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Liverpool Hospital Policy and Guideline Manual Respiratory

Date Issued: September 2018 Patient Care LH_GL2018_P12.41

LH_GL2018_P12.41 Systemic thrombolysis for pulmonary embolism

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Guideline

Systemic Thrombolysis for Pulmonary Embolism

Document Number: LH_GL2018_P12.41

Functional Sub-Group: Clinical

Summary: The guideline will assist in safe prescribing of medication for

thrombolysis and form a basis for future guidelines in

management of high-risk pulmonary embolism.

Approved by: Director of Medical Services

General Manager

Publication (Issue) Date: September 2018

Next Review Date: September 2021

Replaces Existing Document: N/A

Previous Review Dates: N/A






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Contents

Review Process........................................................................................................................ 3

1. Introduction........................................................................................................................ 4

The risk addressed by this guideline:..........................................................................4

2. The Aims / Expected Outcome of this guideline:............................................................... 4

3. Principles........................................................................................................................... 4

4. Roles and Responsibilities.................................................................................................4

5. Background........................................................................................................................5

5.1 Risk stratification:.............................................................................................5

5.2 Evidence for Harm:.......................................................................................... 6

5.3 Evidence for Benefit:........................................................................................6

6. Procedure.......................................................................................................................... 7

6.1 Indications........................................................................................................7

6.2 Contraindications............................................................................................. 8

6.3 Preparation...................................................................................................... 8

6.4 Drug choice, presentation and strength...........................................................9

6.5 Dose and administration.................................................................................. 9

6.6 Adjunctive therapy......................................................................................... 10

6.7 Monitoring...................................................................................................... 10

7. Definitions........................................................................................................................ 10

8. References and Links...................................................................................................... 11

9. Attachments..................................................................................................................... 12






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Review Process

Guideline Author Yewon Chung and Zinta Harrington, Department of Respiratory and

Sleep Medicine

Policy Document Owner Department of Respiratory and Sleep Medicine

Policy Document Sponsor Director of Medical Services

Stakeholders Consulted Dr Serena Ayers, Emergency Department, Liverpool Hospital

Dr Michael Parr, Intensive Care Unit, Liverpool Hospital

Dr Michael Harvey, Department of Haematology, Liverpool Hospital

Dr Glen Schlaphoff, Interventional Radiology, Liverpool Hospital

Search Terms for Document Pulmonary; embolism; thrombolysis; systemic

Approval Process

Committee Name Endorsement/Approval Date

Drugs and Therapeutics Committee July 2017

VTE Committee August 2018

Policy and Guideline Committee August 2018

Revision History

Version Amendment Notes

August 2018 New Hospital Guideline developed.






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1. Introduction

In a subset of patients with pulmonary embolism, thrombolysis (in addition to ‘standard’

anticoagulant therapy) may contribute to improved clinical outcomes. Thrombolysis, also

termed fibrinolysis, confers inherent additional risk and the decision to proceed requires

shared decision making in each individual case.

The risk addressed by this guideline:

Patient Safety

2. The Aims / Expected Outcome of this guideline:

To ensure:

This protocol will assist in safe prescribing of medication for

thrombolysis and form a basis for future guidelines in management of

high-risk pulmonary embolism.

3. Principles

• The decision to proceed with thrombolysis should occur on a case by case basis, ideally

following discussion between the patient, the attending clinician and relevant

subspecialty disciplines.

• The most senior clinician present (consultant, senior registrar) should have primary

responsibility for prescription of the thrombolytic agent, and communication of this to

those responsible for administration (nursing staff).

• The choice of agent should take into account the current evidence base as well as local

availability of the agent.

• Patients should be monitored for signs of clinical decompensation as well as side effects

(bleeding) related to thrombolysis.

4. Roles and Responsibilities

The decision to proceed with and administer thrombolysis, particularly in the patient with

submassive pulmonary embolism, should be made on a case by case basis with careful

consideration of the risks and benefits. This decision should be made in a shared care model

together with the patient and relevant clinicians.

Following the decision to proceed with thrombolysis, the most senior clinician present

(consultant, senior registrar) should have primary responsibility for prescription of the

thrombolytic agent, and communication of this to those responsible for administration

(nursing staff). Given the potential for clinical deterioration including adverse events related to

treatment, ongoing care should be coordinated in a supervised environment (Intensive Care).

