate-

risk pulmonary embolism. Circulation 2014; 129: 479-486.

10.Leacche M, Unic D, Goldhaber SZ, et al. Modern surgical treatment of

massive pulmonary embolism: results in 47 consecutive patients after rapid

diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg

2005; 129: 1018-1023.

Page 14 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

http://www.ncbi.nlm.nih.gov/pubmed?term=B%C4%95lohl%C3%A1vek%20J%5BAuthor%5D&cauthor=true&cauthor_uid=23940438

http://www.ncbi.nlm.nih.gov/pubmed?term=Dytrych%20V%5BAuthor%5D&cauthor=true&cauthor_uid=23940438

http://www.ncbi.nlm.nih.gov/pubmed?term=Linhart%20A%5BAuthor%5D&cauthor=true&cauthor_uid=23940438


Experience and PE

BMJ

15

11.Laporte S, Mismetti P, Décousus H, et al. Clinical predictors for fatal

pulmonary embolism in 15,520 patients with venous thromboembolism:

findings from the RIETE registry. Circulation 2008; 117: 1711-1716.

12.Muriel A, Jiménez D, Aujesky D, et al. Survival effects of inferior vena cava

filter in patients with acute symptomatic venous thromboembolism and a

significant bleeding risk. J Am Coll Cardiol 2014; 63: 1675-1683.

13.Monreal M, Kakkar AK, Caprini JA, et al. The outcome after treatment of

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.

Page 15 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

16

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.

Page 16 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

17

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.

Page 17 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

18

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.

Page 18 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

19

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.

Page 19 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

20

Figure 1. STROBE study cohort flow diagram

Figure 2. Relationship between hospital volume and PE-related mortality

Page 20 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

21

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

Page 21 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

22

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.

Page 22 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

23

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.

Page 23 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

24

Table 3. Adjusted rates of mortality and nonfatal outcomes by volume*

Variable Quartile 1(<15 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)



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.

Page 24 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

25

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.

Page 25 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

1

Figure 1.

Abbreviations: VTE, venous thromboembolism; RIETE, Registro Informatizado de la

Enfermedad TromboEmbólica; PE, pulmonary embolism; DVT, deep vein thrombosis.

Page 26 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Experience and PE

BMJ

1

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.

Page 27 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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]

Page 28 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

mailto:[email protected]

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

Page 29 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 30 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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,

Page 31 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 32 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 33 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 34 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 35 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 36 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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).

Page 37 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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).

Page 38 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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).

Page 39 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 40 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 41 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review OnlyTable S3. Multivariable logistic regression models*





Model 1 (unadjusted)

Odds ratio (95% CI)






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)







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)







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)




Page 42 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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)



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)







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.

Page 43 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review OnlyTable S4. Sensitivity analyses of falsification endpoints*





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.

Page 44 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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.

Page 45 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review OnlyD. References:1. 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.

2. Konstantinides SV, Torbicki A, Agnelli G, et al; Authors/Task Force

Members. 2014 ESC Guidelines on the diagnosis and management of acute

pulmonary embolism: The Task Force for the Diagnosis and Management of

Acute Pulmonary Embolism of the European Society of Cardiology (ESC)

Endorsed by the European Respiratory Society (ERS). Eur Heart J 2014; 35:

3033-3073.

3. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous

thromboembolic disease. American College of Chest Physicians Evidence-

Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 454-545.

4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease:

Chest guideline and expert panel report. Chest 2016; 149: 315-352.

5. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and

submassive pulmonary embolism, iliofemoral deep vein thrombosis, and

chronic thromboembolic pulmonary hypertension: a scientific statement from

the American Heart Association. Circulation 2011; 123: 1788-1830.

6. 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.

7. Prandoni P, Cogo A, Bernardi E, et al. A simple approach for detection of

recurrent proximal vein thrombosis. Circulation 1993; 88: 1730-1735.

8. Riera-Mestre, Jiménez D, Muriel A, et al; RIETE investigators. Thrombolytic

therapy and outcome of patients with an acute symptomatic pulmonary

embolism. J Thromb Haemost 2012; 10: 751-759.

9. Rosenbaum PR. Model-based direct direct adjustment. J Am Stat Assoc

1987; 82: 387-394.

10.Lunceford JK, Davidian M. Stratification and weighting via the propensity

score in estimation of causal treatment effects: acomparative study. Stat

Med 2004; 23: 2937-2960.

Page 46 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Confidential: For Review Only11.Austin PC, Stuart EA. Moving towards best practice when using inverse

probability of treatment weighting (IPTW) using the propensity score to

estimate causal treatment effects in observational studies. Stat Med 2015;

34: 3661-3679.

Page 47 of 47


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

Documents

Confidential: For Review Only - BMJ · 2019. 7. 31. · Confidential: For Review Only Experience and PE BMJ 4 ABSTRACT Background: Patients with acute symptomatic pulmonary embolism