- Email: [email protected]
Contemporary Management and Outcomes of Patients with Massive and Submassive Pulmonary Embolism
Accepted Manuscript
Contemporary Management and Outcomes of Patients with Massive and Submassive Pulmonary Embolism Eric Secemsky , Yuchiao Chang , C. Charles Jain , Joshua A. Beckman , Jay Giri , Michael R. Jaff , Kenneth Rosenfield , Rachel Rosovsky , Christopher Kabrhel , Ido Weinberg PII: DOI: Reference:
S0002-9343(18)30763-0 https://doi.org/10.1016/j.amjmed.2018.07.035 AJM 14787
To appear in:
The American Journal of Medicine
Received date: Revised date: Accepted date:
1 May 2018 17 July 2018 28 July 2018
Please cite this article as: Eric Secemsky , Yuchiao Chang , C. Charles Jain , Joshua A. Beckman , Jay Giri , Michael R. Jaff , Kenneth Rosenfield , Rachel Rosovsky , Christopher Kabrhel , Ido Weinberg , Contemporary Management and Outcomes of Patients with Massive and Submassive Pulmonary Embolism, The American Journal of Medicine (2018), doi: https://doi.org/10.1016/j.amjmed.2018.07.035
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Contemporary Management and Outcomes of Patients with Massive and Submassive Pulmonary Embolism Short title: Modern Outcomes after Massive and Submassive Pulmonary Embolism
CR IP T
Eric Secemsky MD MSca,b,c, Yuchiao Chang PhDb,d, C. Charles Jain MDe, Joshua A. Beckman MDf, Jay Giri MD MPHg, Michael R. Jaff DOb,h, Kenneth Rosenfield MDb,i, Rachel Rosovsky MDj, Christopher Kabrhel MD MPHk, Ido Weinberg MD MScb,i
PT
ED
M
AN US
Author affiliations: a Smith Center for Outcomes Research in Cardiology, Department of Medicine; Beth Israel Deaconess Medical Center, Boston, MA, USA b Harvard Medical School, Boston, MA, USA c Division of Cardiology, Department of Medicine; Beth Israel Deaconess Medical Center, Boston, MA, USA d Department of Medicine; Massachusetts General Hospital, Boston, MA, USA e Cardiovascular Division, Department of Medicine; Mayo Clinic, Rochester, MN, USA f Cardiovascular Division, Department of Medicine; Vanderbilt University Medical Center, Nashville, TN, USA g Penn Cardiovascular Outcomes, Quality, & Evaluative Research Center, Cardiovascular Medicine Division, Department of Medicine; University of Pennsylvania, Philadelphia, PA, USA h Newton-Wellesley Hospital, Boston, MA, USA i Division of Cardiology, The Fireman Vascular Center, Department of Medicine; Massachusetts General Hospital, Boston, MA, USA j Hematology and Oncology Division; Massachusetts General Hospital, Boston, MA, USA k Center for Vascular Emergencies, Department of Emergency Medicine; Massachusetts General Hospital, Boston, MA, USA
CE
Submission type: Clinical Research Study Word Count (Manuscript, Abstract, Acknowledgements): 3,054 words
AC
Address for Correspondence: Ido Weinberg, MD, MSc 55 Fruit Street, GRB-852G Vascular Medicine, Division of Cardiology, Department of Medicine Massachusetts General Hospital Boston, MA 02114 Phone: 617-726-2256 [email protected]
1
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
Role of Sponsors and Funding: None
AN US
CR IP T
Conflict of Interest: Dr. Beckman is a consultant for Aralez, Astra Zeneca, Janssen, Sanofi, and BMS (modest); serves on the data safety and monitoring board for Bayer (modest); and has equity in EMX and Janacare (modest). Dr. Giri is a board member of VIVA Physicians, a 501c3 not-for-profit education and research organization (modest). Dr. Jaff is a compensated advisor for Philips/Volcano and Venarum (modest); an equity Investor for Embolitech, Vascular Therapies, PQ Bypass, MC10, Jana Care, and Sano V (modest). Dr. Kabrhel has received grant funding (paid to his institution) from NIH, Janssen, Diagnostica Stago, Siemens Healthcare Diagnostics and BoehringerIngelheim. Dr. Rosenfield is a consultant for Abbott Vascular, Cardinal Health, Cook, Thrombolex, Surmodics, Volcano/Philips, Amegen; is a consultant, on the scientific advisory board with equity or stock options from Capture Vascular, Contego, Cruzar systems, Endospan, Eximo, MD Insider, Micell, Shockwave, Silkroad Medical, Valcare, Thrombolex; has received equity or stock options for serving on advisory boards from PQ Bypass, Primacea, Capture Vascular, VORTEX, MD Insider, Micell, Shockwave, Cruzar Systems, Endospan, Eximo, Valcare, Contego (modest); has received research grant support to his institution from Atrium-Getinge, Inari Medical, National Institutes of Health, Lutonix-Bard (modest); and is a board member of the National PERT Consortium, a 501c3 non-for-profit education and research organization and VIVA Physicians, a 501c3 not-for-profit education and research organization (modest). Dr. Weinberg is on the scientific advisory board for Novate Medical. All other authors have no relevant disclosures.
2
ACCEPTED MANUSCRIPT
Abstract Background: Few contemporary studies have assessed the management and outcomes of patients with massive and submassive pulmonary embolism. Given advances in therapy,
CR IP T
we report contemporary practice patterns and event rates among these patients.
Methods: We analyzed a prospective database of patients with massive and submassive pulmonary embolism. We report clinical characteristics, therapies and outcomes stratified by pulmonary embolism type. Treatment escalation beyond systemic
AN US
anticoagulation was defined as advanced therapy. Cox proportional hazards regression was used to identify predictors of 90-day mortality.
M
Results: Among 338 patients, 46 (13.6%) presented with massive and 292 (86.4%) with submassive pulmonary embolism. The average age was 63±15 years, 49.9% were female,
ED
32.0% had malignancy and 21.9% had recent surgery. Massive pulmonary embolism patients received advanced therapy in 71.7% (30.4% systemic thrombolysis; 17.4%
PT
catheter-directed thrombolysis; 15.2% surgical embolectomy) and had greater 90-day
CE
mortality rates compared with submassive pulmonary embolism patients (41.3% versus 12.3%, respectively; p<0.01). The majority of massive pulmonary embolism deaths
AC
(78.9%) occurred in-hospital, whereas mortality risk persisted after discharge for submassive pulmonary embolism. After multivariable adjustment, massive pulmonary embolism was associated with a 5.23-fold greater hazard of mortality (95%CI: 2.70, 10.13; p<0.01). Advanced therapies among all pulmonary embolism patients were associated with a 61% reduction in mortality (95%CI: 0.20, 0.76; p<0.01).
3
ACCEPTED MANUSCRIPT
Conclusions: Among contemporary massive and submassive pulmonary embolism patients, mortality remains substantial. Advanced therapies were frequently utilized and independently associated with lower mortality. Further investigation is needed to determine how to improve outcomes among these high-risk patients, including the
AC
CE
PT
ED
M
AN US
CR IP T
optimal use of advanced therapies.
4
ACCEPTED MANUSCRIPT
Introduction Pulmonary embolism is a common cause of cardiovascular death after myocardial infarction and stroke1,2. However, the management of pulmonary embolism is variable and based on less evidence to guide therapy3-5. This may be a result of the heterogeneous
CR IP T
presentation of pulmonary embolism, which ranges from asymptomatic to hemodynamic instability, and sudden death.
Pulmonary embolism risk classification in consensus guidelines is according to
the hemodynamic consequences of the embolus. These classifications have demonstrated
AN US
a strong relationship with outcomes6. In particular, massive pulmonary embolism, the most severe form of pulmonary embolism and defined by the presence of cardiogenic shock, is associated with a high mortality rate7. While hemodynamic stability at
M
presentation is useful to risk stratify patients, these patients represent a small minority of those at risk for death. The ability to tailor therapy for the near massive and submassive
ED
patients in order to optimize outcomes is currently lacking8. Part of the limitation in individualizing therapy is that the majority of published
PT
data regarding the management and outcomes associated with massive pulmonary
CE
embolism are more than a decade old7. For example, the effectiveness of invasive therapies that have become available in recent years, such as catheter-directed lysis and
AC
endovascular clot retrieval9,10, is not well established. Given the significant advances in the diagnostics, therapeutics and multidisciplinary care of patients with massive and submassive pulmonary embolism, an assessment of contemporary practices and outcomes is warranted.
5
ACCEPTED MANUSCRIPT
Methods This analysis used data from the Massachusetts General Hospital Pulmonary Embolism Response Team database, which have been previously described11. Patients are prospectively enrolled into the database upon presentation with pulmonary embolism and
CR IP T
followed in the inpatient and outpatient settings. Data, including demographics,
laboratory data and treatments received, are collected by trained research personnel. Data collection and this analysis were approved by the Human Research Committee of Partners HealthCare.
AN US
From this dataset, we analyzed all patients with massive or submassive pulmonary embolism. Massive pulmonary embolism was defined as any pulmonary embolism that resulted in sustained (>15minutes) hypotension (systolic blood pressure <90mmHg) or
M
any period of pulselessness. Submassive pulmonary embolism was defined as any pulmonary embolism without hemodynamic compromise, but with evidence of right
ED
ventricular strain. Right ventricular strain was defined by any of the following: elevated troponin T (defined as >0.01 ng/mL), elevated N-terminal pro-brain natriuretic peptide
PT
(NT-proBNP) (defined as ≥500 pg/mL), and/or imaging evidence of new right ventricular
CE
strain (right:left ventricular ratio greater than 1.0 on computed tomography or right ventricle hypokinesis/dilation on transthoracic echocardiogram).
