Thrombolytic therapy for pulmonary embolism

Zhiliang Zuo; Jirong Yue; Bi Rong Dong; Taixiang Wu; Guan J Liu; Qiukui Hao

doi:10.1002/14651858.CD004437.pub6

Thrombolytic therapy for pulmonary embolism

Authors' declarations of interest

Version published: 15 April 2021 Version history

https://doi.org/10.1002/14651858.CD004437.pub6

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Abstract

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Background

Thrombolytic therapy is usually reserved for people with clinically serious or massive pulmonary embolism (PE). Evidence suggests that thrombolytic agents may dissolve blood clots more rapidly than heparin and may reduce the death rate associated with PE. However, there are still concerns about the possible risk of adverse effects of thrombolytic therapy, such as major or minor haemorrhage. This is the fourth update of the Cochrane review first published in 2006.

Objectives

To assess the effects of thrombolytic therapy for acute pulmonary embolism.

Search methods

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 17 August 2020. We undertook reference checking to identify additional studies.

Selection criteria

We included randomised controlled trials (RCTs) that compared thrombolytic therapy followed by heparin versus heparin alone, heparin plus placebo, or surgical intervention for people with acute PE (massive/submassive). We did not include trials comparing two different thrombolytic agents or different doses of the same thrombolytic drug.

Data collection and analysis

Two review authors (ZZ, QH) assessed the eligibility and risk of bias of trials and extracted data. We calculated effect estimates using the odds ratio (OR) with a 95% confidence interval (CI) or the mean difference (MD) with a 95% CI. The primary outcomes of interest were death, recurrence of PE and haemorrhagic events. We assessed the certainty of the evidence using GRADE criteria.

Main results

We identified three new studies for inclusion in this update. We included 21 trials in the review, with a total of 2401 participants. No studies compared thrombolytics versus surgical intervention. We were not able to include one study in the meta‐analysis because it provided no extractable data. Most studies carried a high or unclear risk of bias related to randomisation and blinding.

Meta‐analysis showed that, compared to control (heparin alone or heparin plus placebo), thrombolytics plus heparin probably reduce both the odds of death (OR 0.58, 95% CI 0.38 to 0.88; 19 studies, 2319 participants; low‐certainty evidence), and recurrence of PE (OR 0.54, 95% CI 0.32 to 0.91; 12 studies, 2050 participants; low‐certainty evidence). Effects on mortality weakened when six studies at high risk of bias were excluded from analysis (OR 0.71, 95% CI 0.45 to 1.13; 13 studies, 2046 participants) and in the analysis of submassive PE participants (OR 0.61, 95% CI 0.37 to 1.02; 1993 participants). Effects on recurrence of PE also weakened after removing one study at high risk of bias for sensitivity analysis (OR 0.60, 95% CI 0.35 to 1.04; 11 studies, 1949 participants). We downgraded the certainty of evidence to low because of 'Risk of bias' concerns.

Major haemorrhagic events were probably more common in the thrombolytics group than in the control group (OR 2.84, 95% CI 1.92 to 4.20; 15 studies, 2101 participants; moderate‐certainty evidence), as were minor haemorrhagic events (OR 2.97, 95% CI 1.66 to 5.30; 13 studies,1757 participants; low‐certainty evidence). We downgraded the certainty of the evidence to moderate or low because of 'Risk of bias' concerns and inconsistency. Haemorrhagic stroke may occur more often in the thrombolytics group than in the control group (OR 7.59, 95% CI 1.38 to 41.72; 2 studies, 1091 participants).

Limited data indicated that thrombolytics may benefit haemodynamic outcomes, perfusion lung scanning, pulmonary angiogram assessment, echocardiograms, pulmonary hypertension, coagulation parameters, composite clinical outcomes, need for escalation and survival time to a greater extent than heparin alone. However, the heterogeneity of the studies and the small number of participants involved warrant caution when interpreting results.

The length of hospital stay was shorter in the thrombolytics group than in the control group (mean difference (MD) −1.40 days, 95% CI −2.69 to −0.11; 5 studies, 368 participants). Haemodynamic decompensation may occur less in the thrombolytics group than in the control group (OR 0.36, 95% CI 0.20 to 0.66; 3 studies, 1157 participants). Quality of life was similar between the two treatment groups.

None of the included studies provided data on post‐thrombotic syndrome or on cost comparison.

Authors' conclusions

Low‐certainty evidence suggests that thrombolytics may reduce death following acute pulmonary embolism compared with heparin (the effectiveness was mainly driven by one trial with massive PE). Thrombolytic therapy may be helpful in reducing the recurrence of pulmonary emboli but may cause more major and minor haemorrhagic events, including haemorrhagic stroke. More studies of high methodological quality are needed to assess safety and cost effectiveness of thrombolytic therapy for people with pulmonary embolism.

PICOs

Population

Intervention

Comparison

Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

available in

Drugs to dissolve pulmonary embolism (blood clot in the lungs)

Background

A pulmonary embolus is a potentially fatal blood clot that lodges in the main artery of the lungs, straining the right side of the heart and affecting blood circulation. People with this condition are at risk of new emboli forming (recurrence). In the case of a massive pulmonary embolism, treatment to restore blood flow is urgently required. Heparin thins the blood, but newer drugs that actively break up the clots (thrombolytics) may act more quickly and may be more effective. These newer drugs include streptokinase, urokinase, and recombinant tissue‐type plasminogen activator. The major complication of this treatment is bleeding.

Key results

We searched the literature and included 21 studies in this update (evidence current to 17 August 2020). These trials involved 2401 adult participants with pulmonary embolism, who were randomly assigned to a thrombolytic agent followed by heparin or heparin alone or heparin plus placebo. No studies compared thrombolytics versus surgical intervention. We were able to use data from 20 clinical trials with a total of 2371 participants. Thrombolytics may lower the likelihood of death and recurrence of blood clots compared to heparin. On the other hand, thrombolytics caused more side effects, including major and minor bleeding events (haemorrhagic events) and haemorrhagic stroke, than heparin alone. Limited information from a number of individual trials show that thrombolytics might be better at improving blood flow through the lungs, heart function, reducing the need for further treatment and time spent in hospital. None of the studies reported on post‐thrombotic syndrome or compared the costs of the different treatments.

Certainty of the evidence

The certainty of the evidence is moderate or low, because of study design limitations (risk of bias), and small sample sizes. We need more large, well‐designed trials to increase our confidence in any benefits of thrombolytic therapy for pulmonary embolism.

Authors' conclusions

Implications for practice

Low‐certainty evidence suggests that thrombolytics may reduce death following acute pulmonary embolism compared with heparin (the effectiveness was mainly driven by one trial with massive PE).

Thrombolytic therapy may be helpful in reducing the recurrence of PE but may cause more major and minor haemorrhagic events, including haemorrhagic stroke. After sensitivity analyses excluding studies with high risk of bias, results did not change for major and minor haemorrhagic events whereas the effect on PE recurrence was weakened, but all were limited due to small participant numbers and heterogeneity.

We note that most of the studies included in this review considered participants with submassive PE. Only one study focused on participants with massive PE, finding an apparent benefit for thrombolysis.

More studies of high methodological quality are needed to assess the safety and cost effectiveness of thrombolytic therapy for people with acute PE.

