Login | Users Online: 356  
Home Print this page Email this page Small font sizeDefault font sizeIncrease font size   
Home | About us | Editorial board | Search | Ahead of print | Current Issue | Archives | Submit article | Instructions | Subscribe | Advertise | Contact us
 


 
Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 22  |  Issue : 2  |  Page : 115-120  

Thrombolysis in acute pulmonary embolism: Are we overdoing it?


Department of Cardiology, Apollo Main Hospital, Chennai, Tamil Nadu, India

Date of Submission22-Apr-2020
Date of Acceptance27-Jun-2021
Date of Web Publication19-Aug-2021

Correspondence Address:
Dr. Refai Showkathali
Department of Cardiology, Apollo Hospital Educational and Research Foundation, Apollo Main Hospital, Greams Road, Chennai - 600 006, Tamil Nadu
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HEARTVIEWS.HEARTVIEWS_68_20

Rights and Permissions
   Abstract 


Aim and Methods: We aimed to study the clinical data and outcome of patients admitted in our center with acute pulmonary embolism (PE) over a 5-year period from May 2013 to April 2018. The main outcome data included were: in - hospital bleeding, in - hospital right ventricular (RV) function improvement, pulmonary arterial hypertension improvement, duration of hospital stay, and 30- and 90-day mortality.
Results: A total of 114 (69 m, 55 f) patients with the mean age of 55 ± 15 years were included. Patients who had involvement of central pulmonary trunk called as “Central PE” group (n = 82) and others as “Peripheral PE” group (n = 32). There were more women in the peripheral PE group (53.1% vs. 34.1%, P = 0.05), while RBBB (22% vs. 3.1%, P = 0.02) and RV dysfunction (59.8% vs. 25%, P = 0.002) were noted more in the central PE group. Systemic thrombolysis was done in 53 patients (49 central, 4 peripheral), of which only 3 had hypotension and 28 patients were in the Intermediate-high risk group. The overall inhospital, 30-day, and 90-day mortalities were 3.6, 13.2, and 22.8%, respectively. Bleeding was significantly higher in the thrombolysis group compared to the nonthrombolysis group (18.9% vs. 0, P = 0.0003). However, improvement in pulmonary hypertension was noted more in thrombolysis group compared to nonthrombolytic group (49% vs. 21.2%, P = 0.01).
Conclusion: This retrospective data from a tertiary center in South India showed that short- and mid-term mortality of patients with PE still remains high. The high nonguideline use of thrombolysis has been reflected in the increased bleeding noted in our study.

Keywords: Bleeding, central pulmonary embolism, peripheral pulmonary embolism, pulmonary embolism, thrombolysis


How to cite this article:
Showkathali R, Yalamanchi R, Ramakrishnan B, Oomman A, Sivaprakash A, Kumar P. Thrombolysis in acute pulmonary embolism: Are we overdoing it?. Heart Views 2021;22:115-20

How to cite this URL:
Showkathali R, Yalamanchi R, Ramakrishnan B, Oomman A, Sivaprakash A, Kumar P. Thrombolysis in acute pulmonary embolism: Are we overdoing it?. Heart Views [serial online] 2021 [cited 2021 Sep 27];22:115-20. Available from: https://www.heartviews.org/text.asp?2021/22/2/115/324111




   Introduction Top


Acute pulmonary embolism (PE) is a common, potentially life-threatening disease and is the most serious clinical presentation of venous thrombo-embolic disorder.[1] Mortality occurs in approximately 2%–6% of patients in hemodynamically stable PE and in 30% or more in patients with hemodynamic instability or shock.[2],[3],[4] Of note, 25% of the patients do not survive the 1st year after diagnosis of PE, although the majority of deaths during this time are related to underlying conditions such as cancer or chronic heart disease rather than to PE itself.[3],[4]

Over the past 25 years, thrombolytic therapy has consistently demonstrated improvement in hemodynamic parameters in patients with PE.[5] Clinically, although it results in reduced mortality in patients with massive PE, thrombolytic therapy is not beneficial in unselected patients with PE.[6],[7] A review of randomized trials performed before 2004 indicated that thrombolysis may be associated with a reduction in mortality or recurrent PE in high-risk patients who present with hemodynamic instability.[7] According to the European Society of Cardiology (ESC) guidelines on the diagnosis and management of acute PE published in 2014, the only current absolute indication for thrombolysis is high-risk PE (i.e., PE with shock or persistent hypotension).[8] In intermediate-risk patients, full-dose thrombolytic therapy can prevent potentially life-threatening hemodynamic decompensation, but this benefit is counterbalanced by a high risk of hemorrhagic stroke or major nonintracranial bleeding.[9] Even in the latest ESC guidelines published a few months ago, thrombolysis is indicated only in high-risk PE and to consider rescue thrombolysis in intermediate–high-risk PE patients.[10]