AC
Pulmonary embolism presentation was considered day 0 and defined by the
activation of the pulmonary embolism response team. Among patients diagnosed with pulmonary embolism at our institution, the median time from diagnostic computed tomography to pulmonary embolism team consultation was 50 minutes (interquartile range 23-197 minutes). Patient characteristics were collected at baseline. Symptoms were
6
ACCEPTED MANUSCRIPT
collected within 3 days of presentation. Markers of right ventricular involvement were assessed based on laboratory and imaging studies performed closest to the time of presentation. Therapies included systemic anticoagulation (anticoagulant agent not specified for this study), inferior vena cava filter placement, systemic intravenous
CR IP T
thrombolysis, catheter-directed thrombolysis, endovascular clot retrieval, extracorporeal membrane oxygenation and surgical embolectomy. Advanced therapy was defined as the utilization of one or more of these treatment modalities, excluding systemic anticoagulation, as defined previously12,13.
AN US
The primary outcome was all-cause mortality at 90 days. Secondary outcomes included in-hospital mortality, major bleeding, intracranial hemorrhage and 30-day
readmission rates. The major bleeding endpoint was defined by symptomatic bleeding in
M
a critical area or organ that either required surgical consultation or intervention, or resulted in transfusion of two or more units of red blood cells, as used previously14-16.
ED
Readmissions within 30 days of discharge within the Partners HealthCare system were identified. Patients who died prior to 30 days after discharge were excluded, unless the
CE
PT
readmission occurred prior to death.
Statistical Analysis
AC
Categorical variables were reported as counts and percentages, and continuous
variables as means with standard deviations or medians with inter-quartiles. Betweengroup differences were assessed using chi-square tests for categorical variables, and Student’s t-tests or Wilcoxon rank sum tests for continuous variables.
7
ACCEPTED MANUSCRIPT
Follow-up started at the time of presentation and continued until date of death or at study completion of one year. Rates of interventions received were assessed at the prespecified time points of 0, ≤1, ≤3 and ≤7 days from presentation. Patients who died in the earlier time periods were included in the denominator of rate calculation and
CR IP T
considered as no treatment if treatment was not received before death. Kaplan-Meier
curves were used to depict the cumulative incidence of death following presentation and differences were compared using the log-rank test. Based on prior literature and clinical knowledge, a Cox proportional hazards model was created to explore independent factors
AN US
associated with 90-day mortality. This model included massive versus submassive
pulmonary embolism, age per 10 years, sex, history of malignancy, use of advanced therapy within 7 days of presentation and major bleeding within 7 days of presentation. A
M
logistic regression model was used to explore the independent association between massive pulmonary embolism and major bleeding at 90 days, adjusting for age per 10
ED
years, sex and use of advanced therapy within 7 days of presentation. A two-sided p value <0.05 was considered statistically significant. Statistical
CE
PT
analyses were performed using SAS software v9.4 (SAS Institute, Cary, NC, USA).
Results
AC
Patient Characteristics and Symptoms at Presentation Of the 338 patients included in the analysis, 46 (13.6%) presented with massive
and 292 (86.4%) with submassive pulmonary embolism. The average age was 63±15 years, 49.4% were female, 32.0% had malignancy, 21.9% had recent surgery and 2.1% had a history of hypercoagulability. Patients with massive compared with submassive
8
ACCEPTED MANUSCRIPT
pulmonary embolism were of similar age and sex, and had a similar proportion of comorbidities (Table 1). However, massive pulmonary embolism patients had a lower rate of coronary artery disease and a higher rate of recent surgery. Among those with submassive pulmonary embolism, dyspnea was the predominant symptom at presentation
CR IP T
(80.8%), followed by tachycardia (69.9%) and hypoxia (49.7%) (Table 2).
Among all patients, 62.8% had an elevated troponin and 57.9% had an elevated NT-proBNP (Table 2). Imaging evidence of right ventricular strain occurred more
AN US
commonly among those with massive versus submassive pulmonary embolism.
Treatment Patterns of Massive and Submassive Pulmonary Embolism Table 3 outlines the therapies received by the study population. Within 7 days of
M
presentation, 97.6% of all patients had received systemic anticoagulation, 20.7% had received an inferior vena cava filter, 13.9% had received catheter-directed thrombolysis
ED
and 37.9% had received any type of advanced therapy. Among patients with massive pulmonary embolism, 71.7% received advanced
PT
therapies, most commonly systemic thrombolysis and inferior vena cava filter placement
CE
(both 30.4%), followed by catheter-directed thrombolysis (17.4%), surgical embolectomy (15.2%) and extracorpeal membrane oxygenation (13.0%). Of those who did not receive
AC
thrombolysis, the primary reason was contraindication due to bleeding concerns (88.9%). Comparing patients with massive and submassive pulmonary embolism, there
were no significant differences in the proportion of patients who received systemic anticoagulation, catheter-directed thrombolysis, endovascular clot retrieval or inferior vena cava filters within 7 days. However, massive pulmonary embolism patients more
9
ACCEPTED MANUSCRIPT
often received systemic thrombolysis, extracorpeal membrane oxygenation, surgical embolectomy and any advanced therapy (Table 3).
Outcomes Associated with Massive and Submassive Pulmonary Embolism
CR IP T
Death and adverse events occurred more commonly among those with massive compared with submassive pulmonary embolism (Table 4). The rate of in-hospital
mortality was 8.3% for the total cohort, occurring in 32.6% of those with massive and 4.5% of those with submassive pulmonary embolism (p<0.01). By 90 days of
AN US
presentation, 16.3% of the total cohort died, with a death rate of 41.3% among those with massive and 12.3% among those with submassive pulmonary embolism (p<0.01). The majority of deaths (78.9%) among those with massive pulmonary embolism occurred
M
during the index hospitalization, whereas among those with submassive pulmonary embolism, the risk of death persisted post-discharge (Figure 1). For patients with
ED
identifiable causes of death, 90-day mortality was directly related to pulmonary embolism in 45.0% (9/20) of patients with massive pulmonary embolism and 31.6% (10/32) of
PT
patients with submassive pulmonary embolism.
CE
Among all pulmonary embolism patients who received advanced therapies, the 30-day mortality rate was 9.4% and the 90-day mortality rate was 11.7%. Mortality rates
AC
at 30 days and 90 days did not statistically differ between those who received versus did not receive advanced therapies (30 days: 9.4% vs. 13.3%, respectively, p=0.30; 90 days: 11.7% vs. 19.0%, respectively, p=0.09). When stratified by pulmonary embolism type, those with massive pulmonary embolism had a trend towards lower mortality with receipt of advanced therapies (30 days: 27.3% with advanced therapies vs. 53.8% without
10
ACCEPTED MANUSCRIPT
advanced therapies, p=0.17; 90 days: 33.3% with advanced therapies vs. 61.5% without advanced therapies, p=0.10), and those with submassive pulmonary embolism who received advanced therapies had significant reductions in both 30-day and 90-day mortality (30 days: 3.2% with advanced therapies vs. 10.7% without advanced therapies,
CR IP T
p=0.04; 90 days: 4.2% with advanced therapies vs. 16.2% without advanced therapies,
p<0.01). Morality rates for each advanced therapy, stratified by massive and submassive pulmonary embolism, can be found in eTable 1.
Major bleeding occurred in 14.2% of the total patient population within 90 days,
AN US
with a greater frequency among those with massive (26.1%) relative to those with
submassive pulmonary embolism (12.3%) (p=0.01). The frequency of intracranial hemorrhage was also greater among those with massive versus submassive pulmonary
M
embolism (4.3% vs. 0.8%, respectively; p=0.03). Major bleeding rates were greater among those who received advanced therapies relative to those who did not (30-days:
ED
18.8% vs. 7.6%, p<0.01; 90-days: 19.5% vs. 11.4%, p=0.09). When stratified by pulmonary embolism type, those with massive pulmonary embolism treated with
PT
advanced therapies had numerically greater major bleeding at 30 days and 90 days, but
CE
this did not reach statistical significance (30 days: 30.3% with advanced therapies vs. 15.4% without advanced therapies, p=0.46; 90 days: 30.3% with advanced therapies vs.
AC
23.1% without advanced therapies, p=0.73). Similarly, those with submassive pulmonary embolism who received advanced therapies had a trend towards increased major bleeding at 30 days (14.7% with advanced therapies vs. 7.1% without advanced therapies, p=0.06), but no significant difference in major bleeding rates at 90 days (15.8% with advanced therapies vs. 10.7% without advanced therapies, p=0.25).
11
ACCEPTED MANUSCRIPT
The 30-day readmission rate was 16.3%. Readmissions within 30 days were numerically greater among patients with massive pulmonary embolism, but this did not reach statistical significance (29.0% with massive vs. 14.9% with submassive, p=0.07). Patients who received advanced therapies had similar 30-day readmission rates compared
CR IP T
with those who did not receive these interventions (15.9% vs. 17.6%, respectively; p=0.71).
The overall rate of recurrent pulmonary embolism within 90 days after
presentation was 2.4% and within 365 days was 3.8%. All recurrent pulmonary embolism
AN US
events occurred among those with submassive pulmonary embolism.
In adjusted analysis, patients with massive pulmonary embolism had a 5.23-fold greater hazard of 90-day mortality relative to those with submassive pulmonary
M
embolism (95%CI: 2.70, 10.13; p<0.01) (Table 5). Other predictors of 90-day mortality included malignancy (hazard ratio [HR] 2.63; 95%CI: 1.48, 4.17; p<0.01) and age (age
ED
per 10-year increase: HR 1.25; 95%CI: 1.02, 1.52; p=0.03), whereas the use of advanced therapies was independently associated with lower mortality (HR 0.39; 95%CI: 0.20,
PT
0.76; p<0.01). In addition, patients with massive pulmonary embolism had a 2.28-fold
CE
greater adjusted odds of major bleeding compared with those with submassive pulmonary embolism (95%CI: 1.03, 5.03; p=0.04), which included adjustment for use of advanced
AC
therapies.