Implications for research

Investigators planning future randomised trials should:

use a study design that incorporates double‐blinding and adequate concealment of treatment allocation;
focus their assessment on patient‐important outcomes (e.g. mortality, haemorrhagic events (especially for intracranial haemorrhage), escalation of treatment);
plan and evaluate measures of cost effectiveness and quality of life, functional outcomes (e.g. six‐minute walk test, cardiopulmonary exercise testing) in mid‐term to long‐term search;
define the different types of PE to differentiate clinical subgroups;
compare safety and effectiveness of catheter‐based thrombolysis (CDT or USAT) with heparin or systemic thrombolysis; for such patients expanded examinations of haemorrhagic complications (e.g. plasminogen, anti‐Factor Xa, partial thromboplastin time) might be helpful;
assess differences between different age groups.

Summary of findings

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Summary of findings 1. Thrombolytic therapy versus heparin: primary outcome measures for pulmonary embolism

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
Thrombolytic therapy versus heparin: primary outcome measures for pulmonary embolism
Patient or population: people with acute PE Setting: hospital Intervention: thrombolytic therapy Comparison: heparin
Outcomes	Risk with heparin	Risk with thrombolytic therapy	Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
Death from all causes (duration of follow‐up: from 7 days to 12 months)	Study population		OR 0.58 (0.38 to 0.88)	2319 (19)	⊕⊕⊝⊝ low^b
	47 per 1000	28 per 1000 (19 to 42)
	Moderate^a
	49 per 1000	29 per 1000 (19 to 43)
Recurrence of pulmonary emboli (duration of follow‐up: from 7 days to 12 months)	Study population		OR 0.54 (0.32 to 0.91)	2050 (12)	⊕⊕⊝⊝ low^b
	39 per 1000	21 per 1000 (13 to 36)
	Moderate^a
	42 per 1000	23 per 1000 (14 to 38)
Major haemorrhagic events (duration of follow‐up: from 7 days to 12 months)	Study population		OR 2.84 (1.92 to 4.20)	2101 (15)	⊕⊕⊕⊝ moderate^c
	35 per 1000	94 per 1000 (65 to 133)
	Moderate^a
	24 per 1000	66 per 1000 (46 to 95)
Minor haemorrhagic events (duration of follow‐up: from 7 days to 12 months)	Study population		OR 2.97 (1.66 to 5.30)	1757 (13)	⊕⊕⊝⊝ low^c,d
	96 per 1000	239 per 1000 (149 to 359)
	Moderate^a
	86 per 1000	219 per 1000 (135 to 333)
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The risk in the intervention group* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence CI: confidence interval; OR: odds ratio;PE: pulmonary embolism; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effectGRADE Working Group grades of evidence.
^aMedian control group risk from the studies included in this meta‐analysis. ^bDowngraded by two levels for very serious risk of bias (due to serious risk of selection, performance and other bias in most included studies). ^cDowngraded by one level for serious risk of bias (due to serious risk of selection, performance and other bias in some included studies). ^dDowngraded by one level for inconsistency (due to moderate heterogeneity; I² = 55%).

Background

Description of the condition

A pulmonary embolus (a blood clot in the artery of the lungs) is a life‐threatening condition known as pulmonary embolism (PE), that is accompanied by significant morbidity and mortality. Massive and submassive PEs are subtypes of PE that are often encountered in the literature, even though the definitions of these subtypes are often vague and can lead to ambiguity (Goldhaber 2002). Because the severity and prognosis of PE vary widely, risk stratification after PE diagnosis is essential. The American Heart Association defines massive PE, submassive PE, and low‐risk PE based on associated clinical deterioration and short‐term mortality (Table 1; Jaff 2011; Sista 2017). Submassive or massive PE has been used interchangeably with the terms intermediate‐risk or high‐risk PE, respectively (Gupta 2018).

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Table 1. American Heart Association definitions of massive, submassive, and low‐risk PE

Risk classification	Definition	Short‐term mortality
Massive PE	Acute PE with haemodynamically‐unstable manifestations such as sustained hypotension (systolic blood pressure < 90 mmHg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolaemia, sepsis, or left ventricular dysfunction), lack of pulse, or persistent profound bradycardia (heart rate < 40 beats per minute (bpm) with signs or symptoms of shock)	25% to 65%
Submassive PE	Haemodynamically stable (without systemic hypotension (systolic blood pressure > 90 mmHg)) people who present with either right ventricular dysfunction or myocardial necrosis (RV dysfunction (CT, BPN/proBNP, ECG changes) or myocardial necrosis (elevated troponins))	3%
Low‐risk PE	Absence of hypotension, RV dysfunction, and myocardial necrosis	< 1%

BPN: B‐type natriuretic peptide
CT: computed tomography
ECG: electrocardiography
PE: pulmonary embolism
RV: right ventricular

Several options are available for the management of PE. Anticoagulation therapy forms the foundation of PE management (Hepburn‐Brown 2019). In massive or high‐risk PE, where restoration of pulmonary arterial flow is urgently required due to right ventricular failure, prompt therapeutic intervention is imperative. In such cases, thrombolysis (peripheral or catheter‐directed) or surgical embolectomy should be considered (Hepburn‐Brown 2019; Konstantinides 2020; Tapson 2017). For people with submassive or intermediate‐risk PE, guidelines recommend that management strategy should be prospectively planned and rescue thrombolytic treatment is necessary if the situation deteriorates (Kearon 2016; Konstantinides 2020).

Description of the intervention

Although the thrombotic origin of PE has been well documented for almost two centuries, anticoagulation (anti‐clotting drugs) as treatment for venous thromboembolism (VTE) dates back less than a century, and thrombolysis was initiated only relatively recently. In 1962, Browse and James reported that streptokinase could lyse (break up) pulmonary emboli in dogs and humans. Four patients treated with different dosage regimens experienced striking clinical improvement (Browse 1962). Additional studies show that patients who had hypotension (low blood pressure) responded quickly to streptokinase therapy, and their lung scans returned almost completely to normal (Bottiger 1994; Browse 1962; Chesterman 1969). However, improvement was less marked in those with associated cardiopulmonary disease and recurrent emboli (Hirsh 1971; Meneveau 2006).

The findings of four clinical studies of urokinase for PE indicate that improvement with urokinase was more apparent than with heparin alone (Genton 1968; Sasahara 1967; Sautter 1967; Tow 1967). Based on this promising experience, the National Heart and Lung Institute organised a multi‐institutional randomised controlled trial (RCT) to evaluate thrombolytic agents for treatment of PE. Results of Phase I (the Urokinase Pulmonary Embolism Trial ‐ UPET) show that a 12‐hour infusion of urokinase followed by heparin and oral anticoagulants, compared to heparin and oral anticoagulants alone, increased the resolution rate of pulmonary thromboemboli (Hyers 1970). Phase II (the Urokinase‐Streptokinase Pulmonary Embolism Trial ‐ USPET), completed in 1973, shows comparable results for two additional thrombolytic regimens: 24 hours of streptokinase and 24 hours of urokinase. Increasing the duration of urokinase administration to 24 hours conferred little benefit, and the distinction between 24 hours of urokinase and 24 hours of streptokinase was not clear (UPET Study Group 1974). These trials did not document actual improvement in survival; however, people with massive embolism did derive major physiological benefit. Thrombolytic agents may therefore be useful for severely‐ill patients with massive embolism or submassive embolism, especially when accompanied by shock.