We aimed to study the clinical data including management decisions of patients presenting with acute PE in our center over a 5 years period and to analyze the clinical outcome of these patients to understand the “real-world” practice of management of PE in a high volume center in South India.


   Methods Top


Patients who were diagnosed to have acute PE by computed tomography pulmonary angiogram (CTPA) over a period of 5 years (May 2013 to April 2018 inclusive) in our center were identified by the electronic health-care database. All our hospital case records over the last 7 years were scanned and saved electronically in a database. We retrospectively analyzed the case records of these patients with their respective unique identification numbers. Their clinical data including baseline characteristics, imaging reports (ECHO/CTPA), clinical parameters, and management strategies (including thrombolysis) were recorded. A simplified PE Severity Index (PESI) score was calculated for all patients as per the guidelines.[11] The study has been approved by our Institutional Ethics Committee (Ref No-IEC-CS No-AMH-008/03-19) and the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation.

Definitions

Central PE - PE involving the central pulmonary trunk (main pulmonary artery, Right or Left pulmonary artery).

Peripheral PE - PE involving peripheral pulmonary artery only.

Hypotension is defined as systolic BP < 90 mmHg

Tachycardia is defined as heart rate > 100/min.

Right Ventricular (RV) dysfunction: Echocardiographic criteria of RV end-diastolic diameter of >30 mm or hypokinesia of RV free wall noted in any view or Tricuspid annular plane systolic excursion (TAPSE <16 mm).

Pulmonary arterial hypertension (PAH): By echocardiographic criteria of Right Ventricular Systolic Pressure (RVSP) - Normal <40 mmHg, mild PAH - 40-54 mmHg, Moderate PAH - 55-69 mmHg, Severe PAH - >70 mmHg.

Outcome data

The main outcome data included were inhospital mortality, 30-day mortality, 90-day mortality, inhospital bleeding, duration of hospital stay, improvement in PAH, and improvement in RV function during hospital stay. PAH improvement is defined as at least one-step improvement of PAH in the echocardiogram prior to discharge, compared to the index echocardiogram. Except for 30-day and 90-day mortality, all other outcome data were from the index admission and were obtained from the records.

For 30-day and 90-day mortality, we scanned the patients' follow-up visit to the hospital (to any department) with the unique ID number and considered them alive if they have visited the hospital. If the details were not available, patients were contacted through phone and mail to receive further information.

Statistics

Continuous data were presented as mean ± standard deviation and categorical outcomes were presented as percentages. Categorical outcomes were compared by means of Fisher's exact test and permutation unpaired t-test was used to compare continuous variables between two groups. P = 0.05 was considered to be statistically significant.


   Results Top


A total of 114 (69 males, 55 females) patients with the mean age of 55 ± 15 years were diagnosed with acute PE by CTPA during the study period. Eighty-two patients were grouped as “central PE” and the other 32 patients as “Peripheral PE” group. The baseline characteristics of the two groups are compared in [Table 1]. There were more women in the peripheral PE group (53.1% vs. 34.1%, P = 0.05), while RBBB (22% vs. 3.1%, P = 0.02) and RV dysfunction (59.8% vs. 25%, P = 0.002) were noted more in the central PE group.
Table 1: Baseline characteristics and management strategy of central versus peripheral pulmonary embolism patients

Click here to view


A total of 53 patients received thrombolysis for PE (49 in central and 4 in peripheral PE group), of which alteplase is the most commonly used agent [Table 2].
Table 2: Management of patients with central and peripheral pulmonary embolism

Click here to view


Vitamin K antagonists were used in 81 patients and novel oral anticoagulation in 30 patients. Three patients died before starting any oral anticoagulants. Apixaban is the most commonly used NAOC (14.9%) compared to dabigatran (3.5%) and rivaroxaban (7.9%). There was no difference in outcome between the central and peripheral PE group [Table 3].
Table 3: Clinical outcome of central versus peripheral pulmonary embolism