Discussion In this analysis of patients presenting with massive and submassive pulmonary embolism, we demonstrate that heterogeneity in treatment patterns and high mortality
12
ACCEPTED MANUSCRIPT
risks persist in contemporary clinical practice. Advanced therapies were frequently utilized in this population, yet systemic thrombolysis was employed less often than invasive procedures. Nevertheless, advanced therapies were independently associated with decreased mortality. Major bleeding was substantial (14.2% of all patients). Among
CR IP T
massive pulmonary embolism patients, more than 1 in 3 died within 90 days of
presentation. The majority of these deaths occurred in-hospital, whereas among those with submassive pulmonary embolism, the risk of mortality persisted after discharge.
Recent publications have shown a trend towards reduced mortality for pulmonary
AN US
embolism patients17, yet death rates among the subset with massive pulmonary embolism remain high18-20. For example, in a multicenter registry of emergency department patients with pulmonary embolism, the 30-day mortality among those with massive pulmonary
M
embolism was 25.9% and was nearly exclusive to the patients who did not receive systemic thrombolysis21. In a separate statewide analysis of pulmonary embolism-related
ED
treatment and outcomes, 26.5% of 803 patients with pulmonary embolism and hypotension died at 30 days22. In the current analysis, the 30-day mortality rate associated
PT
with massive pulmonary embolism was 34.8% and 41.3% at 90 days, exceeding the
CE
mortality rates in the aforementioned studies, but on par with the mortality rate found in the International Cooperative Pulmonary Embolism Registry (ICOPER) (90-day
AC
mortality rate of 52.4%)7. This may in part be due to the stringent and similar criteria used in our study and ICOPER to classify massive pulmonary embolism, as well as the detailed data available for adjudication. Nevertheless, in the decade encompassing the reporting of the referenced studies and our own, mortality rates among patients with massive pulmonary embolism remain substantial.
13
ACCEPTED MANUSCRIPT
With regards to submassive pulmonary embolism, 12.3% of patients in our study died by 90 days, which is also higher than previous analyses6,21, yet similar to the mortality rate published from ICOPER (90-day mortality rate of 14.7%)7. Importantly, submassive pulmonary embolism represents a heterogeneous group of patients, and our reported
CR IP T
mortality rate may reflect patients that were at higher risk of death compared with other studies. For instance, nearly 50% of submassive patients in the current analysis had
documented hypoxia, 70% had tachycardia, and only 2.1% presented without symptoms. To date, data on the utilization of advanced therapies for massive pulmonary
AN US
embolism are limited19,20,23. In a report from the EMPEROR registry that included 58
patients with massive pulmonary embolism, systemic thrombolysis was administered in only 12.0% of patients21. Additionally, in an analysis of 108 massive pulmonary
M
embolism patients from ICOPER, less than one third of patients received thrombolytic therapy7. However, novel treatments that are available in advanced centers today were
ED
not available at the time these studies were conducted. In the current analysis, more than 70% of patients with massive pulmonary embolism received advanced therapies. The
PT
most commonly used intervention remained systemic thrombolysis, yet this made up less
CE
than half of all advanced therapies employed. Instead, we observed that catheter-directed thrombolysis and surgical embolectomy were often utilized. Notably, we found an
AC
independent association between use of any advanced therapy and reduced mortality among the entire pulmonary embolism population. Although we did not have sufficient power to examine which interventions were most beneficial, this finding supports the continued consideration of escalated care beyond systemic anticoagulation in this highrisk population.
14
ACCEPTED MANUSCRIPT
Consistent with prior studies7, the risk of mortality among those with massive pulmonary embolism was greatest during the index hospitalization, and by 30 days, those alive were likely to survive to 90 days. This differed from those with submassive pulmonary embolism, where the mortality risk persisted throughout the 90-day period of
CR IP T
follow-up. Interestingly, patient characteristics did not vary substantially between groups, and over one-third of all deaths were attributed to the pulmonary embolism event itself
(versus other causes). As such, it is possible that the upfront use of advanced therapies, which were more often utilized in the massive pulmonary embolism population, may
AN US
modify the long-term risks of mortality related to high-risk pulmonary embolism.
However, this finding is only hypothesis generating and requires further investigation. Major bleeding occurred frequently in our analysis, affecting 14% of all patients and
M
26% of those with massive pulmonary embolism. These events were in part the consequence of the use of advanced therapies. Nonetheless, advanced therapies were
ED
found to be independently associated with lower mortality, even after adjustment for bleeding events. As advanced therapies appear associated with better outcomes but
PT
increased bleeding, risk stratification tools to identify patients most likely to benefit from
CE
treatment and least likely to be harmed may assist in optimizing outcomes among these high-risk patients.
AC
The results of this analysis must be considered in the context of the study design.
Strengths of this study include the inclusion of contemporary patients treated at a large, tertiary medical center that offers an array of advanced treatment options for pulmonary embolism. In addition, the database used for this analysis includes detailed, prospectively collected patient-level data and adjudicated outcomes. Limitations include the use of data
15
ACCEPTED MANUSCRIPT
from a single medical center, which offers treatments that may not be readily available in the community and employs a coordinated multi-disciplinary treatment team to care for all high-risk pulmonary embolism patients. In addition, the small sample size and event rates in this study limited the ability to conduct more detailed comparisons, such as the
CR IP T
relationship between individual advanced therapies, pulmonary embolism type, and
mortality. Nonetheless, compared to other analyses, our study includes one of the largest cohorts of massive pulmonary embolism patients with detailed patient data and out-ofhospital follow-up. Finally, treatment decisions may have been decided based on
AN US
unmeasured factors that could not be accounted for in our analysis.
Conclusions
M
In this contemporary cohort of massive and submassive pulmonary embolism patients, mortality rates remain substantial. Risks of mortality were greatest during the
ED
hospitalization for those with massive pulmonary embolism, yet persisted after discharge for those with submassive pulmonary embolism. Advanced therapies were frequently
PT
utilized in this population, and demonstrated an independent association with lower
CE
mortality. Further investigation is needed to determine how to improve outcomes among
AC
these high-risk patients, including the optimal use of advanced therapies.
Acknowledgements: Role of Sponsors and Funding: None
16
ACCEPTED MANUSCRIPT
References
6. 7. 8. 9.
10.
AC
CE
11.
CR IP T
5.
AN US
4.
M
3.
ED
2.
Heit JA. The epidemiology of venous thromboembolism in the community. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(3):370-372. Anderson FA, Jr., Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Archives of internal medicine. 1991;151(5):933-938. 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(16):1788-1830. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-3069, 3069a-3069k. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352. Becattini C, Agnelli G. Predictors of mortality from pulmonary embolism and their influence on clinical management. Thrombosis and haemostasis. 2008;100(5):747-751. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation. 2006;113(4):577-582. Weinberg I, Jaff MR. Accelerated thrombolysis for pulmonary embolism: will clinical benefit be ULTIMAtely realized? Circulation. 2014;129(4):420-421. 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(2):384-393. Sista AK, Friedman OA, Dou E, et al. A Pulmonary Embolism Response Team's initial 20 month experience treating 87 patients with submassive and massive pulmonary embolism. Vascular medicine (London, England). 2017:1358863x17730430. Provias T, Dudzinski DM, Jaff MR, et al. The Massachusetts General Hospital Pulmonary Embolism Response Team (MGH PERT): creation of a multidisciplinary program to improve care of patients with massive and submassive pulmonary embolism. Hospital practice (1995). 2014;42(1):3137. Jain CC, Chang Y, Kabrhel C, et al. Impact of Pulmonary Arterial Clot Location on Pulmonary Embolism Treatment and Outcomes (90 Days). The American journal of cardiology. 2017;119(5):802-807. Goldhaber SZ. Advanced treatment strategies for acute pulmonary embolism, including thrombolysis and embolectomy. Journal of thrombosis and haemostasis : JTH. 2009;7 Suppl 1:322-327. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):1386-1389.
PT
1.
12. 13. 14.
17
ACCEPTED MANUSCRIPT
18. 19. 20. 21.
22.
AC
CE
PT
ED
23.
CR IP T
17.
AN US
16.
Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediaterisk pulmonary embolism. The New England journal of medicine. 2014;370(15):1402-1411. Cefalo P, Weinberg I, Hawkins BM, et al. A comparison of patients diagnosed with pulmonary embolism who are >/=65 years with patients <65 years. The American journal of cardiology. 2015;115(5):681-686. Jimenez D, de Miguel-Diez J, Guijarro R, et al. Trends in the Management and Outcomes of Acute Pulmonary Embolism: Analysis From the RIETE Registry. Journal of the American College of Cardiology. 2016;67(2):162-170. Riera-Mestre A, Jimenez D, Muriel A, et al. Thrombolytic therapy and outcome of patients with an acute symptomatic pulmonary embolism. Journal of thrombosis and haemostasis : JTH. 2012;10(5):751-759. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. European heart journal. 2015;36(10):605-614. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. Jama. 2014;311(23):2414-2421. Lin BW, Schreiber DH, Liu G, et al. Therapy and outcomes in massive pulmonary embolism from the Emergency Medicine Pulmonary Embolism in the Real World Registry. The American journal of emergency medicine. 2012;30(9):1774-1781. Ibrahim SA, Stone RA, Obrosky DS, Geng M, Fine MJ, Aujesky D. Thrombolytic therapy and mortality in patients with acute pulmonary embolism. Archives of internal medicine. 2008;168(20):2183-2190. Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, et al. Streptokinase and Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled Trial. Journal of thrombosis and thrombolysis. 1995;2(3):227-229.
M
15.