In the late 1980s, recombinant tissue‐type plasminogen activator (rt‐PA) was introduced for treatment of acute PE, and an RCT reported its faster action and greater safety in comparison with urokinase (Goldhaber 1988). One multicentre study showed that rt‐PA decreased mean pulmonary arterial pressure (Meyer 1992). Effects of intravenous rt‐PA on arterial blood gases and right ventricular function were compared with the effect of heparin treatment in acute PE. Results show that rt‐PA is more effective for acute PE than heparin alone, and that a high dose of rt‐PA leads to rapid improvement in arterial blood gases and lung perfusion images, with no clinical episodes of recurrent PE (Goldhaber 1993; Yamasawa 1992). The collaborative PIOPED study suggested that rt‐PA given over two hours has little effect on angiographic clot burden but may produce some improvement in haemodynamics. However, this treatment is not without risk (Tapson 2017). In the PEITHO trial, people with submassive PE treated with tenecteplase had less haemodynamic decompensation but an increased risk of major haemorrhage and stroke (Meyer 2014). Until now, the effectiveness of thrombolytic therapy in PE remains under discussion (Eberle 2018; Hepburn‐Brown 2019).

Why it is important to do this review

Although good evidence shows that thrombolytic agents are superior to heparin alone in accelerating the lysis of pulmonary emboli, restoring normal pulmonary circulation, and decreasing strain on the right side of the heart, few data are available on their long‐term benefits for PE (Chatterjee 2014). Studies of the long‐term benefit of thrombolytic therapy for people with PE suggest that thrombolytic therapy preserves the normal haemodynamic response to exercise and maintains cardiac output during long‐term follow‐up, possibly preventing recurrence of VTE and development of pulmonary hypertension (Sharma 2000).

Although it is difficult to prove that thrombolytic agents decrease mortality from pulmonary emboli, one large registry shows that thrombolytic treatment was associated with a 50% reduction in death risk among clinically‐stable patients with right ventricular enlargement (Konstantinides 1999), and another prospective RCT showed that thrombolytic therapy reduced the mortality rate of massive acute PE (Jerjes‐Sánchez 1995).

Different thrombolytic agents ‐ rt‐PA (e.g. alteplase), streptokinase, and urokinase ‐ are efficacious in dissolving clots (Stambaugh 1981; Stewart 2020). However, these agents are not without risk, sometimes leading to frequent massive bleeding, including intracranial haemorrhage (Chatterjee 2014; Dalla‐Volta 1992). Other studies show that bleeding and fever were increased in streptokinase‐treated patients, but both were generally controllable, with most bleeding occurring at the puncture site (Goldhaber 1993; Sasahara 1973). Several recent meta‐analyses conducted to assess the efficacy and safety of thrombolytic therapy for treatment of PE show no obvious differences in mortality, nor in risk of PE relapse between the group of people receiving thrombolytic agents and the group not receiving them (Cao 2014; Gao 2015; Liu 2014; Marti 2014; Nakamura 2014). However, they reveal substantial differences between these two groups in the risk of bleeding events (Chatterjee 2014; Gao 2015).

Although most studies agree that thrombolytic agents are superior to heparin alone in accelerating the lysis of pulmonary thromboemboli, their benefits for reduced death rates from PE and influence on survival and risks of associated haemorrhagic complications remain unclear, especially for people with submassive (intermediate‐risk) PE. This review attempts to ascertain the efficacy of thrombolytic agents for treatment of PE. This is the fourth update of a review first published in 2006.

Objectives

To assess the effects of thrombolytic therapy for acute pulmonary embolism.

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised controlled trials (RCTs) that compared thrombolytic therapy (e.g. streptokinase, urokinase, recombinant tissue plasminogen activator (rt‐PA), alteplase) followed by heparin versus heparin alone, heparin plus placebo, or surgical intervention (e.g. embolectomy) for people with acute pulmonary embolism (PE). We did not include trials that compared two different thrombolytic agents or different doses of the same thrombolytic drug.

Types of participants

We included participants who had symptoms or signs of PE, confirmed by pulmonary angiography, ventilation/perfusion lung scan, or another validated measurement.

Types of interventions

We included any type of thrombolytic drug (e.g. streptokinase, urokinase, rt‐PA, alteplase) followed by heparin versus heparin alone, heparin plus placebo, or surgical intervention (e.g. embolectomy).

Types of outcome measures

We analysed the following clinical outcome measures on an intention‐to‐treat (ITT) basis.

Primary outcomes

Death from all causes
Recurrence of pulmonary emboli
Haemorrhagic events
- Major haemorrhagic events: a decreased haemoglobin concentration > 2 G/dL; retroperitoneal or intracranial bleeding; transfusion of two or more units of blood, which may or may not lead to discontinuation of anticoagulant treatment
- Minor haemorrhagic events: other bleeding events not meeting the criteria for major bleeding

Secondary outcomes

Haemodynamic improvement and thrombolysis: immediate clinical, haemodynamic, angiographic, perfusion lung scanning, or echocardiographic outcomes or the rapidity of resolution of PE as judged by the change in total pulmonary resistance (TPR) over the initial hours
Chronic thromboembolic pulmonary hypertension after three months, six months, and one year, and at the end of the follow‐up period
Differences in coagulation parameters over time
Post‐thrombotic syndrome (PTS): complications after deep vein thrombosis (DVT) may include persistent oedema (swelling), pain, purpura (bleeding into the skin), increased skin pigmentation, eczematoid (eczema‐like) dermatitis, pruritus (itchiness), ulceration, and cellulitis (bacterial infection just below the skin). All of these complications result from impaired return of blood through the veins of the lower leg to the heart. This is determined by using any validated measurement for PTS
Escalation of treatment
Hospital stay
Survival time
Composite clinical outcome: sum per participant of mortality, recurrent PE, and major and minor haemorrhagic events
Quality of life (QoL)
Healthcare cost comparison

Search methods for identification of studies

Electronic searches

The Cochrane Vascular Information Specialist conducted systematic searches of the following databases for RCTs and controlled clinical trials without language, publication year, or publication status restrictions.

Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web, searched on 17 August 2020)
Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, and Cochrane Register of Studies Online (CRSO; 2020, Issue 8)
MEDLINE (Ovid MEDLINE® Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily, and Ovid MEDLINE®) (searched from 1 January 2017 to 17 August 2020)
Embase Ovid (searched from 1 January 2017 to 17 August 2020)
Cumulative Index to Nursing and Allied Health Literature (CINAHL) Ebsco (searched from 1 January 2017 to 17 August 2020)
Allied and Complementary Medicine Database (AMED) Ovid (searched from 1 January 2017 to 17 August 2020)

The Information Specialist modelled search strategies for other databases on the search strategy designed for CENTRAL. When appropriate, we combined these strategies with adaptations of the highly‐sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 6; Lefebvre 2011). We have provided the search strategies used for major databases in Appendix 1.

The Information Specialist searched the following trials registries on 17 August 2020.

World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch);
ClinicalTrials.gov (clinicaltrials.gov).

Searching other resources

For this update, review authors searched all references from included studies.

Data collection and analysis

Selection of studies

Two review authors (ZZ, QH) independently assessed the titles and abstracts of all trial reports identified by the searches. Whenever possible, we obtained the full‐text hard copies for studies that appeared to fulfil the selection criteria. Each review author had a list of selected papers and duplicate sets of the papers for independent analyses. To ascertain that the study met the inclusion criteria, we used a standard form to collect information on type of study, types of participants, and types of interventions, and we resolved disagreements through discussion.

