Accepted Manuscript

Pulmonary Embolism with Right Ventricular Dysfunction: Who Should Receive

Thrombolytic Agents?

Hem Desai, MD, MPH, Bhupinder Natt, MD, Christian Bime, MD MSc, Joshua Dill,
MD, James E. Dalen, MD, MPH, Joseph S. Alpert, MD
PII: S0002-9343(16)30828-2
DOI: 10.1016/j.amjmed.2016.07.023
Reference: AJM 13651

To appear in: The American Journal of Medicine

Received Date: 15 July 2016

Revised Date: 20 July 2016
Accepted Date: 20 July 2016

Please cite this article as: Desai H, Natt B, Bime C, Dill J, Dalen JE, Alpert JS, Pulmonary Embolism
with Right Ventricular Dysfunction: Who Should Receive Thrombolytic Agents?, The American Journal of
Medicine (2016), doi: 10.1016/j.amjmed.2016.07.023.

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 ACCEPTED MANUSCRIPT

Title Page

Pulmonary Embolism with Right Ventricular Dysfunction: Who Should Receive

Thrombolytic Agents?

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Hem Desai MD, MPHa, Bhupinder Natt MDb, Christian Bime MD MScb, Joshua Dill
MDb, James E Dalen, MD, MPHa,c , Joseph S Alpert, MDa,c

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Author Affiliations:
a: Department of Medicine, University of Arizona Health Sciences, Tucson,

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Arizona, 85724
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b: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of
Arizona Health Sciences, Tucson Arizona, 85724
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c: Sarver Heart Center, University of Arizona Health Sciences, Tucson,

Arizona,85724
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Corresponding Author:
Bhupinder Natt, MD
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Division of Pulmonary, Allergy, Critical Care and Sleep

University of Arizona Health Sciences
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1501 N. Campbell Ave.

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Tucson, AZ 85724-5040
Tel: (520) 626-6114
Email: bnatt@deptofmed.arizona.edu

Article Type: Clinical research

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Running Head: Thrombolysis in RV Failure

Key Words: Pulmonary Embolism, Right Ventricular Failure, Thrombolytics

Verification: This is original research with no previous publication and is not

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currently under consideration elsewhere. It is verified that all authors had an
access to data and a role in writing the manuscript. All authors have approved this

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manuscript.

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Funding Source: None

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Conflict of Interest: None of the authors have any conflict of interest or
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disclosures.
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Abstract

Background: Appropriate management of pulmonary embolism patients with right

ventricular dysfunction is uncertain. Recent guidelines have stressed the need for

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more data on the use of thrombolytic agents in the stable pulmonary embolism

patient with right ventricular dysfunction. The objective of this study is to

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investigate the hypothesis that thrombolytic therapy in hemodynamically stable

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pulmonary embolism patients with right ventricular dysfunction is not associated

with improved mortality.

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Methods: We did a retrospective analysis using multi institutional observational
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data from the Nationwide Inpatient Sample database. ICD-9-CM diagnosis codes
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were used to identify the patients with pulmonary embolism and right ventricular
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dysfunction. In-hospital mortality was defined as the primary outcome of interest.

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Results: Over the 4 years of the study period, 3668 patients with right ventricular
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dysfunction and pulmonary embolism were found, of which 3253 patients were
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identified as hemodynamically stable right sided heart failure with pulmonary

embolism. There was no significant difference in mortality between

hemodynamically stable pulmonary embolism patients with right ventricular

dysfunction who received thrombolytic agents compared to those who did not.
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When outcomes were assessed for patients with right ventricular dysfunction and

hemodynamic instability, a significant improvement in mortality was noted for

patients with right ventricular dysfunction who received thrombolytic agents which

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confirmed previous reports that thrombolytic therapy decreases mortality in

pulmonary embolism patients who are hemodynamically unstable.

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Conclusion: Our data support the use of less aggressive treatment for stable

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pulmonary embolism patients with right ventricular dysfunction. These results

argue against the reflexive use of thrombolytic agents in stable pulmonary

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embolism patients with right ventricular dysfunction.
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Pulmonary Embolism with Right Ventricular Dysfunction: Who Should

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Receive Thrombolytic Agents?
Introduction

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Pulmonary embolism affects at least 1 in every 1000 individuals in USA,

and it is the third leading cause of death amongst hospitalized patients.1 With a 3-

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month mortality rate of 15%, it is deadlier then myocardial infraction.2 A negative

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correlation has been noted between right ventricular failure and clinical outcomes
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of patients with pulmonary embolism.3 Progressive right ventricular failure is one

of the most common causes of death in survivors of acute pulmonary embolism 4.