18
ACCEPTED MANUSCRIPT
Table 1. Demographics and Comorbidities, Stratified by Massive versus Submassive Pulmonary Embolism
Comorbidity (N,%)
PE Classification Massive Submassive (N=46) (N=292)
Female
167 (49.4%)
26 (56.5%)
141 (48.3%)
0.30
Coronary artery disease
42 (12.4%)
1 (2.2%)
41 (14.0%)
0.02
Congestive heart failure
25 (7.4%)
2 (4.3%)
23 (7.9%)
0.40
Diabetes mellitus
64 (18.9%)
10 (21.7%)
54 (18.5%)
0.60
Hypertension
192 (56.8%)
25 (54.3%)
167 (57.2%)
0.72
Asthma/COPD
56 (16.6%)
6 (13.0%)
50 (17.1%)
0.49
Chronic kidney disease
33 (9.8%)
3 (6.5%)
30 (10.3%)
0.43
108 (32.0%)
18 (39.1%)
90 (30.8%)
0.26
74 (21.9%)
16 (34.8%)
58 (19.9%)
0.02
7 (2.1%)
1 (2.2%)
6 (2.1%)
0.96
AN US
ED
PT
Surgery within 28 days of presentation
CE
History of hypercoagulability
AC
Abbreviations: COPD, chronic obstructive pulmonary disease; PE, pulmonary embolism; SD, standard deviation
19
0.91
CR IP T
63 ± 14
Malignancy
63 ± 16
P value
63 ± 15
M
Age, years (mean ± SD)
All PE (N=338)
ACCEPTED MANUSCRIPT
Table 2. Symptoms and Markers of Right Ventricular Involvement, Stratified by Massive versus Submassive Pulmonary Embolism All PE (N=338)
Comorbidity (N,%)
Massive (N=46)
PE Classification Submassive (N=292)
P value
Symptoms 0 (0.0%)
Dyspnea
264 (78.1%)
28 (60.9%)
Chest Pain
115 (34.0%)
18 (39.1%)
---
12 (26.1%)
9 (2.7%)
2 (4.3%)
Hypotension*
---
39 (84.8%)
Tachycardia†
246 (72.8%)
Hypoxia‡
173 (51.2%)
Syncope Hemoptysis
97 (33.2%)
0.43
---
---
7 (2.4%)
0.44
---
---
42 (91.3%)
204 (69.9%)
<0.01
28 (60.9%)
145 (49.7%)
0.16
169/286 (59.1%) 156/274 (56.9%)
208 (61.5%)
38 (82.6%)
170 (58.2%)
<0.01
204 (60.4%)
39 (84.8%)
165 (56.5%)
<0.01
149 (44.1%)
28 (60.9%)
121 (41.4%)
0.01
186 (55.0%)
35 (76.1%)
151 (51.7%)
<0.01
ED
PT
CE
RV dilation on CT
<0.01
39/45 (86.7%) 24/37 (64.9%)
Elevated NT-proBNP||
RV hypokinesis on TTE RV systolic dysfunction on TTE
236 (80.8%)
208/331 (62.8%) 180/311 (57.9%)
Elevated troponin T§
RV dilation on TTE
0.33
M
Markers of RV involvement
6 (2.1%)
CR IP T
6 (1.8%)
AN US
Asymptomatic
<0.01 0.38
AC
*Hypotension defined as systolic blood pressure <90mmHg for >15 minutes †Tachycardia defined as heart rate >100 beats per minute ‡Hypoxia defined as noninvasive oxygen saturation <92% §Elevated troponin T defined as >0.01 ng/mL ||Elevated NT-proBNP defined as ≥500 pg/mL Abbreviations: BNP, brain natriuretic peptide; CT, computed tomography; PE, pulmonary embolism; RV, right ventricular; TTE, transthoracic echocardiography
20
ACCEPTED MANUSCRIPT
Table 3. Therapeutic Interventions, Stratified by Massive versus Submassive Pulmonary Embolism All PE (N=338)
0 ≤1 ≤3 ≤7
247 (73.1%) 314 (92.9%) 328 (97.0%) 330 (97.6%)
37 (80.4%) 44 (95.7%) 45 (97.8%) 46 (100.0%)
210 (71.9%) 270 (92.5%) 283 (96.9%) 284 (97.3%)
0.23 0.43 0.74 0.26
0 ≤1
5 (1.5%) 23 (6.8%)
1 (2.2%) 5 (10.9%)
4 (1.4%) 18 (6.2%)
0.67 0.24
≤3
55 (16.3%)
11 (23.9%)
44 (15.1%)
0.13
≤7
70 (20.7%)
14 (30.4%)
56 (19.2%)
0.08
0 ≤1 ≤3 ≤7
5 (1.5%) 13 (3.8%) 16 (4.7%) 16 (4.7%)
5 (10.9%) 11 (23.9%) 14 (30.4%) 14 (30.4%)
0 (0.0%) 2 (0.7%) 2 (0.7%) 2 (0.7%)
<0.01 <0.01 <0.01 <0.01
AN US
IVC filter insertion
ED
PT
AC
P value
0 ≤1 ≤3 ≤7
3 (0.9%) 23 (6.8%) 47 (13.9%) 47 (13.9%)
2 (4.3%) 4 (8.7%) 8 (17.4%) 8 (17.4%)
1 (0.3%) 19 (6.5%) 39 (13.4%) 39 (13.4%)
<0.01 0.58 0.46 0.46
0 ≤1 ≤3 ≤7
7 (2.1%) 34 (10.1%) 60 (17.8%) 60 (17.8%)
6 (13.0%) 14 (30.4%) 20 (43.5%) 20 (43.5%)
1 (0.3%) 20 (6.8%) 40 (13.7%) 40 (13.7%)
<0.01 <0.01 <0.01 <0.01
0 ≤1 ≤3 ≤7
0 (0.0%) 2 (0.6%) 2 (0.6%) 3 (0.9%)
0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
0 (0.0%) 2 (0.7%) 2 (0.7%) 3 (1.0%)
--0.57 0.57 0.49
CE
All thrombolysis
M
Systemic thrombolysis
Catheterdirected thrombolysis
CR IP T
Therapy (N,%) Systemic anticoagulation
PE Classification Massive Submassive (N=46) (N=292)
Days from Presentati on
Endovascular clot retrieval
21
ACCEPTED MANUSCRIPT
ECMO 0 ≤1 ≤3 ≤7
1 (0.3%) 4 (1.2%) 6 (1.8%) 7 (2.1%)
1 (2.2%) 4 (8.7%) 5 (10.9%) 6 (13.0%)
0 (0.0%) 0 (0.0%) 1 (0.3%) 1 (0.3%)
0.01 <0.01 <0.01 <0.01
0 ≤1 ≤3 ≤7
0 (0.0%) 9 (2.7%) 13 (3.8%) 15 (4.4%)
0 (0.0%) 4 (8.7%) 6(13.0%) 7 (15.2%)
0 (0.0%) 5 (1.7%) 7 (2.4%) 8 (2.7%)
--<0.01 <0.01 <0.01
0 ≤1 ≤3 ≤7
12 (3.6%) 64 (18.9%) 115 (34.0%) 128 (37.9%)
7 (15.2%) 22 (47.8%) 32 (69.6%) 33 (71.7%)
5 (1.7%) 42 (14.4%) 83 (28.4%) 95 (32.5%)
<0.01 <0.01 <0.01 <0.01
AN US
Advanced therapy*
CR IP T
Surgical embolectomy
AC
CE
PT
ED
M
*Advanced therapy defined as treatment with IVC filter, systemic thrombolysis, catheter-directed thrombolysis, endovascular suction embolectomy, surgical embolectomy, or ECMO Abbreviations: ECMO, extracorporeal membrane oxygenation; IVC, inferior vena cava; PE, pulmonary embolism
22
ACCEPTED MANUSCRIPT
Table 4. Death and Adverse Outcomes, Stratified by Massive versus Submassive Pulmonary Embolism All PE (N=338)
In-hospital ≤1 ≤30 ≤90
28 (8.3%) 8 (2.4%) 40 (11.8%) 55 (16.3%)
15 (32.6%) 7 (15.2%) 16 (34.8%) 19 (41.3%)
13 (4.5%) 1 (0.3%) 24 (8.2%) 36 (12.3%)
<0.01 <0.01 <0.01 <0.01
≤1 ≤30 ≤90
9 (2.7%) 39 (11.5%) 48 (14.2%)
4 (8.7%) 11 (23.9%) 12 (26.1%)
5 (1.7%) 28 (9.6%) 36 (12.3%)
<0.01 <0.01 0.01
≤1 ≤30 ≤90
1 (0.3%) 3 (0.9%) 4 (1.2%)
0 (0.0%) 2 (4.3%) 2 (4.3%)
1 (0.3%) 1 (0.4%) 2 (0.8%)
0.69 <0.01 0.03
AN US
Major bleeding
CR IP T
Variable (N,%) Death
PE Classification Massive Submassive (N=46) (N=292)
Days from Presentation
Intracranial hemorrhage
AC
CE
PT
ED
M
Abbreviations: PE, pulmonary embolism
23
P value
ACCEPTED MANUSCRIPT
Table 5. Predictors of 90-Day Mortality
P value
Massive PE (versus submassive PE)
5.23
2.70, 10.13
<0.01
Malignancy
2.63
1.48, 4.71
<0.01
Major bleeding within 7 days
1.98
0.84, 4.64
0.12
Age (per 10 years)
1.25
1.02, 1.52
0.03
Male (versus female)
1.13
0.65, 1.97
0.67
AN US
Variable
CR IP T
Hazard Ratio
95% Confidence Interval
Advanced therapy at 7 days
0.39
AC
CE
PT
ED
M
Abbreviations: PE, pulmonary embolism
24
0.20, 0.76
<0.01
ACCEPTED MANUSCRIPT
Figures Figure 1. Mortality following Presentation with Massive versus Submassive Pulmonary
CE
PT
ED
M
AN US
CR IP T
Embolism
AC
Figure 1 Legend. Displayed are Kaplan-Meier curves comparing the cumulative incidence of mortality between patients with massive and submassive pulmonary embolism. In unadjusted analysis, massive pulmonary embolism was associated with significantly lower 90-day survival compared with those with submassive pulmonary embolism (log-rank p<0.01).