Click here to view


There was no significant difference in mortality between thrombolysis and nonthrombolysis groups [Figure 1]. Bleeding was significantly higher in thrombolysis group compared to the nonthrombolysis group (18.9% vs. 0%, P = 0.0003). There was one-step improvement in PAH in the thrombolysis group (50.9% vs. 23%, P = 0.003).
Figure 1: Mortality outcome of thrombolysed versus nonthrombolysed patients

Click here to view


Out of those patients with central PE (n = 82), 49 were thrombolysed – the indication was high risk in 3 (6.1%), intermediate high in 28 (57.1%), but no clear indication in 18 (36.8%) patients. On comparing with central PE patients who did not receive thrombolysis (n = 33), the thrombolysis group had more patients with any form of PAH (77.6% vs. 51.5%, P = 0.02) or RV dysfunction (73.5% vs. 39.4%, P = 0.002) [Table 4].
Table 4: Clinical characteristics of central pulmonary embolism patients who were thrombolysed versus nonthrombolysed

Click here to view


Comparison of outcome of thrombolysis versus nonthrombolysis groups showed bleeding occurred more commonly in thrombolysed patients (20.4% vs. 0%, P = 0.004) with no difference in mortality or duration of hospital stay [Table 5]. However, PAH improvement was noted more in thrombolysis group compared to nonthrombolytic group (49% vs. 21.2%, P = 0.01). The bleeding rate was much higher in patients who had streptokinase (50%). Patients who had alteplase and tenecteplase had 16.7% and 22.2% bleeding, respectively.
Table 5: Outcome differences of central pulmonary embolism patients who were thrombolysed versus not thrombolysed

Click here to view


Two patients who had central PE and hypotension were not thrombolysed (one due to previous intracranial hemorrhage (ICH) and the other due to unknown reasons). Four thrombolysed patients in the peripheral PE group had it in the first year of the study (2013–2014), before proper guidelines were released.

Ten patients who were thrombolysed had some form of bleeding – 4 had gastric, 2 had rectal, one had ICH, one had hemoptysis, one had gum, and another one had conjunctival bleeding. Three patients who had gastric bleed and one who had rectal bleed needed red blood cell transfusion. One patient who had gastric bleed died while in hospital and another patient who had gastric bleed died within 90 days. The other eight patients were alive until 90 days of follow-up.


   Discussion Top


This “real-world” study of patients with PE in a high-volume center suggests that thrombolysis was more commonly used than guideline-advised indications. In 18 patients in the central PE group who had thrombolysis (5 in the year 2013, 5 in 2014, 4 in 2015, 3 in 2016, and 1 in 2017), there was no clear indication identified from the medical notes of the patient for initiating thrombolysis. In general, there was a low threshold for giving thrombolytic treatment, particularly for patients with central PE, and this was adapted by most clinicians and hospitals until recent years.

Even though there was no significant mortality noted in this retrospective data from a high-volume center in patients who were thrombolysed, there was an increased risk of bleeding with thrombolytic therapy.

The latest ESC and the American College of Chest Physicians guidelines recommend thrombolysis only for those patients with clinical signs of hemodynamic decompensation.[8],[10],[12],[13] The ESC, for example, classifies thrombolytic administration in patients with acute high-risk PE as a 1B recommendation, and the 2016 updated CHEST guidelines list it as a grade 2B recommendation.[8],[12] The guidelines for thrombolysis in high-risk PE patient comes from randomized trials. A large meta-analysis done in 2004 showed that there were benefits in thrombolysing high-risk PE patients.[7]

There has been always a controversy about the use of thrombolytic therapy in intermediate-risk patients until the PE thrombolysis (PEITHO) trial was published.[14] PEITHO trial is a large randomized study which compared the outcome of intermediate-risk PE patients with or without thrombolysis. In this study, thrombolysis with tenecteplase showed a significant reduction in the risk of hemodynamic decompensation within 7 days. However, thrombolysis was also associated with a 10-fold increase in ICH (2% vs. 0.2%) and a five-fold increase in major hemorrhage (6.3% vs. 1.2%).[9] The follow-up results of the same study showed that thrombolysis with tenecteplase in intermediate-risk PE patients did not affect the long-term survival.[14] Despite this study publication in 2017, tenecteplase is not approved by FDA and ESC for usage in PE.