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Patients with pulmonary embolism and right ventricular dysfunction often present
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with a spectrum of symptoms, and treatment is based on the presentation.5

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Hemodynamically stable patients and patients with preserved right ventricular

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function are treated with systemic anticoagulation and have an excellent

prognosis.5 Hemodynamically unstable patients who present with systemic

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hypotension, syncope, or cardiac arrest are considered to be candidates for

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thrombolysis.5,14 Preferred treatment for a hemodynamically stable patient with

worsened right ventricular function is controversial. The US Food and Drug

Administration has only authorized the use of fibrinolytic agents for

hemodynamically unstable patients with massive pulmonary embolism.6 However,

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physicians continue to use thrombolysis for stable patients with right ventricular

dysfunction. The prognostic value of right ventricular failure in hemodynamically

stable patients has not been well studied.3 Normotensive patients with right

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ventricular dysfunction represent a large portion of pulmonary embolism patients.

The benefit of extending thrombolytic treatment to this subgroup needs to be

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weighed against potential disadvantages in terms of bleeding risk and added costs.7

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Pulmonary embolism thrombolysis trials have shown that normotensive patients

with right ventricular dysfunction might benefit from the early use of

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thrombolysis, but the benefits were offset by the bleeding complications.8 Current

guidelines have stressed the need for more data on the use of thrombolytic agents
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in pulmonary embolism patients with stable right ventricular dysfunction.9 No

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multicenter studies have been performed to assess the outcomes of thrombolytic

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therapy in patients with right ventricular dysfunction. Our goal is to use recent data

from the Nationwide inpatient sample database from the years 2009 to 2012 to
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investigate the hypothesis that thrombolytic therapy in hemodynamically stable

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patients with right ventricular dysfunction is not associated with improved

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mortality.

Methods

We conducted a retrospective analysis using the study cohort derived from the
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Nationwide Inpatient Sample database which is one of the largest all-payer

inpatient health care databases in the United States. This is a well-characterized

clinical database maintained by the Agency for Healthcare Research and Quality

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(AHRQ) since 1988. Data quality assessment of the NIS database is performed

annually, and it is well validated for use in epidemiological studies.10 Results of

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this database have correlated well with studies done on other hospital discharge

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databases of the United States.11 NIS is the largest publicly available inpatient care

database in the United States representing approximately 8 million hospitalizations

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in the USA. Unweighted, it represents 20% of all the in hospital admissions in the

USA. When expanded to estimate nation-wide discharges (using inbuilt weighted

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values), it estimates data corresponding to about 40 million annual hospitalizations.

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Each hospitalization is treated as an individual database entry. The HCUP-NIS

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database contains variables to assess the following patient characteristics:

demographics such as age, race, sex, admission and treating diagnoses, in-patient
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procedures, in-hospital mortality, hospital length of stays and discharge status.

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This analysis conforms to the data-use agreement for the HCUP-NIS

database. Institutional Review Board exemption was obtained for this study.

From the HCUP-NIS database, we extracted the data for patients with age>18

years who had pulmonary embolism. Patients with pulmonary embolism were
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identified using the (International Classification of Diseases, Ninth Revision,

Clinical Modification [ICD-9-CM]) codes 415.19,415.11, 415.1 Weighted values

were used to generate the nationwide estimates.

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The final sample size of this analysis was 1,277,574. The ICD-9 code of

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415.0 was used to identify patients with acute right sided heart failure. A total of

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3668 patients with acute right sided heart failure and pulmonary embolism were

identified. ICD- 9 codes of 785.59,785.51,785.50 were used to identify patients

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who were hemodynamically unstable. In total, 415 patients with hemodynamically

unstable right sided heart failure with pulmonary embolism were identified. ICD-9
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procedure code 99.10 was used to identify patients undergoing thrombolysis.

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Details of the patient selection algorithm and the ICD-9-CM codes used are
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presented in Figure 1.

All statistical analysis was done using STATA/IC 13.1 (StataCorp; Texas,
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USA) In hospital mortality is defined as the primary outcome of interest.

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We expressed the demographic and clinical characteristics for each group as

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mean (SD) for continuous variables or percentages for categorical or ordinal

variables. The chi-square (2) test was used to test for statistical significance when

comparing categorical data. A two sample t -test was used for comparison of

continuous variables. Statistical significance was evaluated at an alpha level of

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0.05.

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Results

No major change in the incidence of the pulmonary embolism was noted

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between 2009 and 2012 (Table 1). Mean age of the patients with pulmonary

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embolism remained stable at around 63 years. Our data show that only 32 % of the

patients with pulmonary embolism were diagnosed with deep venous thrombosis.

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The percentage of patients receiving thrombolysis or embolectomy also

remained stable. Minimal change in mortality was noted. The diagnosis of right
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ventricular failure with pulmonary embolism increased from 2.4 per 1000 patients
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to 3.6 per 1000 patients (Table 1).