25
Contemporary Management and Outcomes of Patients with Massive and Submassive Pulmonary Embolism Eric Secemsky , Yuchiao Chang , C. Charles Jain , Joshua A. Beckman , Jay Giri , Michael R. Jaff , Kenneth Rosenfield , Rachel Rosovsky , Christopher Kabrhel , Ido Weinberg PII: DOI: Reference:
S0002-9343(18)30763-0 https://doi.org/10.1016/j.amjmed.2018.07.035 AJM 14787
To appear in:
The American Journal of Medicine
Received date: Revised date: Accepted date:
1 May 2018 17 July 2018 28 July 2018
Please cite this article as: Eric Secemsky , Yuchiao Chang , C. Charles Jain , Joshua A. Beckman , Jay Giri , Michael R. Jaff , Kenneth Rosenfield , Rachel Rosovsky , Christopher Kabrhel , Ido Weinberg , Contemporary Management and Outcomes of Patients with Massive and Submassive Pulmonary Embolism, The American Journal of Medicine (2018), doi: https://doi.org/10.1016/j.amjmed.2018.07.035
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Contemporary Management and Outcomes of Patients with Massive and Submassive Pulmonary Embolism Short title: Modern Outcomes after Massive and Submassive Pulmonary Embolism
CR IP T
Eric Secemsky MD MSca,b,c, Yuchiao Chang PhDb,d, C. Charles Jain MDe, Joshua A. Beckman MDf, Jay Giri MD MPHg, Michael R. Jaff DOb,h, Kenneth Rosenfield MDb,i, Rachel Rosovsky MDj, Christopher Kabrhel MD MPHk, Ido Weinberg MD MScb,i
PT
ED
M
AN US
Author affiliations: a Smith Center for Outcomes Research in Cardiology, Department of Medicine; Beth Israel Deaconess Medical Center, Boston, MA, USA b Harvard Medical School, Boston, MA, USA c Division of Cardiology, Department of Medicine; Beth Israel Deaconess Medical Center, Boston, MA, USA d Department of Medicine; Massachusetts General Hospital, Boston, MA, USA e Cardiovascular Division, Department of Medicine; Mayo Clinic, Rochester, MN, USA f Cardiovascular Division, Department of Medicine; Vanderbilt University Medical Center, Nashville, TN, USA g Penn Cardiovascular Outcomes, Quality, & Evaluative Research Center, Cardiovascular Medicine Division, Department of Medicine; University of Pennsylvania, Philadelphia, PA, USA h Newton-Wellesley Hospital, Boston, MA, USA i Division of Cardiology, The Fireman Vascular Center, Department of Medicine; Massachusetts General Hospital, Boston, MA, USA j Hematology and Oncology Division; Massachusetts General Hospital, Boston, MA, USA k Center for Vascular Emergencies, Department of Emergency Medicine; Massachusetts General Hospital, Boston, MA, USA
CE
Submission type: Clinical Research Study Word Count (Manuscript, Abstract, Acknowledgements): 3,054 words
AC
Address for Correspondence: Ido Weinberg, MD, MSc 55 Fruit Street, GRB-852G Vascular Medicine, Division of Cardiology, Department of Medicine Massachusetts General Hospital Boston, MA 02114 Phone: 617-726-2256 [email protected]
1
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
M
Role of Sponsors and Funding: None
AN US
CR IP T
Conflict of Interest: Dr. Beckman is a consultant for Aralez, Astra Zeneca, Janssen, Sanofi, and BMS (modest); serves on the data safety and monitoring board for Bayer (modest); and has equity in EMX and Janacare (modest). Dr. Giri is a board member of VIVA Physicians, a 501c3 not-for-profit education and research organization (modest). Dr. Jaff is a compensated advisor for Philips/Volcano and Venarum (modest); an equity Investor for Embolitech, Vascular Therapies, PQ Bypass, MC10, Jana Care, and Sano V (modest). Dr. Kabrhel has received grant funding (paid to his institution) from NIH, Janssen, Diagnostica Stago, Siemens Healthcare Diagnostics and BoehringerIngelheim. Dr. Rosenfield is a consultant for Abbott Vascular, Cardinal Health, Cook, Thrombolex, Surmodics, Volcano/Philips, Amegen; is a consultant, on the scientific advisory board with equity or stock options from Capture Vascular, Contego, Cruzar systems, Endospan, Eximo, MD Insider, Micell, Shockwave, Silkroad Medical, Valcare, Thrombolex; has received equity or stock options for serving on advisory boards from PQ Bypass, Primacea, Capture Vascular, VORTEX, MD Insider, Micell, Shockwave, Cruzar Systems, Endospan, Eximo, Valcare, Contego (modest); has received research grant support to his institution from Atrium-Getinge, Inari Medical, National Institutes of Health, Lutonix-Bard (modest); and is a board member of the National PERT Consortium, a 501c3 non-for-profit education and research organization and VIVA Physicians, a 501c3 not-for-profit education and research organization (modest). Dr. Weinberg is on the scientific advisory board for Novate Medical. All other authors have no relevant disclosures.
2
ACCEPTED MANUSCRIPT
Abstract Background: Few contemporary studies have assessed the management and outcomes of patients with massive and submassive pulmonary embolism. Given advances in therapy,
CR IP T
we report contemporary practice patterns and event rates among these patients.
Methods: We analyzed a prospective database of patients with massive and submassive pulmonary embolism. We report clinical characteristics, therapies and outcomes stratified by pulmonary embolism type. Treatment escalation beyond systemic
AN US
anticoagulation was defined as advanced therapy. Cox proportional hazards regression was used to identify predictors of 90-day mortality.
M
Results: Among 338 patients, 46 (13.6%) presented with massive and 292 (86.4%) with submassive pulmonary embolism. The average age was 63±15 years, 49.9% were female,
ED
32.0% had malignancy and 21.9% had recent surgery. Massive pulmonary embolism patients received advanced therapy in 71.7% (30.4% systemic thrombolysis; 17.4%
PT
catheter-directed thrombolysis; 15.2% surgical embolectomy) and had greater 90-day
CE
mortality rates compared with submassive pulmonary embolism patients (41.3% versus 12.3%, respectively; p<0.01). The majority of massive pulmonary embolism deaths
AC
(78.9%) occurred in-hospital, whereas mortality risk persisted after discharge for submassive pulmonary embolism. After multivariable adjustment, massive pulmonary embolism was associated with a 5.23-fold greater hazard of mortality (95%CI: 2.70, 10.13; p<0.01). Advanced therapies among all pulmonary embolism patients were associated with a 61% reduction in mortality (95%CI: 0.20, 0.76; p<0.01).
3
ACCEPTED MANUSCRIPT
Conclusions: Among contemporary massive and submassive pulmonary embolism patients, mortality remains substantial. Advanced therapies were frequently utilized and independently associated with lower mortality. Further investigation is needed to determine how to improve outcomes among these high-risk patients, including the
AC
CE
PT
ED
M
AN US
CR IP T
optimal use of advanced therapies.
4
ACCEPTED MANUSCRIPT
Introduction Pulmonary embolism is a common cause of cardiovascular death after myocardial infarction and stroke1,2. However, the management of pulmonary embolism is variable and based on less evidence to guide therapy3-5. This may be a result of the heterogeneous
CR IP T
presentation of pulmonary embolism, which ranges from asymptomatic to hemodynamic instability, and sudden death.
Pulmonary embolism risk classification in consensus guidelines is according to
the hemodynamic consequences of the embolus. These classifications have demonstrated
AN US
a strong relationship with outcomes6. In particular, massive pulmonary embolism, the most severe form of pulmonary embolism and defined by the presence of cardiogenic shock, is associated with a high mortality rate7. While hemodynamic stability at
M
presentation is useful to risk stratify patients, these patients represent a small minority of those at risk for death. The ability to tailor therapy for the near massive and submassive
ED
patients in order to optimize outcomes is currently lacking8. Part of the limitation in individualizing therapy is that the majority of published
PT
data regarding the management and outcomes associated with massive pulmonary
CE
embolism are more than a decade old7. For example, the effectiveness of invasive therapies that have become available in recent years, such as catheter-directed lysis and
AC
endovascular clot retrieval9,10, is not well established. Given the significant advances in the diagnostics, therapeutics and multidisciplinary care of patients with massive and submassive pulmonary embolism, an assessment of contemporary practices and outcomes is warranted.
5
ACCEPTED MANUSCRIPT
Methods This analysis used data from the Massachusetts General Hospital Pulmonary Embolism Response Team database, which have been previously described11. Patients are prospectively enrolled into the database upon presentation with pulmonary embolism and
CR IP T
followed in the inpatient and outpatient settings. Data, including demographics,
laboratory data and treatments received, are collected by trained research personnel. Data collection and this analysis were approved by the Human Research Committee of Partners HealthCare.
AN US
From this dataset, we analyzed all patients with massive or submassive pulmonary embolism. Massive pulmonary embolism was defined as any pulmonary embolism that resulted in sustained (>15minutes) hypotension (systolic blood pressure <90mmHg) or
M
any period of pulselessness. Submassive pulmonary embolism was defined as any pulmonary embolism without hemodynamic compromise, but with evidence of right
ED
ventricular strain. Right ventricular strain was defined by any of the following: elevated troponin T (defined as >0.01 ng/mL), elevated N-terminal pro-brain natriuretic peptide
PT
(NT-proBNP) (defined as ≥500 pg/mL), and/or imaging evidence of new right ventricular
CE
strain (right:left ventricular ratio greater than 1.0 on computed tomography or right ventricle hypokinesis/dilation on transthoracic echocardiogram).