5. Background






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Pulmonary embolism is common in hospital settings, both as a presenting illness and incident

as a complication of surgical and/or other medical conditions. Anticoagulation with heparin,

warfarin and/or direct-acting oral anticoagulants forms the mainstay of therapy and

substantially reduces associated mortality.

In a subgroup of patients with severe or life-threatening pulmonary embolism, consideration

may be given to thrombolysis in addition to anticoagulation. Thrombolysis actively reduces

clot burden, and in some patients may allow more rapid resolution of symptoms as well as

improvements in physiological measurements and long-term morbidity and mortality.

However, patient selection is critical in order to achieve net clinical benefit due to the

significant increase in risk of bleeding and associated adverse events. Alternatives to

systemic thrombolysis include:

Catheter-directed thrombolysis

Catheter-directed mechanical clot disruption

Surgical embolectomy

Limitations include local availability of relevant services, and the paucity of literature

regarding comparative efficacy and safety. As such, discussion between clinicians from

Emergency Medicine, Intensive Care Medicine, Respiratory Medicine, Interventional

Radiology and Cardiothoracic Surgery is encouraged to reach a consensus regarding optimal

treatment for individual patients.

5.1 Risk stratification:

Most studies regarding selection of patients for thrombolysis have focused on ‘massive’ and

‘submassive’ pulmonary embolism. These descriptors suggest some anatomical or

radiological basis for categorising disease. However, the potential for deterioration depends

not only on the size of the clot but also age and pre-existing comorbidities that impact

cardiopulmonary reserve. Thus, current definitions for risk stratification are based on

physiological indicators of disease severity.1 The use of physiological parameters in risk

stratification is supported by registry data which demonstrate that hypotension and circulatory

collapse are associated with increased short-term mortality.

It is essential to recognise that the absolute mortality rates associated with submassive and

massive pulmonary embolism when treated with anticoagulation are approximately <5% and

20%, respectively. Thus the absolute, incremental benefit of thrombolysis (and net clinical

benefit following consideration of bleeding risk) is greater in those with massive pulmonary

embolism compared with those without significant haemodynamic instability.

In summary, massive PE causes obstructive shock leading to sustained hypotension,

bradycardia or pulselessness. Submassive PE is characterised by the absence of

haemodynamic instability, but with features of right ventricular (RV) dysfunction (e.g. RV

dilation on imaging, ECG changes) or myocardial necrosis (e.g. elevated troponin T). Low-

risk PE is characterised by the absence of any features of massive or submassive PE.






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5.2 Evidence for Harm:

Thrombolysis is associated with increased rates of major and minor bleeding compared with

heparin alone. This is related to the pharmacological effects of thrombolytic drugs, which

actively promote clot dissolution. A meta-analysis found the risk of major bleeding to be

13.7% with thrombolysis compared to 7.7% using heparin alone (RR 1.76, 95% CI 1.04 to

2.98). This difference corresponded to a number needed to harm of 17 (95% CI 7 to 325). It

is worthwhile noting that in a more recent trial on thrombolysis which has incorporated the

largest number of patients to date, the rate of major bleeding within the first 7 days was

11.4% with tenecteplase compared with 2.2% in the non-thrombolysis group. The absolute

increase in the risk of major bleeding must be taken into consideration to assess the potential

for net clinical benefit.

Older age is a significant risk factor for increased risk of major bleeding following

thrombolysis for pulmonary embolism. A retrospective study found significantly greater risk in

patients aged 75 years and over (OR 1.7, 95% CI 1.3 to 2.1). Conversely, a later meta-

analysis found no significant increase in the rate of major bleeding when considering patients

aged 65 years and younger. Along with a number of other factors extrapolated from trials

using thrombolysis for indications other than pulmonary embolism, age over 75 years is

presented as a relative contraindication to thrombolysis (see Procedure below).

5.3 Evidence for Benefit:

Systemic thrombolysis for unstable ‘massive’ pulmonary embolism

Only one randomised controlled trial has exclusively enrolled patients with massive

pulmonary embolism, with the goal of comparing streptokinase followed by heparin with

heparin alone.9 Despite small numbers (4 in each group), the study was terminated early due

to the stark difference in mortality (0% vs 100%, p=0.02). Subsequent meta-analysis of trials

including patients with massive pulmonary embolism supported this finding with significant

reduction in recurrent pulmonary embolism or death (9.4% vs 19.0%, OR 0.45, 95% CI 0.22-

0.92, NNT=10).4 Four of five studies included in this meta-analysis included patients with

non-massive pulmonary embolism, and all studies used either streptokinase or urokinase.