Data extraction and management

Two review authors (ZZ, QH) independently extracted information on participants, methods, interventions, outcomes, and results using a pre‐tested form and resolving disagreements through discussion.

Assessment of risk of bias in included studies

We recorded data about the methodological criteria used by investigators in all included studies. We have presented these in the 'Risk of bias' tables and have discussed them in the text where relevant. Two review authors (ZZ, QH) independently assessed trials for risks of bias in adequate sequence generation; allocation concealment; blinding of participants, personnel, and outcomes assessors; attrition bias (i.e. whether all participants were accounted for in the analysis (intention‐to‐treat, or ITT)); selective reporting; and other potential types of bias. We graded each domain as 'low risk of bias', 'high risk of bias', or 'unclear risk of bias', according to the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Sequence generation

Examples of randomisation methods falling into each 'Risk of bias' category for generation of the allocation sequence include the following:

Low risk of bias: adequate generation of allocation sequence encompasses randomisation methods such as computer‐generated numbers, a table of random numbers, shuffling of cards or envelopes, coin‐ or dice‐tossing, and drawing of lots;
High risk of bias: inadequate generation of allocation sequence refers to group allocations by case record number; date of birth; day, month, or year of admission; judgement of the clinician or the participant; laboratory test or series of tests; and availability of the intervention;
Unclear risk of bias: study authors reported generation of the allocation sequence unclearly.

Allocation concealment

Examples of methods used for allocation concealment that fall into each category include the following:

Low risk of bias: adequate allocation concealment was achieved through central randomisation (including telephone, web‐based, and pharmacy‐controlled randomisation; sealed opaque containers administered serially to participants);
High risk of bias: inadequate allocation concealment occurred by any procedure that was transparent before allocation;
Unclear risk of bias: trials provided insufficient information to allow a judgement on risk of bias.

Blinding

Double‐blinding methods include masking the clinician (person delivering treatment), the participant, and the outcomes assessor to treatment allocation. We determined risk of bias in line with the following examples:

Low risk of bias: we considered masking of both participants and the results assessor as carrying low risk of performance and detection bias. We did not consider blinding necessary for mortality or other outcomes not influenced by blinding;
High risk of bias: non‐blinded assessment of outcomes such as quality of life (QoL) carry high risk of bias; for objective outcomes (e.g. death), we did not consider this necessary;
Unclear risk of bias: studies did not provide sufficient information for a judgement of 'yes' or 'no'. We considered single‐blinding of the results assessor to carry moderate risk of performance bias, detection bias, or both. If single‐blinding was performed on participants but not on the results assessor, we considered the outcomes to carry high risk of detection bias.

Incomplete outcome data

'Incomplete outcome data' refers to a mismatch between the number of randomised participants and the number included in the main analysis. Examples of the three risk categories include the following:

Low risk of bias: trials are not missing outcome data or note few exclusions and attrition; an ITT analysis is possible;
High risk of bias: the rate of exclusion, attrition, or both is higher than 15%, or there are wide differences in exclusions between intervention group and control group, whichever ITT analysis is used;
Unclear risk of bias or moderate risk of bias: trials report the rate of exclusion or attrition (or both) as higher than 10%, whichever ITT analysis is used.

Selective reporting

If the protocol of the included study was available, we compared outcomes in the protocol versus those in the published report. If the protocol was not available, we compared outcomes listed in the Methods section of the study against those presented in the Results.

Other bias

We assessed potential factors affecting the precision of an estimate of included studies.

All quality criteria met: low risk of bias;
One or more of the quality criteria met in part: unclear risk of bias;
One or more criteria not met: high risk of bias.

We resolved disagreements about whether or not a trial fulfilled certain quality criteria through discussion with a third review author (BD). We have detailed all quality criteria ratings and supporting information in the 'Risk of bias' tables (see Characteristics of included studies).

Measures of treatment effect

We analysed the data using Review Manager 5 (Review Manager 2020). We summarised dichotomous data as an odds ratio (OR) and continuous data as a mean difference (MD), using a 95% confidence interval (CI) throughout.

Unit of analysis issues

For multiple‐arm trials, we included the intervention group of interest according to the objective in our review. We took care to avoid double‐counting of participants when we included multiple‐arm trials. For cross‐over trials, we planned to include the first period of the trial and to exclude the subsequent period to prevent interference with previous drugs, even if the trial reported a washout period. For cluster‐RCTs, we planned to calculate the effective sample size both in the intervention group and in the control group based on the numbers of clusters and participants, and then, when necessary, to use the generic inverse variance method to pool this type of data according to recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We contacted trial authors for missing data. For this review, we analysed outcome measures on an ITT basis.

Assessment of heterogeneity

For detecting heterogeneity across studies, we used the Chi² test with a 10% level of statistical significance, establishing a P value of 0.1 as the cutoff value to determine statistical significance. We used the I² statistic to estimate total variation across studies. We considered an I² value less than 40% to represent low‐level heterogeneity, 40% to 50% as representing a moderate level of heterogeneity, 50% to 90% as showing a substantial level of heterogeneity, and 75% to 100% as indicating considerable heterogeneity (Higgins 2011).

Within each subgroup, we used Chi² analyses to test for statistical evidence of heterogeneity among studies, and we used I² to measure the degree of inconsistency across studies. When Chi² analysis was significant and I² values were in excess of 50%, we analysed differences in participant selection, baseline values, risk of bias, design, and methods that could possibly explain the heterogeneity.

Assessment of reporting biases

Funnel plots have a limited role when used with small numbers of studies (fewer than 10) in a meta‐analysis. Our review included only a few studies (fewer than 10) in each subgroup, so we did not use this approach to assess reporting bias. In the future, if we can include more studies in a subgroup, we will use a funnel plot to assess the presence of publication bias. However, we did attempt to access the protocols of the included studies to assess selective reporting bias.

Data synthesis

We used a random‐effects model for pooled analysis of heterogeneous data (I² = 40% to 100%) and a fixed‐effect model for individual study data and pooled analyses of homogeneous data (I² < 40%). We used the Mantel‐Haenszel method to synthesise dichotomous data and the inverse variance method to synthesise continuous data. When it was not possible to undertake meta‐analyses, we described a systematic approach to synthesising the findings of multiple studies.

Subgroup analysis and investigation of heterogeneity

We analysed subgroups according to the different types of interventions included in the review. We also performed a subgroup analysis according to different types of PE (massive/submassive) for the primary outcomes. We analysed studies of submassive PE that used an ultrasound‐assisted, catheter‐directed thrombolysis system (USAT (rt‐PA)) separately from other studies investigating submassive PE, because USAT (rt‐PA) is a new and different intervention from traditional thrombolytic therapy. For studies that included both massive and other unknown PE types, we categorised participants as 'type of PE unknown'. We used the interaction test (whereby an I² statistic is computed for heterogeneity across subgroup results) for subgroup differences in Review Manager 2020 as the basis for interpreting subgroup analyses. For future updates, and if the necessary data become available, we plan to analyse subgroups according to different doses and durations of intervention.

Sensitivity analysis

We performed a sensitivity analysis based on the methodological quality of included studies. We excluded very low‐quality studies from the pooled meta‐analysis. In this review, we defined very low‐quality studies as having high risk in two or more 'Risk of bias' domains.