AC
Pulmonary embolism presentation was considered day 0 and defined by the
activation of the pulmonary embolism response team. Among patients diagnosed with pulmonary embolism at our institution, the median time from diagnostic computed tomography to pulmonary embolism team consultation was 50 minutes (interquartile range 23-197 minutes). Patient characteristics were collected at baseline. Symptoms were
6
ACCEPTED MANUSCRIPT
collected within 3 days of presentation. Markers of right ventricular involvement were assessed based on laboratory and imaging studies performed closest to the time of presentation. Therapies included systemic anticoagulation (anticoagulant agent not specified for this study), inferior vena cava filter placement, systemic intravenous
CR IP T
thrombolysis, catheter-directed thrombolysis, endovascular clot retrieval, extracorporeal membrane oxygenation and surgical embolectomy. Advanced therapy was defined as the utilization of one or more of these treatment modalities, excluding systemic anticoagulation, as defined previously12,13.
AN US
The primary outcome was all-cause mortality at 90 days. Secondary outcomes included in-hospital mortality, major bleeding, intracranial hemorrhage and 30-day
readmission rates. The major bleeding endpoint was defined by symptomatic bleeding in
M
a critical area or organ that either required surgical consultation or intervention, or resulted in transfusion of two or more units of red blood cells, as used previously14-16.
ED
Readmissions within 30 days of discharge within the Partners HealthCare system were identified. Patients who died prior to 30 days after discharge were excluded, unless the
CE
PT
readmission occurred prior to death.
Statistical Analysis
AC
Categorical variables were reported as counts and percentages, and continuous
variables as means with standard deviations or medians with inter-quartiles. Betweengroup differences were assessed using chi-square tests for categorical variables, and Student’s t-tests or Wilcoxon rank sum tests for continuous variables.
7
ACCEPTED MANUSCRIPT
Follow-up started at the time of presentation and continued until date of death or at study completion of one year. Rates of interventions received were assessed at the prespecified time points of 0, ≤1, ≤3 and ≤7 days from presentation. Patients who died in the earlier time periods were included in the denominator of rate calculation and
CR IP T
considered as no treatment if treatment was not received before death. Kaplan-Meier
curves were used to depict the cumulative incidence of death following presentation and differences were compared using the log-rank test. Based on prior literature and clinical knowledge, a Cox proportional hazards model was created to explore independent factors
AN US
associated with 90-day mortality. This model included massive versus submassive
pulmonary embolism, age per 10 years, sex, history of malignancy, use of advanced therapy within 7 days of presentation and major bleeding within 7 days of presentation. A
M
logistic regression model was used to explore the independent association between massive pulmonary embolism and major bleeding at 90 days, adjusting for age per 10
ED
years, sex and use of advanced therapy within 7 days of presentation. A two-sided p value <0.05 was considered statistically significant. Statistical
CE
PT
analyses were performed using SAS software v9.4 (SAS Institute, Cary, NC, USA).
Results
AC
Patient Characteristics and Symptoms at Presentation Of the 338 patients included in the analysis, 46 (13.6%) presented with massive
and 292 (86.4%) with submassive pulmonary embolism. The average age was 63±15 years, 49.4% were female, 32.0% had malignancy, 21.9% had recent surgery and 2.1% had a history of hypercoagulability. Patients with massive compared with submassive
8
ACCEPTED MANUSCRIPT
pulmonary embolism were of similar age and sex, and had a similar proportion of comorbidities (Table 1). However, massive pulmonary embolism patients had a lower rate of coronary artery disease and a higher rate of recent surgery. Among those with submassive pulmonary embolism, dyspnea was the predominant symptom at presentation
CR IP T
(80.8%), followed by tachycardia (69.9%) and hypoxia (49.7%) (Table 2).
Among all patients, 62.8% had an elevated troponin and 57.9% had an elevated NT-proBNP (Table 2). Imaging evidence of right ventricular strain occurred more
AN US
commonly among those with massive versus submassive pulmonary embolism.
Treatment Patterns of Massive and Submassive Pulmonary Embolism Table 3 outlines the therapies received by the study population. Within 7 days of
M
presentation, 97.6% of all patients had received systemic anticoagulation, 20.7% had received an inferior vena cava filter, 13.9% had received catheter-directed thrombolysis
ED
and 37.9% had received any type of advanced therapy. Among patients with massive pulmonary embolism, 71.7% received advanced
PT
therapies, most commonly systemic thrombolysis and inferior vena cava filter placement
CE
(both 30.4%), followed by catheter-directed thrombolysis (17.4%), surgical embolectomy (15.2%) and extracorpeal membrane oxygenation (13.0%). Of those who did not receive
AC
thrombolysis, the primary reason was contraindication due to bleeding concerns (88.9%). Comparing patients with massive and submassive pulmonary embolism, there
were no significant differences in the proportion of patients who received systemic anticoagulation, catheter-directed thrombolysis, endovascular clot retrieval or inferior vena cava filters within 7 days. However, massive pulmonary embolism patients more
9
ACCEPTED MANUSCRIPT
often received systemic thrombolysis, extracorpeal membrane oxygenation, surgical embolectomy and any advanced therapy (Table 3).
Outcomes Associated with Massive and Submassive Pulmonary Embolism
CR IP T
Death and adverse events occurred more commonly among those with massive compared with submassive pulmonary embolism (Table 4). The rate of in-hospital
mortality was 8.3% for the total cohort, occurring in 32.6% of those with massive and 4.5% of those with submassive pulmonary embolism (p<0.01). By 90 days of
AN US
presentation, 16.3% of the total cohort died, with a death rate of 41.3% among those with massive and 12.3% among those with submassive pulmonary embolism (p<0.01). The majority of deaths (78.9%) among those with massive pulmonary embolism occurred
M
during the index hospitalization, whereas among those with submassive pulmonary embolism, the risk of death persisted post-discharge (Figure 1). For patients with
ED
identifiable causes of death, 90-day mortality was directly related to pulmonary embolism in 45.0% (9/20) of patients with massive pulmonary embolism and 31.6% (10/32) of
PT
patients with submassive pulmonary embolism.
CE
Among all pulmonary embolism patients who received advanced therapies, the 30-day mortality rate was 9.4% and the 90-day mortality rate was 11.7%. Mortality rates
AC
at 30 days and 90 days did not statistically differ between those who received versus did not receive advanced therapies (30 days: 9.4% vs. 13.3%, respectively, p=0.30; 90 days: 11.7% vs. 19.0%, respectively, p=0.09). When stratified by pulmonary embolism type, those with massive pulmonary embolism had a trend towards lower mortality with receipt of advanced therapies (30 days: 27.3% with advanced therapies vs. 53.8% without
10
ACCEPTED MANUSCRIPT
advanced therapies, p=0.17; 90 days: 33.3% with advanced therapies vs. 61.5% without advanced therapies, p=0.10), and those with submassive pulmonary embolism who received advanced therapies had significant reductions in both 30-day and 90-day mortality (30 days: 3.2% with advanced therapies vs. 10.7% without advanced therapies,
CR IP T
p=0.04; 90 days: 4.2% with advanced therapies vs. 16.2% without advanced therapies,
p<0.01). Morality rates for each advanced therapy, stratified by massive and submassive pulmonary embolism, can be found in eTable 1.
Major bleeding occurred in 14.2% of the total patient population within 90 days,
AN US
with a greater frequency among those with massive (26.1%) relative to those with
submassive pulmonary embolism (12.3%) (p=0.01). The frequency of intracranial hemorrhage was also greater among those with massive versus submassive pulmonary
M
embolism (4.3% vs. 0.8%, respectively; p=0.03). Major bleeding rates were greater among those who received advanced therapies relative to those who did not (30-days:
ED
18.8% vs. 7.6%, p<0.01; 90-days: 19.5% vs. 11.4%, p=0.09). When stratified by pulmonary embolism type, those with massive pulmonary embolism treated with
PT
advanced therapies had numerically greater major bleeding at 30 days and 90 days, but
CE
this did not reach statistical significance (30 days: 30.3% with advanced therapies vs. 15.4% without advanced therapies, p=0.46; 90 days: 30.3% with advanced therapies vs.
AC
23.1% without advanced therapies, p=0.73). Similarly, those with submassive pulmonary embolism who received advanced therapies had a trend towards increased major bleeding at 30 days (14.7% with advanced therapies vs. 7.1% without advanced therapies, p=0.06), but no significant difference in major bleeding rates at 90 days (15.8% with advanced therapies vs. 10.7% without advanced therapies, p=0.25).
11
ACCEPTED MANUSCRIPT
The 30-day readmission rate was 16.3%. Readmissions within 30 days were numerically greater among patients with massive pulmonary embolism, but this did not reach statistical significance (29.0% with massive vs. 14.9% with submassive, p=0.07). Patients who received advanced therapies had similar 30-day readmission rates compared
CR IP T
with those who did not receive these interventions (15.9% vs. 17.6%, respectively; p=0.71).
The overall rate of recurrent pulmonary embolism within 90 days after
presentation was 2.4% and within 365 days was 3.8%. All recurrent pulmonary embolism
AN US
events occurred among those with submassive pulmonary embolism.
In adjusted analysis, patients with massive pulmonary embolism had a 5.23-fold greater hazard of 90-day mortality relative to those with submassive pulmonary
M
embolism (95%CI: 2.70, 10.13; p<0.01) (Table 5). Other predictors of 90-day mortality included malignancy (hazard ratio [HR] 2.63; 95%CI: 1.48, 4.17; p<0.01) and age (age
ED
per 10-year increase: HR 1.25; 95%CI: 1.02, 1.52; p=0.03), whereas the use of advanced therapies was independently associated with lower mortality (HR 0.39; 95%CI: 0.20,
PT
0.76; p<0.01). In addition, patients with massive pulmonary embolism had a 2.28-fold
CE
greater adjusted odds of major bleeding compared with those with submassive pulmonary embolism (95%CI: 1.03, 5.03; p=0.04), which included adjustment for use of advanced
AC
therapies.