Observational data in the form of case series suggest that recombinant tissue plasminogen

activator may have value even during cardiopulmonary resuscitation (CPR) maneuvers when

administered as a bolus dose.

In keeping with this body of evidence, many international guidelines support the use of

thrombolysis in patients with massive pulmonary embolism and with acceptable risk of major

bleeding events.

Systemic thrombolysis for high-risk ‘submassive’ pulmonary embolism

A more contentious area is that of high-risk ‘submassive’ pulmonary embolism. As described

above, the absolute mortality in this group when treated with heparin alone is <3-5%. Thus

even a significant relative risk reduction in mortality translates into, at best, a modest

reduction in absolute risk. At this stage, whether thrombolysis improves secondary adverse






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outcomes such as persistent right ventricular dysfunction, chronic thromboembolic disease-

related pulmonary hypertension and future impairments in quality of life requires further

study. Meta-analyses have been hindered by substantial heterogeneity between trials in

terms of defining submassive disease as well as thrombolytic agent and dosing regimen.

Nevertheless, analyses of pooled data have failed to consistently demonstrate statistically

significant benefits in mortality with use of thrombolysis compared with standard care. In the

largest multi-centre RCT to date which focused specifically on the impact of thrombolysis in

submassive pulmonary embolism, tenecteplase was associated with a reduction in the

composite primary endpoint of death or haemodynamic collapse at 7 days (2.6% vs 5.6%,

OR 0.44, 95% CI 0.23-0.87, p=0.02), but with an overall difference in haemorrhage of 9%

between groups. The difference in bleeding risk was most pronounced in patients aged over

75 years. There was no difference in mortality at 30 days.

It may be that subgroups at lower risk of bleeding events and greater risk for long-term

morbidity related to the sequelae of pulmonary embolism would benefit most from

thrombolysis. Such patients with submassive pulmonary embolism may be considered for

thrombolysis, acknowledging that this is an area of clinical equipoise warranting further study

and expert discussion regarding risks and benefits.

Reduced dose systemic thrombolysis

One unblinded, randomised trial of 121 patients is notable for use of half-dose alteplase.

While the population was selected for moderate risk based on imaging criteria (>70%

thrombus in lobar or main pulmonary arteries) rather than using biomarkers or right

ventricular dysfunction, the primary outcome of pulmonary hypertension at 28 months was

decreased at 16% compared with 57% (p<0.001, NNT=2). No bleeding events were reported,

reflecting either the absolute reduction in risk associated with reduced-dose thrombolysis, or

alternatively, calling into question the quality of data collection.

6. Procedure

6.1 Indications

The indications for systemic thrombolysis are:

Massive pulmonary embolism

Submassive pulmonary embolism (clinician discretion)Definitions for massive and submassive PE are reiterated in Section 7.

It is preferable to confirm the diagnosis of pulmonary embolism with imaging prior to

thrombolysis. This may not be feasible if the patient is unstable; however, management

should proceed if there is high pre-test probability of pulmonary embolism and right

ventricular dysfunction seen on bedside echocardiogram.

6.2 Contraindications






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Contraindications to systemic thrombolysis are predominantly related to bleeding risk,

particularly the risk of intracranial haemorrhage.

ABSOLUTE CONTRAINDICATIONS

Active bleeding or bleeding diathesis (excluding menses)

Any prior intracranial haemorrhage

Known structural intracranial cerebrovascular disease (e.g.arteriovenous malformation)

Known malignant intracranial neoplasm

Ischaemic stroke within 3 months

Recent surgery encroaching on spinal canal or brain

Recent significant closed-head or facial trauma with radiographicevidence of bony fracture or brain injury

Suspected aortic dissection

DO NOT PROCEED

WITH

THROMBOLYSIS

RELATIVE CONTRAINDICATIONS

Age >75 years

Current use of anticoagulation

Pregnancy

Non-compressible vascular punctures

Traumatic or prolonged cardiopulmonary resuscitation (>10 min)

Recent internal bleeding (within 2-4 weeks)

History of chronic, severe and poorly controlled hypertension(systolic blood pressure >180mmHg or diastolic blood pressure>110mmHg)

Remote (>3 months) ischaemic stroke

Major surgery within 3 weeks

Decision to proceed

based on shared

decision making

6.3 Preparation

Check for clear documentation of acute pulmonary embolism

Check for confirmed and documented decision to proceed with thrombolysis

Review contraindications

Ensure baseline blood tests including coagulation studies have been collected

Ensure intravenous heparin has been discontinued

Arrange supportive care and monitoring (cardiac monitoring with blood pressure,pulse and oxygen saturation)

6.4 Drug choice, presentation and strength






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There is no head-to-head data comparing the relative efficacy of various thrombolytic agents.