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The total number of patients with right ventricular failure was 3668. There

was no significant difference in mortality or length of stay noted for those who
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received thrombolysis vs those who did not (Table 2).

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A total 420 unstable patients with right ventricular failure were present in the
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database. The mortality rate was significantly higher (33% vs 18.12%, p-value=

0.0015) among those who did not receive thrombolysis compared to those who

received thrombolysis. No significant difference in the length of stay was noted

(Tables 2 and 3).

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Discussion:

Analysis of this multi institutional observational database shows that while the

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number of newly diagnosed patients with acute pulmonary embolism has remained

stable, the number of patients diagnosed with right ventricular dysfunction has

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steadily increased. One of the major reasons for this might be increased awareness

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and availability of improved imaging techniques resulting in increased diagnosis.

As previously documented in other studies, deep vein thrombosis is present in

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about one third of the patients with pulmonary embolism.12 The percentage of the

patient population undergoing surgical embolectomy declined from 6.92% in 2009

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to 6.1% in 2012.
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Our analysis shows that there was no significant difference in mortality

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between stable pulmonary embolism patients with right ventricular dysfunction

who received thrombolytics compared to those who did not. (p=0.51) When
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outcomes were assessed for patients with right ventricular dysfunction and
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hemodynamic instability, a significant improvement in mortality was noted for

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patients with right ventricular failure who received thrombolytic agents.

The finding that there was no improvement in mortality with thrombolysis in

hemodynamically stable patients with right ventricular dysfunction is relevant

because of its implications for the future management of these patients. Our data
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supports the use of less aggressive treatment for stable pulmonary embolism

patients with right ventricular dysfunction. These results argue against the

reflexive us of thrombolytic agents in stable pulmonary embolism patients with

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right ventricular failure. As seen in the results, treating every pulmonary embolism

patient with right ventricular dysfunction would lead to an almost 7-8-fold increase

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in the use of thrombolytic agents among these stable patients. Not only would it

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not make any difference in mortality as shown here, but its use would likely

increase the risk for hemorrhagic complications. In the spectrum of pulmonary

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embolism, normotensive patients with right ventricular dysfunction have always

existed in the wide gray area between mild disease and severe hemodynamic
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impairment. 13 However, based on the results of our study, enthusiasm for the use
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of thrombolytic agents in pulmonary embolism needs to be tempered.

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Strength of our findings lie in the fact that the HCUP is a well validated
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database and has been previously utilized in similar research studies. Weighted
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values generated through this data can reliably predict nationwide trends.
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One of the major limitations of such retrospective data is that identification of right

heart failure is based on the pre-formed data and on ICD codes. It is difficult to

confirm diagnostic accuracy. Some of the results of our data, such as the

improvement in mortality for patients with right ventricular dysfunction and

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hemodynamic instability are similar to previous results suggesting good

predictability of this method which employs diagnostic codes.14 A large patient

population has been identified using this database which might possibly blunt the

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effect of modifying factors. Our results were confined to the in-patient period. No

conclusions can be drawn concerning long term outcomes for hemodynamically

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stable pulmonary embolism patients with right ventricular dysfunction.

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In conclusion, our study shows that thrombolysis is not associated with

improvement in mortality in hemodynamically stable pulmonary embolism

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patients with right ventricular failure.
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1. SZ Goldhaber, CG Elliott. Acute pulmonary embolism: part I:

epidemiology, pathophysiology, and diagnosis. Circulation 2003; 108:

2726-2729.

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2. G Piazza, SZ Goldhaber. Management of submassive pulmonary embolism.

Circulation 2010;122: 1124-1129.

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3. S Grifoni, I Olivotto, P Cecchini, F Pieralli, A Camaiti, G Santoro, A Conti ,

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G Afnelli, G Berni. Short-term clinical outcome of patients with acute

pulmonary embolism, normal blood pressure, and echocardiographic right

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ventricular dysfunction. Circulation 2000; 101: 2817-2822.

4. G Piazza, SZ Goldhaber. The acutely decompensated right ventricle:

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pathways for diagnosis and management. Chest 2005; 128:1836-1852.

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5. SV Konstantinides, A Torbicki, G Agnelli, N Danchin, D Fitzmaurice, N

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Galie, JS Gibbs, MV Huisman, M Humbert , N Kucher , I Lang , M Lankeit

, J Lekakis , C Maack , E Mayer , N Meneveau , A Perrier , P Pruszcyk , LH

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Rasmussen, TH Schindler, P Svitil, A Vonk Noordegraaf , JL Zamorano ,

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M Zompatori. Task force for the diagnosis and management of acute

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pulmonary embolism of the European society of cardiology. 2014 ESC

guidelines on the diagnosis and management of acute pulmonary embolism.

Eur Heart J 2014; 35: 3033-3069, 3069a-3069k.