Discussion In this analysis of patients presenting with massive and submassive pulmonary embolism, we demonstrate that heterogeneity in treatment patterns and high mortality
12
ACCEPTED MANUSCRIPT
risks persist in contemporary clinical practice. Advanced therapies were frequently utilized in this population, yet systemic thrombolysis was employed less often than invasive procedures. Nevertheless, advanced therapies were independently associated with decreased mortality. Major bleeding was substantial (14.2% of all patients). Among
CR IP T
massive pulmonary embolism patients, more than 1 in 3 died within 90 days of
presentation. The majority of these deaths occurred in-hospital, whereas among those with submassive pulmonary embolism, the risk of mortality persisted after discharge.
Recent publications have shown a trend towards reduced mortality for pulmonary
AN US
embolism patients17, yet death rates among the subset with massive pulmonary embolism remain high18-20. For example, in a multicenter registry of emergency department patients with pulmonary embolism, the 30-day mortality among those with massive pulmonary
M
embolism was 25.9% and was nearly exclusive to the patients who did not receive systemic thrombolysis21. In a separate statewide analysis of pulmonary embolism-related
ED
treatment and outcomes, 26.5% of 803 patients with pulmonary embolism and hypotension died at 30 days22. In the current analysis, the 30-day mortality rate associated
PT
with massive pulmonary embolism was 34.8% and 41.3% at 90 days, exceeding the
CE
mortality rates in the aforementioned studies, but on par with the mortality rate found in the International Cooperative Pulmonary Embolism Registry (ICOPER) (90-day
AC
mortality rate of 52.4%)7. This may in part be due to the stringent and similar criteria used in our study and ICOPER to classify massive pulmonary embolism, as well as the detailed data available for adjudication. Nevertheless, in the decade encompassing the reporting of the referenced studies and our own, mortality rates among patients with massive pulmonary embolism remain substantial.
13
ACCEPTED MANUSCRIPT
With regards to submassive pulmonary embolism, 12.3% of patients in our study died by 90 days, which is also higher than previous analyses6,21, yet similar to the mortality rate published from ICOPER (90-day mortality rate of 14.7%)7. Importantly, submassive pulmonary embolism represents a heterogeneous group of patients, and our reported
CR IP T
mortality rate may reflect patients that were at higher risk of death compared with other studies. For instance, nearly 50% of submassive patients in the current analysis had
documented hypoxia, 70% had tachycardia, and only 2.1% presented without symptoms. To date, data on the utilization of advanced therapies for massive pulmonary
AN US
embolism are limited19,20,23. In a report from the EMPEROR registry that included 58
patients with massive pulmonary embolism, systemic thrombolysis was administered in only 12.0% of patients21. Additionally, in an analysis of 108 massive pulmonary
M
embolism patients from ICOPER, less than one third of patients received thrombolytic therapy7. However, novel treatments that are available in advanced centers today were
ED
not available at the time these studies were conducted. In the current analysis, more than 70% of patients with massive pulmonary embolism received advanced therapies. The
PT
most commonly used intervention remained systemic thrombolysis, yet this made up less
CE
than half of all advanced therapies employed. Instead, we observed that catheter-directed thrombolysis and surgical embolectomy were often utilized. Notably, we found an
AC
independent association between use of any advanced therapy and reduced mortality among the entire pulmonary embolism population. Although we did not have sufficient power to examine which interventions were most beneficial, this finding supports the continued consideration of escalated care beyond systemic anticoagulation in this highrisk population.
14
ACCEPTED MANUSCRIPT
Consistent with prior studies7, the risk of mortality among those with massive pulmonary embolism was greatest during the index hospitalization, and by 30 days, those alive were likely to survive to 90 days. This differed from those with submassive pulmonary embolism, where the mortality risk persisted throughout the 90-day period of
CR IP T
follow-up. Interestingly, patient characteristics did not vary substantially between groups, and over one-third of all deaths were attributed to the pulmonary embolism event itself
(versus other causes). As such, it is possible that the upfront use of advanced therapies, which were more often utilized in the massive pulmonary embolism population, may
AN US
modify the long-term risks of mortality related to high-risk pulmonary embolism.
However, this finding is only hypothesis generating and requires further investigation. Major bleeding occurred frequently in our analysis, affecting 14% of all patients and
M
26% of those with massive pulmonary embolism. These events were in part the consequence of the use of advanced therapies. Nonetheless, advanced therapies were
ED
found to be independently associated with lower mortality, even after adjustment for bleeding events. As advanced therapies appear associated with better outcomes but
PT
increased bleeding, risk stratification tools to identify patients most likely to benefit from
CE
treatment and least likely to be harmed may assist in optimizing outcomes among these high-risk patients.
AC
The results of this analysis must be considered in the context of the study design.
Strengths of this study include the inclusion of contemporary patients treated at a large, tertiary medical center that offers an array of advanced treatment options for pulmonary embolism. In addition, the database used for this analysis includes detailed, prospectively collected patient-level data and adjudicated outcomes. Limitations include the use of data
15
ACCEPTED MANUSCRIPT
from a single medical center, which offers treatments that may not be readily available in the community and employs a coordinated multi-disciplinary treatment team to care for all high-risk pulmonary embolism patients. In addition, the small sample size and event rates in this study limited the ability to conduct more detailed comparisons, such as the
CR IP T
relationship between individual advanced therapies, pulmonary embolism type, and
mortality. Nonetheless, compared to other analyses, our study includes one of the largest cohorts of massive pulmonary embolism patients with detailed patient data and out-ofhospital follow-up. Finally, treatment decisions may have been decided based on
AN US
unmeasured factors that could not be accounted for in our analysis.
Conclusions
M
In this contemporary cohort of massive and submassive pulmonary embolism patients, mortality rates remain substantial. Risks of mortality were greatest during the
ED
hospitalization for those with massive pulmonary embolism, yet persisted after discharge for those with submassive pulmonary embolism. Advanced therapies were frequently
PT
utilized in this population, and demonstrated an independent association with lower
CE
mortality. Further investigation is needed to determine how to improve outcomes among
AC
these high-risk patients, including the optimal use of advanced therapies.
Acknowledgements: Role of Sponsors and Funding: None
16
ACCEPTED MANUSCRIPT
References
6. 7. 8. 9.
10.
AC
CE
11.
CR IP T
5.
AN US
4.
M
3.
ED
2.
Heit JA. The epidemiology of venous thromboembolism in the community. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(3):370-372. Anderson FA, Jr., Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Archives of internal medicine. 1991;151(5):933-938. 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(16):1788-1830. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-3069, 3069a-3069k. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352. Becattini C, Agnelli G. Predictors of mortality from pulmonary embolism and their influence on clinical management. Thrombosis and haemostasis. 2008;100(5):747-751. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation. 2006;113(4):577-582. Weinberg I, Jaff MR. Accelerated thrombolysis for pulmonary embolism: will clinical benefit be ULTIMAtely realized? Circulation. 2014;129(4):420-421. 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(2):384-393. Sista AK, Friedman OA, Dou E, et al. A Pulmonary Embolism Response Team's initial 20 month experience treating 87 patients with submassive and massive pulmonary embolism. Vascular medicine (London, England). 2017:1358863x17730430. Provias T, Dudzinski DM, Jaff MR, et al. The Massachusetts General Hospital Pulmonary Embolism Response Team (MGH PERT): creation of a multidisciplinary program to improve care of patients with massive and submassive pulmonary embolism. Hospital practice (1995). 2014;42(1):3137. Jain CC, Chang Y, Kabrhel C, et al. Impact of Pulmonary Arterial Clot Location on Pulmonary Embolism Treatment and Outcomes (90 Days). The American journal of cardiology. 2017;119(5):802-807. Goldhaber SZ. Advanced treatment strategies for acute pulmonary embolism, including thrombolysis and embolectomy. Journal of thrombosis and haemostasis : JTH. 2009;7 Suppl 1:322-327. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):1386-1389.
PT
1.
12. 13. 14.
17
ACCEPTED MANUSCRIPT
18. 19. 20. 21.
22.
AC
CE
PT
ED
23.
CR IP T
17.
AN US
16.
Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediaterisk pulmonary embolism. The New England journal of medicine. 2014;370(15):1402-1411. Cefalo P, Weinberg I, Hawkins BM, et al. A comparison of patients diagnosed with pulmonary embolism who are >/=65 years with patients <65 years. The American journal of cardiology. 2015;115(5):681-686. Jimenez D, de Miguel-Diez J, Guijarro R, et al. Trends in the Management and Outcomes of Acute Pulmonary Embolism: Analysis From the RIETE Registry. Journal of the American College of Cardiology. 2016;67(2):162-170. Riera-Mestre A, Jimenez D, Muriel A, et al. Thrombolytic therapy and outcome of patients with an acute symptomatic pulmonary embolism. Journal of thrombosis and haemostasis : JTH. 2012;10(5):751-759. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. European heart journal. 2015;36(10):605-614. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. Jama. 2014;311(23):2414-2421. Lin BW, Schreiber DH, Liu G, et al. Therapy and outcomes in massive pulmonary embolism from the Emergency Medicine Pulmonary Embolism in the Real World Registry. The American journal of emergency medicine. 2012;30(9):1774-1781. Ibrahim SA, Stone RA, Obrosky DS, Geng M, Fine MJ, Aujesky D. Thrombolytic therapy and mortality in patients with acute pulmonary embolism. Archives of internal medicine. 2008;168(20):2183-2190. Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, et al. Streptokinase and Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled Trial. Journal of thrombosis and thrombolysis. 1995;2(3):227-229.
M
15.