Tissue plasminogen activator (tPA) is the most commonly used, at least in part due to the

shorter infusion duration required (2 hours) which may have some benefit in promoting clot

lysis and reducing the incidence of bleeding.

Alteplase is registered for use as a thrombolytic agent for a number of other clinical

indications (i.e. myocardial infarction, acute ischaemic stroke), and is readily available in

most settings.

Alteplase (Actilyse) 10 mg – Vial contains 10 mg alteplase, to be reconstitutedwith 10 mL sterilised water for injection

Alteplase (Actilyse) 50 mg – Vial contains 50 mg alteplase, to be reconstitutedwith 50 mL sterilised water for injection

6.5 Dose and administration

The dose of alteplase is based on the FDA-approved regimen. The regimen described in Box

3 is consistent across a number of readily accessible guidelines (MIMS, Therapeutic

Guidelines, Australian Medicines Handbook, UpToDate).

TOTAL DOSE FOR SYSTEMIC THROMBOLYSIS

ALTEPLASE 100 mg to be administered over 2 hours:

10 mg alteplase as an intravenous bolus over 1-2 minutes, followed by

90 mg alteplase as an intravenous infusion over 2 hours.

Total dose should not exceed 1.5 mg/kg in patients with weight below 65 kg.

If reduced-dose thrombolysis is recommended, the infusion dose should be adjusted

accordingly (10 mg alteplase bolus followed by 40 mg alteplase over 2 hours).

Should cardiac arrest occur and massive PE is strongly suspected clinically, an immediate

intravenous BOLUS of ALTEPLASE 50 mg should be administered during

cardiopulmonary resuscitation. A second bolus of 50 mg may be considered after a 30

minute interval.

Thrombolysis may be administered via a peripheral intravenous cannula (i.e. a central line is

not required). Alteplase should not be mixed with other drugs, neither in the same infusion

vial nor same venous line (including with heparin).

A summary flowchart is attached (Attachment 1).

6.6 Adjunctive therapy

After the infusion is complete, blood tests should be repeated to guide adjunctive heparin

therapy:






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If APTT is less than 2 times upper limit of normal, re-commence heparin infusion

If APTT greater than 2 times upper limit of normal, repeat blood tests at 4-hourlyintervals until criteria is met to recommence heparin

6.7 Monitoring

Despite thrombolysis, patients may continue to deteriorate with worsening haemodynamic

instability. Failure to respond should be escalated to a senior clinician, for review of potential

factors and further avenues for therapy. The most frequent adverse association is bleeding;

haemorrhage at any site or body cavity may occur. Should serious bleeding occur, alteplase

should be discontinued immediately. Neurological symptoms such as somnolence, aphasia,

hemiparesis, convulsion, epileptic seizure, speech disorder, delirium, agitation and confusion

may be associated with intracranial haemorrhage. Anaphylactoid reactions are rare and

usually mild, but may be life threatening.

7. Definitions

Term Definition

Massive

Pulmonary

Embolism

Acute pulmonary embolism with ANY of:

• Sustained hypotension (Systolic blood pressure <90 mmHg for at

least 15 minutes or requiring inotropic support, not due to a cause such

as arrhythmia, hypovolaemia, sepsis or left ventricular dysfunction)

• Persistent profound bradycardia (heart rate <40 bpm with signs or

symptoms of shock)

• Pulselessnes

Submassive

Pulmonary

Embolism

Acute pulmonary embolism with EITHER right ventricular dysfunction

OR myocardial necrosis:

• Right ventricular (RV) dysfunction means the presence of AT LEAST

one of the following:

RV dilation (apical 4-chamber RV diameter divided by LV

diameter >0.9) or RV systolic dysfunction on echocardiography

RV dilation (4-chamber RV diameter divided by LV diameter

>0.9) on CT

Elevation of BNP

Elevation of N-terminal pro-BNP

Electrocardiographic changes (new complete or incomplete right

bundle branch block, anteroseptal ST elevation or depression,

or anteroseptal T-wave inversion)

• Myocardial necrosis is defined by elevated troponin or brain natriuretic

peptide.