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6. MR Jaff, MS McMurtry, SL Archer, M Cushman, N Goldenberg, SZ

Goldhaber, JS Jenkins, JA Kline, AD Michales, P Thistlewhistle, S

Vedantha, RJ White, BK Zierier. Management of massive and submassive

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pulmonary embolism, iliofemoral deep vein thrombosis, and chronic

thromboembolic pulmonary hypertension: a scientific statement from the

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

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7. JE Dalen, JS Alpert, J Hirsh. Thrombolytic therapy for pulmonary

embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med

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1997; 157: 2550-2556.

8. G Meyer, E Vicaut, T Danays, G Agnelli, C Becattini, J Beyer-Westendorf,

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E Bluhmki, H Bouvaist, F Couturaud, C Dellas, K Empen, A Franca, N

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Gailre, A Geibel, SZ Goldhaber D Jimenez, M Kodak, C Kupatt, N Kucher,

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IM Lang, M Lankeit, N Meneveau, G Pacouret, M Palazzini, A Petris, P

Pruszczyk, M Rugolotto, A Salvi, S Schellong, M Sebbane, BS Stefanovic,

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H Thiele, A Torbicki, F Verschuren, SV Konstantinides; PEITHO

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Investigators. Fibrinolysis for patients with intermediate-risk pulmonary

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embolism. N Engl J Med 2014; 370:1402-1411.

9. S Chatterjee, A Chakraborty, I Weinberg, M Kadakia, RL Wilensky, P

Sardar, DJ Kumbhani, D Mukherjee, MR Jaff, J Giri. Thrombolysis for

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pulmonary embolism and risk of all-cause mortality, major bleeding, and

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10. C Steiner, A Elixhauser, J Schnaier: The healthcare cost and utilization

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11. D Whalen D, R Houchens , A Elixhauser. 2004 HCUP Nationwide Inpatient

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Sample (NIS) Comparison Report. HCUP Method Series Report # 2007-03.

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Online December 2, 2007. U.S. Agency for Healthcare Research and

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12. M Meignan, J Rosso, H Gauthier, F Brunengo, S Claudel, L Sagnard, P

dAzemar, G Simonneau, B Charbonnier. Systematic lung scans reveal a

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high frequency of silent pulmonary embolism in patients with proximal deep

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13. JC Lualdi, SZ Goldhaber. Right ventricular dysfunction after acute

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implications. Am Heart J 1995;130 (6): 1276-1282.

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14. PD Stein, F Matta. Thrombolytic therapy in unstable patients with acute

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pulmonary embolism: saves lives but underused. Am J Med 2012; 125: 465-

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Table 1: Trends of Pulmonary Embolism and outcomes.

2009 2010 2011 2012

Total Pulmonary 310307 323776 334714 308775

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embolism

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Mean Age 63.4 63 63 63
Mortality 99149(32%) 105725(32.65%) 109192(32.6%) 101415(32.84%)

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DVT 10129(3.26%) 11026(3.4%) 12626(3.77%) 11845(3.84%)

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Shock 6039(1.95%) 6781(2.1%) 6801(2.03%) 6460(2.09%)
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Thrombolysis 1911(0.62%) 2121(0.66%) 2149(0.64%) 2170(0.7%)
Embolectomy 21481(6.92%) 21018(6.55) 21911(6.55%) 18835(6.1%)
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Right Ventricular 745(0.24%) 889(0.27%) 944(0.28%) 1100(0.36%)

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Table 2: Outcomes of stable patients with acute RVF who received thrombolysis
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Alive Died LOS

Thrombolytics 394 33 8.8 days

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No thrombolytics 2580 245 9.57 days

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p-value 0.5094 0.5

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Table 3: Outcomes of unstable patients with acute RVF who received

thrombolysis

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Alive Died LOS

Thrombolytics 113 25 9.8 days

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No thrombolytics 189 88 11 days

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p-value 0.003 0.7

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Figure 1: Flow chart showing patient selection process.

HCUP- NIS database 2009-2012

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ICD-9 Codes:
415.19,415.11,415.1 to
identify PE

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Excluded patients less
than age 18

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Total patients with PE 1,277,574
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ICD-9 code 415.0 was used to

identify acute right ventricular
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failure with PE: Total patients 3668

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ICD9 Codes:
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785.59,785.51,785.50 to identify
unstable patients.
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415 total PE patients who had RVF

with hemodynamic instability.
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Clinical Significance

Role of thrombolytic therapy in right ventricular failure due to pulmonary

embolism is unclear.

Patients may or may not be hemodynamically unstable due to right

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ventricular failure.

Our study suggests less aggressive therapy such as thrombolytics in patients

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who are hemodynamically stable despite other evidence of right ventricular
failure due to pulmonary embolism.

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