18
ACCEPTED MANUSCRIPT
Table 1. Demographics and Comorbidities, Stratified by Massive versus Submassive Pulmonary Embolism
Comorbidity (N,%)
PE Classification Massive Submassive (N=46) (N=292)
Female
167 (49.4%)
26 (56.5%)
141 (48.3%)
0.30
Coronary artery disease
42 (12.4%)
1 (2.2%)
41 (14.0%)
0.02
Congestive heart failure
25 (7.4%)
2 (4.3%)
23 (7.9%)
0.40
Diabetes mellitus
64 (18.9%)
10 (21.7%)
54 (18.5%)
0.60
Hypertension
192 (56.8%)
25 (54.3%)
167 (57.2%)
0.72
Asthma/COPD
56 (16.6%)
6 (13.0%)
50 (17.1%)
0.49
Chronic kidney disease
33 (9.8%)
3 (6.5%)
30 (10.3%)
0.43
108 (32.0%)
18 (39.1%)
90 (30.8%)
0.26
74 (21.9%)
16 (34.8%)
58 (19.9%)
0.02
7 (2.1%)
1 (2.2%)
6 (2.1%)
0.96
AN US
ED
PT
Surgery within 28 days of presentation
CE
History of hypercoagulability
AC
Abbreviations: COPD, chronic obstructive pulmonary disease; PE, pulmonary embolism; SD, standard deviation
19
0.91
CR IP T
63 ± 14
Malignancy
63 ± 16
P value
63 ± 15
M
Age, years (mean ± SD)
All PE (N=338)
ACCEPTED MANUSCRIPT
Table 2. Symptoms and Markers of Right Ventricular Involvement, Stratified by Massive versus Submassive Pulmonary Embolism All PE (N=338)
Comorbidity (N,%)
Massive (N=46)
PE Classification Submassive (N=292)
P value
Symptoms 0 (0.0%)
Dyspnea
264 (78.1%)
28 (60.9%)
Chest Pain
115 (34.0%)
18 (39.1%)
---
12 (26.1%)
9 (2.7%)
2 (4.3%)
Hypotension*
---
39 (84.8%)
Tachycardia†
246 (72.8%)
Hypoxia‡
173 (51.2%)
Syncope Hemoptysis
97 (33.2%)
0.43
---
---
7 (2.4%)
0.44
---
---
42 (91.3%)
204 (69.9%)
<0.01
28 (60.9%)
145 (49.7%)
0.16
169/286 (59.1%) 156/274 (56.9%)
208 (61.5%)
38 (82.6%)
170 (58.2%)
<0.01
204 (60.4%)
39 (84.8%)
165 (56.5%)
<0.01
149 (44.1%)
28 (60.9%)
121 (41.4%)
0.01
186 (55.0%)
35 (76.1%)
151 (51.7%)
<0.01
ED
PT
CE
RV dilation on CT
<0.01
39/45 (86.7%) 24/37 (64.9%)
Elevated NT-proBNP||
RV hypokinesis on TTE RV systolic dysfunction on TTE
236 (80.8%)
208/331 (62.8%) 180/311 (57.9%)
Elevated troponin T§
RV dilation on TTE
0.33
M
Markers of RV involvement
6 (2.1%)
CR IP T
6 (1.8%)
AN US
Asymptomatic
<0.01 0.38
AC
*Hypotension defined as systolic blood pressure <90mmHg for >15 minutes †Tachycardia defined as heart rate >100 beats per minute ‡Hypoxia defined as noninvasive oxygen saturation <92% §Elevated troponin T defined as >0.01 ng/mL ||Elevated NT-proBNP defined as ≥500 pg/mL Abbreviations: BNP, brain natriuretic peptide; CT, computed tomography; PE, pulmonary embolism; RV, right ventricular; TTE, transthoracic echocardiography
20
ACCEPTED MANUSCRIPT
Table 3. Therapeutic Interventions, Stratified by Massive versus Submassive Pulmonary Embolism All PE (N=338)
0 ≤1 ≤3 ≤7
247 (73.1%) 314 (92.9%) 328 (97.0%) 330 (97.6%)
37 (80.4%) 44 (95.7%) 45 (97.8%) 46 (100.0%)
210 (71.9%) 270 (92.5%) 283 (96.9%) 284 (97.3%)
0.23 0.43 0.74 0.26
0 ≤1
5 (1.5%) 23 (6.8%)
1 (2.2%) 5 (10.9%)
4 (1.4%) 18 (6.2%)
0.67 0.24
≤3
55 (16.3%)
11 (23.9%)
44 (15.1%)
0.13
≤7
70 (20.7%)
14 (30.4%)
56 (19.2%)
0.08
0 ≤1 ≤3 ≤7
5 (1.5%) 13 (3.8%) 16 (4.7%) 16 (4.7%)
5 (10.9%) 11 (23.9%) 14 (30.4%) 14 (30.4%)
0 (0.0%) 2 (0.7%) 2 (0.7%) 2 (0.7%)
<0.01 <0.01 <0.01 <0.01
AN US
IVC filter insertion
ED
PT
AC
P value
0 ≤1 ≤3 ≤7
3 (0.9%) 23 (6.8%) 47 (13.9%) 47 (13.9%)
2 (4.3%) 4 (8.7%) 8 (17.4%) 8 (17.4%)
1 (0.3%) 19 (6.5%) 39 (13.4%) 39 (13.4%)
<0.01 0.58 0.46 0.46
0 ≤1 ≤3 ≤7
7 (2.1%) 34 (10.1%) 60 (17.8%) 60 (17.8%)
6 (13.0%) 14 (30.4%) 20 (43.5%) 20 (43.5%)
1 (0.3%) 20 (6.8%) 40 (13.7%) 40 (13.7%)
<0.01 <0.01 <0.01 <0.01
0 ≤1 ≤3 ≤7
0 (0.0%) 2 (0.6%) 2 (0.6%) 3 (0.9%)
0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
0 (0.0%) 2 (0.7%) 2 (0.7%) 3 (1.0%)
--0.57 0.57 0.49
CE
All thrombolysis
M
Systemic thrombolysis
Catheterdirected thrombolysis
CR IP T
Therapy (N,%) Systemic anticoagulation
PE Classification Massive Submassive (N=46) (N=292)
Days from Presentati on
Endovascular clot retrieval
21
ACCEPTED MANUSCRIPT
ECMO 0 ≤1 ≤3 ≤7
1 (0.3%) 4 (1.2%) 6 (1.8%) 7 (2.1%)
1 (2.2%) 4 (8.7%) 5 (10.9%) 6 (13.0%)
0 (0.0%) 0 (0.0%) 1 (0.3%) 1 (0.3%)
0.01 <0.01 <0.01 <0.01
0 ≤1 ≤3 ≤7
0 (0.0%) 9 (2.7%) 13 (3.8%) 15 (4.4%)
0 (0.0%) 4 (8.7%) 6(13.0%) 7 (15.2%)
0 (0.0%) 5 (1.7%) 7 (2.4%) 8 (2.7%)
--<0.01 <0.01 <0.01
0 ≤1 ≤3 ≤7
12 (3.6%) 64 (18.9%) 115 (34.0%) 128 (37.9%)
7 (15.2%) 22 (47.8%) 32 (69.6%) 33 (71.7%)
5 (1.7%) 42 (14.4%) 83 (28.4%) 95 (32.5%)
<0.01 <0.01 <0.01 <0.01
AN US
Advanced therapy*
CR IP T
Surgical embolectomy
AC
CE
PT
ED
M
*Advanced therapy defined as treatment with IVC filter, systemic thrombolysis, catheter-directed thrombolysis, endovascular suction embolectomy, surgical embolectomy, or ECMO Abbreviations: ECMO, extracorporeal membrane oxygenation; IVC, inferior vena cava; PE, pulmonary embolism
22
ACCEPTED MANUSCRIPT
Table 4. Death and Adverse Outcomes, Stratified by Massive versus Submassive Pulmonary Embolism All PE (N=338)
In-hospital ≤1 ≤30 ≤90
28 (8.3%) 8 (2.4%) 40 (11.8%) 55 (16.3%)
15 (32.6%) 7 (15.2%) 16 (34.8%) 19 (41.3%)
13 (4.5%) 1 (0.3%) 24 (8.2%) 36 (12.3%)
<0.01 <0.01 <0.01 <0.01
≤1 ≤30 ≤90
9 (2.7%) 39 (11.5%) 48 (14.2%)
4 (8.7%) 11 (23.9%) 12 (26.1%)
5 (1.7%) 28 (9.6%) 36 (12.3%)
<0.01 <0.01 0.01
≤1 ≤30 ≤90
1 (0.3%) 3 (0.9%) 4 (1.2%)
0 (0.0%) 2 (4.3%) 2 (4.3%)
1 (0.3%) 1 (0.4%) 2 (0.8%)
0.69 <0.01 0.03
AN US
Major bleeding
CR IP T
Variable (N,%) Death
PE Classification Massive Submassive (N=46) (N=292)
Days from Presentation
Intracranial hemorrhage
AC
CE
PT
ED
M
Abbreviations: PE, pulmonary embolism
23
P value
ACCEPTED MANUSCRIPT
Table 5. Predictors of 90-Day Mortality
P value
Massive PE (versus submassive PE)
5.23
2.70, 10.13
<0.01
Malignancy
2.63
1.48, 4.71
<0.01
Major bleeding within 7 days
1.98
0.84, 4.64
0.12
Age (per 10 years)
1.25
1.02, 1.52
0.03
Male (versus female)
1.13
0.65, 1.97
0.67
AN US
Variable
CR IP T
Hazard Ratio
95% Confidence Interval
Advanced therapy at 7 days
0.39
AC
CE
PT
ED
M
Abbreviations: PE, pulmonary embolism
24
0.20, 0.76
<0.01
ACCEPTED MANUSCRIPT
Figures Figure 1. Mortality following Presentation with Massive versus Submassive Pulmonary
CE
PT
ED
M
AN US
CR IP T
Embolism
AC
Figure 1 Legend. Displayed are Kaplan-Meier curves comparing the cumulative incidence of mortality between patients with massive and submassive pulmonary embolism. In unadjusted analysis, massive pulmonary embolism was associated with significantly lower 90-day survival compared with those with submassive pulmonary embolism (log-rank p<0.01).
25