Low Risk

Pulmonary

Embolism

Acute pulmonary embolism with no features of massive or submassive

PE as described above.






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8. References and Links

Related Policy Directives / Guidelines

SWSLHD_GL2017_007 Anticoagulation: Heparin (LMWH, UFH) and Warfarin Link

Articles / Research / Resources

Jaff MR, McMurtry MS, Archer SL, et al.(2011). 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 123:1788-830.

Goldhaber SZ, Visani L, De Rosa M. (1999). Acute pulmonary embolism: clinical outcomes in

the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet;353:1386-9.

Kasper W, Konstantinides S, Geibel A, et al.(1997) Management strategies and determinants

of outcome in acute major pulmonary embolism: results of a multicenter registry. Journal of

the American College of Cardiology;30:1165-71.

Wan S, Quinlan DJ, Agnelli G, Eikelboom JW.(2004). Thrombolysis compared with heparin

for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled

trials. Circulation;110:744-9.

Thabut G, Thabut D, Myers RP, et al. (2002).Thrombolytic therapy of pulmonary embolism: a

meta-analysis. Journal of the American College of Cardiology;40:1660-7.

Meyer G, Vicaut E, Konstantinides SV.(2014). Fibrinolysis for intermediate-risk pulmonary

embolism. The New England Journal of Medicine;371:581-2.

Ruiz-Gimenez N, Suarez C, Gonzalez R, et al. (2008). Predictive variables for major bleeding

events in patients presenting with documented acute venous thromboembolism. Findings

from the RIETE Registry. Thrombosis and haemostasis;100:26-31.

Chatterjee S, Chakraborty A, Weinberg I, et al. (2014). Thrombolysis for pulmonary embolism

and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis.

Jama;311:2414-21.

Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, et al.(1995). Streptokinase and

Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled

Trial. Journal of Thrombosis and Thrombolysis;2:227-9.

Ruiz-Bailen M, Aguayo-de-Hoyos E, Serrano-Corcoles MC, et al. (2001).Thrombolysis with

recombinant tissue plasminogen activator during cardiopulmonary resuscitation in fulminant

pulmonary embolism. A case series. Resuscitation;51:97-101.

Kearon C, Akl EA, Comerota AJ, et al. (2012). Antithrombotic therapy for VTE disease:

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest

Physicians Evidence-Based Clinical Practice Guidelines. Chest;141:e419S-94S.

British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline

http://swslhd-intranet.sswahs.nsw.gov.au/SSWPolicies/pdf/SWSLHD/SWSLHD_GL2017_007.pdf






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Development G. British.(2003).Thoracic Society guidelines for the management of suspected

acute pulmonary embolism. Thorax;58:470-83.

Konstantinides SV, Torbicki A, Agnelli G, et al.(2014). 2014 ESC guidelines on the diagnosis

and management of acute pulmonary embolism. European Heart Journal;35:3033-69, 69a-

69k.

Laporte S, Mismetti P, Decousus H, et al.(2008). Clinical predictors for fatal pulmonary

embolism in 15,520 patients with venous thromboembolism: findings from the Registro

Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry.

Circulation;117:1711-6.

Pollack CV, Schreiber D, Goldhaber SZ, et al. (2011). Clinical characteristics, management,

and outcomes of patients diagnosed with acute pulmonary embolism in the emergency

department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary

Embolism in the Real World Registry). Journal of the American College of Cardiology;57:700-

6.

Nakamura S, Takano H, Kubota Y, Asai K, Shimizu W.(2014). Impact of the efficacy of

thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism:

a meta-analysis. Journal of Thrombosis and Haemostasis : JTH;12:1086-95.

Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M, Investigators M.(2013). Moderate

pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). The American

Journal of Cardiology;111:273-7.

9. Attachments

Attachment 1 - Adapted from Sir Charles Gairdner Hospital Pulmonary Embolism Advanced

Care Pathway






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Attachment 1 – Adapted from Sir Charles Gairdner Hospital Pulmonary Embolism

Advanced Care Pathway

http://scghed.com/wp-content/uploads/2015/07/Pulmonary-Embolism-Treatment-Algorithm-

Final.pdf

http://scghed.com/wp-content/uploads/2015/07/Pulmonary-Embolism-Treatment-Algorithm-Final.pdf











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