The ESC 2014 and 2019 guidelines recommend clinical risk assessment of those PE patients without hypotension by using The PESI score to further stratify the management strategy. Patients who have a PESI ≥1 are considered intermediate risk and further divided into intermediate–high-risk and intermediate–low-risk depending on RV function and laboratory tests such as natriuretic peptides and troponin. Those intermediate–high-risk patients can also be considered for rescue reperfusion therapy with thrombolytic agents. There is no other indication for thrombolysis in PE according to these guidelines.

Even in the latest published retrospective study from a single center in the US, only 15 out of 196 (7.6%) patients had thrombolytic therapy.[15] Out of the 15 patients, 4 are considered high risk and the other 11 were considered to be intermediate risk according to the PESI score. Alteplase is the only agent used in their study, as that is the only FDA-approved thrombolytic therapy for PE in the US.

Major extracranial bleeding occurred in 12 patients (6.1%) of the whole cohort in their study, but interestingly, only 2 out of 15 patients (13.3%) who received thrombolysis had bleeding. The other 10 patients who had major extracranial bleed did not undergo thrombolysis.[15]

In our study, thrombolysis rates were much higher at 46.5%. Out of the 53 patients who were thrombolysed, alteplase was used in 42 (79.2%), tenecteplase in 9 (16.9%), and streptokinase in 2 (3.7%) patients. Some form of bleeding occurred in 10 patients in our study, but all these 10 patients had thrombolytic therapy (18.9%), with zero bleeding in the nonthrombolytic group.

Limitations

We included only patients who had confirmed PE on CTPA. Patients with massive PE sometimes can present with sudden cardiac arrest with no time to undergo CTPA – a CT pulmonary angiogram (patient either died or had thrombolysis with echocardiographic findings). This particular group of patients was not included in our study. As this was a retrospective study, we did not have accurate data about these patients and therefore were not included.


   Conclusion Top


This retrospective data from a tertiary center in South India showed that short- and mid-term mortality of patients with PE remains high despite early diagnosis and management. This study has shown that there was increased usage of thrombolytic therapy, even in those patients who did not fulfill the criteria for thrombolysis. This has led to a higher incidence of bleeding, even though some of them are nonlife-threatening bleeds. Clinicians should be aware of the indications for thrombolysis in PE and to risk stratify them accordingly in their day-to-day clinical practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: Clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) Lancet 1999;353:1386-9.  Back to cited text no. 1
    
2.
Wood KE. Major pulmonary embolism: Review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002;121:877-905.  Back to cited text no. 2
    
3.
Eichinger S, Weltermann A, Minar E, Stain M, Schönauer V, Schneider B, et al. Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med 2004;164:92-6.  Back to cited text no. 3
    
4.
Carson JL, Kelley MA, Duff A, Weg JG, Fulkerson WJ, Palevsky HI, et al. The clinical course of pulmonary embolism. N Engl J Med 1992;326:1240-5.  Back to cited text no. 4
    
5.
Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, et al. Alteplase versus heparin in acute pulmonary embolism: Randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993;341:507-11.  Back to cited text no. 5
    
6.
Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: Saves lives but underused. Am J Med 2012;125:465-70.  Back to cited text no. 6
    
7.
Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: A meta-analysis of the randomized controlled trials. Circulation 2004;110:744-9.  Back to cited text no. 7
    
8.
Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033-69.  Back to cited text no. 8
    
9.
Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11.  Back to cited text no. 9
    
10.
Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonaryembolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2019;Eur Heart J 2020;41:543-603. [doi: 10.1093/eurheartj/ehz405].  Back to cited text no. 10
    
11.
Jiménez D, Aujesky D, Moores L, Gómez V, Lobo JL, Uresandi F, et al. Simplication of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010;170:1383-9.  Back to cited text no. 11
    
12.
Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:S419-96.  Back to cited text no. 12
    
13.
Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315-52.  Back to cited text no. 13
    
14.
Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, et al. Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism. J Am Coll Cardiol 2017;69:1536-44.  Back to cited text no. 14
    
15.
Freeland ZK, Clayton JT, Rosenblatt RL. Management of pulmonary embolism at a large academic hospital. Proc (Bayl Univ Med Cent) 2019;32:9-13.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
   Methods
   Results
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed288    
    Printed4    
    Emailed0    
    PDF Downloaded16    
    Comments [Add]    

Recommend this journal