Summary of findings and assessment of the certainty of the evidence

In this review, we included only RCTs. We used GRADEpro software to help us create summary of findings Table 1 for the comparison 'Thrombolytic therapy versus heparin' (GRADEpro GDT). We reported the primary outcomes of death from all causes; recurrence of pulmonary emboli; and major and minor haemorrhagic events based on an ITT population. We downgraded the evidence from 'high certainty' by one or two levels for serious or very serious study limitations (risk of bias), indirectness and inconsistency of evidence, imprecision of effect estimates, or potential publication bias, according to recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions (Ryan 2016).

Results

Description of studies

Results of the search

We included three new studies in this update (Ahmed 2018; Sinha 2017; Zhang 2018). Of these, two were identified from database search results (Ahmed 2018; Zhang 2018), and one from reference checking (Sinha 2017). We identified two additional reports for two already included studies (Kline 2014; Meyer 2014). We excluded an additional 11 studies (Allen 2020; Avgerinos 2018; Bin 2019; Cimen 2019; Er 2018; NCT03581877; Petolat 2019; Tapson 2018; Wang 2018; Yilmaz 2019; Zhao 2018). We identified four new ongoing studies (IRCT2014042017343N1; NCT03854266; NCT03988842; NCT04430569) and one additional record for a study previously assessed as ongoing (EudraCT: 2017‐005075‐91‐DK). See Figure 1.

Figure 1

Study flow diagram.

Included studies

We included a total of 21 studies with 2401 participants (Ahmed 2018; Becattini 2010; Dalla‐Volta 1992; Dotter 1979; Fasullo 2011; Goldhaber 1993; Jerjes‐Sánchez 1995; Kline 2014; Konstantinides 2002; Kucher 2014; Levine 1990; Ly 1978; Marini 1988; Meyer 2014; PIOPED 1990; Sharifi 2013; Sinha 2017; Taherkhani 2014; Tibbutt 1974; UPETSG 1970; Zhang 2018). We were able to use 20 of the included trials (2371 participants) in the meta‐analysis; the other study lacked outcome data (Marini 1988).

Design

All included RCTs except for Marini 1988 used a parallel design and included two study arms (Marini 1988 had three arms). Nine were multi‐centre RCTs (Becattini 2010; Dalla‐Volta 1992; Kline 2014; Konstantinides 2002; Kucher 2014; Levine 1990; Meyer 2014; PIOPED 1990; UPETSG 1970); one was a two‐centre study (Tibbutt 1974); and the remainder were single‐centre studies (Ahmed 2018; Dotter 1979; Fasullo 2011; Goldhaber 1993; Jerjes‐Sánchez 1995; Ly 1978; Marini 1988; Sharifi 2013; Sinha 2017; Taherkhani 2014; Zhang 2018).

Participants

All trials focused on adults aged 18 or over. Trials took place in Italy (Becattini 2010; Dalla‐Volta 1992; Fasullo 2011), the United States (Dotter 1979; Goldhaber 1993; Kline 2014; PIOPED 1990; UPETSG 1970), Canada (Levine 1990), China (Zhang 2018), Egypt (Ahmed 2018), Norway (Ly 1978), Germany (Konstantinides 2002), Germany and other European countries (Kucher 2014; Meyer 2014), India (Sinha 2017), Iran (Taherkhani 2014), and the United Kingdom (Tibbutt 1974). Three studies did not describe the study setting or country (Jerjes‐Sánchez 1995; Marini 1988; Sharifi 2013). All trials stated baseline data and analysed comparability. Fourteen trials included participants with submassive PE (Ahmed 2018; Becattini 2010; Dalla‐Volta 1992; Fasullo 2011; Goldhaber 1993; Kline 2014; Konstantinides 2002; Kucher 2014; Levine 1990; Meyer 2014; Sharifi 2013; Sinha 2017; Taherkhani 2014; Zhang 2018), and only one study included only participants with massive PE (Jerjes‐Sánchez 1995). We were unable to identify the type of PE in six studies (Dotter 1979; Ly 1978; Marini 1988; PIOPED 1990; Tibbutt 1974; UPETSG 1970).

Interventions

Studies involved different types of thrombolytics, including alteplase, urokinase, streptokinase, rt‐PA, ultrasound‐assisted catheter‐directed thrombolysis system, and tenecteplase, usually followed by heparin. The control intervention was heparin alone in 13 included trials (Ahmed 2018; Dalla‐Volta 1992; Dotter 1979; Goldhaber 1993; Jerjes‐Sánchez 1995; Kucher 2014; Ly 1978; Marini 1988; Sharifi 2013; Taherkhani 2014; Tibbutt 1974; UPETSG 1970; Zhang 2018). The remaining eight trials used placebo plus heparin (Becattini 2010; Fasullo 2011; Kline 2014; Konstantinides 2002; Levine 1990; Meyer 2014; PIOPED 1990; Sinha 2017). No studies compared thrombolytics versus surgical intervention.

Outcome measures

Investigators reported a variety of outcome measures. Most trials reported overall mortality, recurrence of PE, and haemorrhagic events. Main outcome measures also included perfusion lung scanning, haemodynamic outcomes, and angiographic score. Two trials that performed perfusion lung scanning reported data at several time points (first, third, and seventh days post‐treatment) (Levine 1990; UPETSG 1970). Six trials reported haemodynamic outcomes in 10 subgroups (Meyer 2014; PIOPED 1990; Sinha 2017; Tibbutt 1974; UPETSG 1970; Zhang 2018). Six other trials reported length of hospital stay or hospitalised status of the participant, including rate of rehospitalisation (Ahmed 2018; Kucher 2014; Meyer 2014; Sharifi 2013; Sinha 2017; Taherkhani 2014). Kline 2014 reported on functional capacity and quality of life (using the Venous Insufficiency Epidemiological and Economic Study, or VEINES, questionnaire and score). None of the trials assessed healthcare costs.

See the Characteristics of included studies table for further details.

Ongoing studies

We identified four new ongoing studies for this update (IRCT2014042017343N1; NCT03854266; NCT03988842; NCT04430569). We found an additional report to a study previously listed as ongoing (NCT04088292). The total number of ongoing studies is therefore nine (EudraCT: 2005‐001070‐27; IRCT2014042017343N1; NCT01531829; NCT02604238; NCT03218410; NCT03854266; NCT03988842; EudraCT: 2017‐005075‐91‐DK; NCT04430569). See Characteristics of ongoing studies for further details.

Excluded studies

For this 2020 update, we identified 11 new excluded studies (Allen 2020; Avgerinos 2018; Bin 2019; Cimen 2019; Er 2018; NCT03581877; Petolat 2019; Tapson 2018; Wang 2018; Yilmaz 2019; Zhao 2018), bringing the total number of excluded studies to 66 (Abdelsamad 2011; Agnelli 1997; Alexandru Ion 2017; Allen 2020; Avgerinos 2018; Barrios 2017; Bell 1974; Bell 1976; Bell 1977; Bhardwaj 2010; Bin 2019; Carroll 2018; Charbonnier 1984; Chen 2009; Cimen 2019; Comerota 2009; De Takats 1973; Er 2018; Erkan 2002; Francois 1986; Goldhaber 1989; Goldhaber 1992; Goldhaber 1994; IRCT201104245625N2; Jin 2012; Jing 2018; Konstantinides 1998; Lehnert 2017; Liu 2012; Marder 1978; Meneveau 1997; Meneveau 1998; Meyer 1992; Miller 1971; Muhl 2007; NCT00968929; NCT01956955; NCT03581877; Ohayon 1986; Palla 1997; Pang 2007; Petolat 2019; Prandoni 1985; Research Group on Urokinase and PE 1984; Saponjski 2002; Sasahara 1975; Sharma 2000; Sors 1994; Tapson 2018; Tebbe 1999; Tebbe 2009; UKEP Study Group 1987; UPET Study Group 1974; Verstraete 1988; Wang 2009; Wang 2010; Wang 2018; Wu 2010; Xu 2016; Yang 2007; Yang 2009; Yang 2011; Yilmaz 2019; Yilmazel 2018; Zhao 2018; Zhu 2008). See the Characteristics of excluded studies table for further details. The reasons for exclusion were mainly as follows: not a true RCT, compared different thrombolytic agents and compared different doses or usages of thrombolytics. One previously excluded study (NCT00680628) was reclassified as an additional publication of included study Kline 2014.

Risk of bias in included studies

We judged all included studies to be at low or unclear risk for selection bias (allocation concealment) and reporting bias. Two studies were at high risk of selection bias (random sequence generation) (Jerjes‐Sánchez 1995; Ly 1978), two studies were at high risk of attrition bias (Ly 1978; Tibbutt 1974), three studies were at high risk of performance and detection bias (Ahmed 2018; Goldhaber 1993; Taherkhani 2014), three studies are at high risk of performance bias (Kucher 2014; Sharifi 2013; Tibbutt 1974), and seven studies were at high risk of other bias (Dotter 1979; Jerjes‐Sánchez 1995; Kline 2014; Kucher 2014; Meyer 2014; Taherkhani 2014; Tibbutt 1974). Only Meyer 2014 provided sufficient detail for assessment of all domains as having low or high risk of bias. Marini 1988 did not provide enough information on any domain to allow a clear determination of risk. One study had either unclear or high risk of bias in all domains (Dotter 1979).

We defined studies as being at high risk of overall bias if two or more assessment domains carried a high risk of bias, with seven studies meeting this criterion (Ahmed 2018; Goldhaber 1993; Jerjes‐Sánchez 1995; Kucher 2014; Ly 1978; Taherkhani 2014; Tibbutt 1974). See Figure 2 and Figure 3 for a summary of the general risk of bias of included studies.

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Six trials clearly described appropriate random sequence generation (Fasullo 2011; Goldhaber 1993; Kline 2014; Konstantinides 2002; Meyer 2014; UPETSG 1970). Thirteen trials did not clearly describe random sequence generation so were judged to be at unclear risk (Ahmed 2018; Becattini 2010; Dalla‐Volta 1992; Dotter 1979; Kucher 2014; Levine 1990; Marini 1988; PIOPED 1990; Sharifi 2013; Sinha 2017; Taherkhani 2014; Tibbutt 1974; Zhang 2018). Although two studies used the appropriate method to generate the sequence, Ly 1978 did not randomise five included participants (four in the streptokinase group, one in the heparin group); and numbers were unbalanced between the intervention group and the control group at the onset of PE in Jerjes‐Sánchez 1995. We therefore judged these two studies as having high risk of selection bias.

Only three of the 21 trials described adequate allocation concealment (Goldhaber 1993; Meyer 2014; UPETSG 1970). Thirteen trials poorly reported methods, mainly by omitting any mention of allocation concealment (Becattini 2010; Dalla‐Volta 1992; Dotter 1979; Fasullo 2011; Jerjes‐Sánchez 1995; Konstantinides 2002; Kucher 2014; Levine 1990; Marini 1988; PIOPED 1990; Sinha 2017; Taherkhani 2014; Tibbutt 1974). Five trials reported using sealed envelopes, closed envelopes or envelopes during concealment, but their descriptions were not detailed enough (sequential numbering and opaqueness) to allow a definitive judgement (Ahmed 2018; Kline 2014; Ly 1978; Sharifi 2013; Zhang 2018). We contacted trial authors for further clarification but received no response.

Blinding

Seven trials used double‐blinding (Fasullo 2011; Kline 2014; Konstantinides 2002; Levine 1990; Meyer 2014; PIOPED 1990; UPETSG 1970) and so were at low risk of bias for both performance and detection bias. Six trials reported single‐blinding of outcome assessment and so were at low risk of detection bias (Becattini 2010; Dalla‐Volta 1992; Kucher 2014; Ly 1978; Sharifi 2013; Tibbutt 1974). Three of these were at unclear risk of performance bias as insufficient details were provided (Becattini 2010; Dalla‐Volta 1992; Ly 1978), but three were at high risk because they were described as open (Kucher 2014; Sharifi 2013), or because they were unable to blind due to differences in physical characteristics of the intervention (Tibbutt 1974). Five trials did not document blinding and were assessed at unclear risk of both performance and detection bias (Dotter 1979; Jerjes‐Sánchez 1995; Marini 1988; Sinha 2017; Zhang 2018). Two trials were described as non‐blinded and were judged to be at high risk of performance and detection bias (Ahmed 2018; Goldhaber 1993). Taherkhani 2014 reported single‐blinding of participants and the blinding was broken, so we assigned it high risk of bias.

Incomplete outcome data

Apart from Dalla‐Volta 1992 and Dotter 1979, all trials either described the withdrawal rate or provided sufficient information for this to be calculated. Withdrawal rates varied from 0% in Ahmed 2018, Fasullo 2011, Jerjes‐Sánchez 1995, Levine 1990, PIOPED 1990, Sinha 2017, Taherkhani 2014, UPETSG 1970 and Zhang 2018 (low risk of bias), to 45% in Ly 1978 (among participants with an angiographic response to 72 hours of treatment in the heparin group) and 63% in Tibbutt 1974 (for long‐term follow‐up at six months; data unstable between different follow‐up periods), both of which were judged to be at high risk of attrition bias. The remaining two studies described post‐randomisation exclusions well and were at low risk of bias (Goldhaber 1993; Meyer 2014).

Selective reporting

Four studies had low reporting bias according to their study protocols (Becattini 2010; Fasullo 2011; Kline 2014; Meyer 2014). We were unable to access the protocols of the remaining included studies, so they were all at an unclear risk of selective reporting bias.

Other potential sources of bias

We judged seven trials to be at high risk of other bias, and the rest carried unclear risk. Reasons included small sample size, potential conflicts of interest, inconsistent randomisation, and non‐ITT methods of analysing outcome data. All included studies had relatively small sample sizes. The largest sample size in the included studies was 1006 participants (Meyer 2014), and the smallest was eight (Jerjes‐Sánchez 1995). The limited number of participants could introduce a potential source of bias. Similarly, pharmaceutical companies funded some studies, which may constitute a conflict of interest, even though some study authors state there was no influence from these companies during the whole study period (Dotter 1979; Kline 2014; Kucher 2014; Meyer 2014). Taherkhani 2014 included a small sample size, and although 59 participants had submassive pulmonary thromboembolism, only 50 participants were randomised. In the same way, Tibbutt 1974 included a small sample size, and two participants were transferred from the control group to the treatment group; moreover, investigators did not analyse outcome data on an ITT basis. We therefore assessed these studies as having high risk of other potential bias (Dotter 1979; Jerjes‐Sánchez 1995; Kline 2014; Kucher 2014; Meyer 2014; Taherkhani 2014; Tibbutt 1974). All other studies were at an unclear risk of other bias.

Effects of interventions

See: Summary of findings 1 Thrombolytic therapy versus heparin: primary outcome measures for pulmonary embolism

We were not able to include in the meta‐analyses one of the 21 included trials, because it provided no data that we could extract (Marini 1988). Our meta‐analyses therefore included up to 20 trials with a total of 2371 participants. We analysed primary outcome measures on an ITT basis. We analysed all participants who dropped out of the study according to their original group, regardless of whether or not they completed or received that treatment.

Primary outcome measures

Death from all causes

Nineteen trials reported on death from all causes (Becattini 2010; Dalla‐Volta 1992; Dotter 1979; Fasullo 2011; Goldhaber 1993; Jerjes‐Sánchez 1995; Kline 2014; Konstantinides 2002; Kucher 2014; Levine 1990; Ly 1978; Meyer 2014; PIOPED 1990; Sharifi 2013; Sinha 2017; Taherkhani 2014; Tibbutt 1974; UPETSG 1970; Zhang 2018). The 19 trials included in the meta‐analysis reported a total of 87 deaths: 32 in the thrombolytics group and 55 in the heparin group. Pooled analyses showed that across all studies, giving thrombolytics reduced the incidence of death (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.38 to 0.88; 19 studies, 2319 participants, low‐certainty evidence; Analysis 1.1). The analysis showed that statistical heterogeneity between studies was at a low level (I² = 0%). The test for subgroup differences indicated no clear difference between the types of thrombolytic used for death from all causes (P = 0.73; Analysis 1.1).

We carried out a sensitivity analysis by excluding studies at high risk of bias (Goldhaber 1993; Jerjes‐Sánchez 1995; Kucher 2014; Ly 1978; Taherkhani 2014; Tibbutt 1974). However, we no longer found clear evidence to support a difference between the two groups for all‐cause mortality (OR 0.71, 95% CI 0.45 to 1.13; 13 studies, 2046 participants; Analysis 2.1). The analysis still shows that statistical heterogeneity between studies was at a low level (I² = 0%). Because some studies carried a high risk of bias, we downgraded the certainty of the evidence for this outcome from high to low (summary of findings Table 1). We also performed a subgroup analysis according to different types of PE (massive/submassive/unknown types of PE), and found no clear effects between subgroups (P = 0.30). Only the massive PE subgroup showed that thrombolytic therapy may have an effect on death (Analysis 3.1). We found no clear evidence to support a difference between thrombolytic therapy and heparin for death in the other subgroups.

Meyer 2014 reported long‐term mortality rates for participants with intermediate‐risk PE. Researchers in this study followed about 70% of participants over two years (median 37.8 months) and reported that tenecteplase treatment did not affect long‐term mortality rates compared to placebo and heparin. We were unable to include the data in our meta‐analysis, as the other included studies reported short‐term mortality (follow‐up period less than three months for most studies). Further analyses may be possible in future updates.

Recurrence of pulmonary emboli

Twelve studies reported on the recurrence of pulmonary emboli (Becattini 2010; Dalla‐Volta 1992; Dotter 1979; Fasullo 2011; Goldhaber 1993; Konstantinides 2002; Levine 1990; Meyer 2014; Sharifi 2013; Sinha 2017; UPETSG 1970; Zhang 2018). Pooled data comparing thrombolytics versus heparin show that the thrombolytics group experienced less recurrence than the heparin group (OR 0.54, 95% CI 0.32 to 0.91; 12 studies, 2050 participants, low‐certainty evidence; Analysis 1.2). Analyses show that statistical heterogeneity between studies was at a low level (I² = 0%).The test for subgroup differences indicated no clear difference between types of thrombolytic used and recurrence of PE (P = 0.59; Analysis 1.2).

We performed a sensitivity analysis by removing one study at high risk of bias (Goldhaber 1993). The analysis showed no clear effect of thrombolytics on recurrence of PE comparing with heparin (OR 0.60, 95% CI 0.35 to 1.04; 11 studies, 1949 participants; Analysis 2.2). Hence, we downgraded the certainty of the evidence for this outcome from high to low for very serious risk of bias (selection, performance, and detection bias) (summary of findings Table 1). We also performed a subgroup analysis by different types of PE (submassive/unknown types of PE) and found no conclusive evidence showing a difference between subgroups (test for subgroup differences: P = 0.46). The 'unknown types of PE' subgroup provided no clear evidence to support a difference between thrombolytic therapy and heparin (Analysis 3.2).

Major and minor haemorrhagic events

Major haemorrhagic events

Fifteen studies reported on major haemorrhagic events (Ahmed 2018; Becattini 2010; Dalla‐Volta 1992; Fasullo 2011; Goldhaber 1993; Kline 2014; Konstantinides 2002; Levine 1990; Ly 1978; Meyer 2014; PIOPED 1990; Sinha 2017; Tibbutt 1974; UPETSG 1970; Zhang 2018). The total number of these events was 136: 99 in the thrombolytics group and 37 in the heparin group. Pooled analyses showed that across 15 studies comparing thrombolytics versus heparin, more major bleeding events occurred after treatment with thrombolytics (OR 2.84, 95% CI 1.92 to 4.20; 15 studies, 2101 participants; moderate‐certainty evidence; Analysis 1.3). The result was not changed even after four studies at high risk of bias (Ahmed 2018; Goldhaber 1993; Ly 1978; Tibbutt 1974), were excluded in a sensitivity analysis (OR 2.91, 95% CI 1.92 to 4.39; 11 studies, 1893 participants; Analysis 2.3). Analysis showed low levels of statistical heterogeneity between studies, both before (I² = 3%) and after (I² = 26%) the sensitivity analysis. We downgraded the certainty of the evidence for this outcome from high to moderate for 'Risk of bias' concerns (summary of findings Table 1).

The test for subgroup differences indicated no clear difference between types of thrombolytic used and major haemorrhagic events (P = 0.05; Analysis 1.3). We also performed a subgroup analysis by different types of PE (submassive/unknown types of PE) and found no subgroup effects between subgroups (P = 0.30; Analysis 3.3).

Two studies explicitly reported on the occurrence of haemorrhagic stroke after treatment (Meyer 2014; Sinha 2017). Both studies compared tenecteplase plus heparin versus placebo plus heparin, with a total number of events of 12: 11 in the thrombolytic group and 1 in the heparin group. Pooled data show more haemorrhagic stroke occurred in the thrombolytic groups than in the heparin group (OR 7.59, 95% CI 1.38 to 41.72; 2 studies, 1091 participants; Analysis 1.4).

Minor haemorrhagic events

Thirteen studies reported on minor haemorrhagic events (Ahmed 2018; Becattini 2010; Dalla‐Volta 1992; Fasullo 2011; Kucher 2014; Levine 1990; Ly 1978; Meyer 2014; Sinha 2017; Taherkhani 2014; Tibbutt 1974; UPETSG 1970; Zhang 2018). Pooled analyses comparing thrombolytics versus heparin show more minor haemorrhagic events occurred in the thrombolytics group (OR 2.97, 95% CI 1.66 to 5.30; 13 studies, 1757 participants; low‐certainty evidence; Analysis 1.5). Analyses show that statistical heterogeneity between the included studies was at a substantial level (I² = 55%), so we used a random‐effects model for the pooled analysis. After excluding the five studies at high risk of bias (Ahmed 2018; Kucher 2014; Ly 1978; Taherkhani 2014; Tibbutt 1974), we still observed this difference between the two groups (OR 3.82, 95% CI 2.06 to 7.09; 8 studies, 1541 participants; Analysis 2.4). We downgraded the certainty of the evidence for this outcome from high to low for 'Risk of bias' concerns and inconsistency (large heterogeneity) (summary of findings Table 1). The test for subgroup differences indicated no clear difference between types of thrombolytic used and minor haemorrhagic events (P = 0.07; Analysis 1.5). We also performed a subgroup analysis by different types of PE (submassive/unknown types of PE) and found a subgroup effect between subgroups (P = 0.02); we found a difference between the two groups in the 'submassive PE' subgroup but not in the 'unknown types of PE' subgroup (Analysis 3.4).

Secondary outcome measures

Haemodynamic improvement and thrombolysis

Pulmonary arterial systolic pressure improvement

Four studies comparing thrombolytics with heparin show consistent results in the improvement of pulmonary arterial systolic pressure at follow‐up times of 24 hours, 72 hours and 7 days (Sinha 2017; Tibbutt 1974; UPETSG 1970; Zhang 2018). At 24 hours after treatment, UPETSG 1970 compared urokinase versus heparin in 147 participants and Zhang 2018 compared rt‐PA versus heparin in 66 participants; both show that thrombolytic treatment had a small effect on pulmonary arterial systolic pressure improvement (mean difference (MD) −4.41 mmHg, 95% CI −4.62 to −4.20; MD −12.4 mmHg, 95% CI −17.23 to −7.57, respectively; Analysis 4.1). Of the two remaining studies, one compared streptokinase versus heparin in 21 participants at 72 hours (Tibbutt 1974) and the other compared tenecteplase versus heparin in 86 participants at 7 days (Sinha 2017). These also showed a possible effect following thrombolytic treatment (MD −11.60 mmHg, 95% CI −20.81 to −2.39; MD −3.02 mmHg, 95% CI −4.75 to −1.29, respectively; Analysis 4.1). Although not pooled, these results indicate that thrombolytics may decrease pulmonary arterial systolic pressure to a greater extent than heparin, and that the effect is similar for various thrombolytics. However, the small number of overall participants involved and the high risk of bias attached to Tibbutt 1974 warrants caution when interpreting the results.

Mean pulmonary arterial pressure improvement

Three studies comparing thrombolytics versus heparin showed contradictory results in the improvement in mean pulmonary arterial pressure (PIOPED 1990; Tibbutt 1974; UPETSG 1970). Although rt‐PA versus heparin at 1½ hours showed no clear effect for thrombolytic treatment in PIOPED 1990 (MD −3.00 mmHg, 95% CI −16.91 to 10.91; 13 participants; Analysis 4.2), the two remaining studies reported a small effect on mean pulmonary arterial pressure improvement at 24 and 72 hours in favour of thrombolytic treatment (MD −4.41 mmHg, 95% CI −4.62 to −4.20; 147 participants; MD −7.50 mmHg, 95% CI −12.80 to −2.20; 17 participants, respectively; Analysis 4.2). However, the small number of participants involved warrants caution when interpreting the results.

Right ventricular end‐diastolic pressure improvement

Two studies showed contradictory results for right ventricular end‐diastolic pressure improvement. UPETSG 1970 compared urokinase versus heparin in 142 participants, and after 24 hours noted a small difference in right ventricular end‐diastolic pressure improvement in favour of thrombolytic treatment (MD −2.21 mmHg, 95% CI −2.35 to −2.07; Analysis 4.3). On the other hand, Tibbutt 1974 compared streptokinase versus heparin in 19 participants, observing no clear difference after 72 hours (MD 1.20 mmHg, 95% CI −2.59 to 4.99; Analysis 4.3). However, we judged Tibbutt 1974 to be at high risk of bias in this review and the number of participants involved in this analysis was small, so results must be interpreted with caution.

Total pulmonary resistance improvement

UPETSG 1970 compared urokinase versus heparin in 113 participants, finding a small difference in favour of urokinase at 24 hours after treatment (MD −0.33 dyn·s·cm^‐5, 95% CI −0.35 to −0.31; Analysis 4.4). Tibbutt 1974 compared streptokinase versus heparin in 12 participants at 72 hours after treatment, finding no clear difference between treatment and control (MD 0.30 dyn·s·cm^‐5, 95% CI −0.83 to 1.43; Analysis 4.4). PIOPED 1990 compared rt‐PA versus heparin in 13 participants at 1½ hours after treatment, and although these results appear to favour rt‐PA, no clear difference between the two groups is evident (MD −180.00 dyn·s·cm^‐5, 95% CI −883.55 to 523.55; Analysis 4.4). Again, the small number of participants involved and the high risk of bias for Tibbutt 1974 warrants caution when interpreting the results.

Cardiac index improvement (L/min/m²)

Two studies show contradictory results for cardiac index improvement (Tibbutt 1974; UPETSG 1970). Tibbutt 1974 compared streptokinase versus heparin in 13 participants, observing a small difference in cardiac index improvement in favour of heparin (MD −0.60, 95% CI −1.05 to −0.15; Analysis 4.5). UPETSG 1970, which compared urokinase versus heparin in 115 participants, reported a small difference in cardiac index improvement in favour of urokinase (MD 0.20, 95% CI 0.15 to 0.25; Analysis 4.5). Results must be interpreted with caution due to high risk of bias in Tibbutt 1974, and the small number of participants involved.

Other haemodynamic outcomes

UPETSG 1970, with 160 participants, compared urokinase versus heparin at 24 hours after treatment, showing small differences in favour of urokinase in right ventricular systolic pressure (MD −6.90 mmHg, 95% CI −7.25 to −6.55; Analysis 4.6), right arterial mean pressure (MD −1.94 mmHg, 95% CI −2.05 to −1.83; Analysis 4.7), arterial‐venous oxygen difference (MD −0.31 vol %, 95% CI −0.37 to −0.25; Analysis 4.8), and arterial PO₂ (MD 8.45 mmHg, 95% CI 7.84 to 9.06; Analysis 4.9).

Three studies reported haemodynamic decompensation rates among submassive PE participants in the thrombolytics group and the heparin group (Meyer 2014; Sinha 2017; Zhang 2018). Zhang 2018 compared rt‐PA versus heparin in 66 participants, while Meyer 2014 and Sinha 2017 compared tenecteplase versus heparin in 1005 and 86 participants, respectively. The total number of these events was 46: 10 in the thrombolytics group and 36 in the heparin group. Pooled analyses show that fewer haemodynamic decompensation events occurred after thrombolytic therapy (OR 0.26, 95% CI 0.13 to 0.53; 3 studies, 1157 participants; Analysis 4.10).

Perfusion lung scanning

UPETSG 1970 compared urokinase versus heparin, expressing perfusion defects as a percentage of total normal perfusion of both lungs. At days 1 and 2, results show a difference in favour of urokinase (day 1: MD 3.50%, 95% CI 1.32 to 5.68; 142 participants; Analysis 5.1; day 2: MD 3.10%, 95% CI 0.15 to 6.05; 133 participants; Analysis 5.2). Subsequent results include the following: at day 5: MD 2.00% (95% CI −1.60 to 5.60; 126 participants; Analysis 5.3); at day 14: MD 0.20% (95% CI −4.26 to 4.66; 116 participants; Analysis 5.5); and at one year MD −1.10% (95% CI −7.57 to 5.37; 57 participants; Analysis 5.7). These results show that on days 1 and 2 after treatment, either the total normal perfusion of both lungs or the proportion of lung not perfused in those treated with thrombolytics was greater than in those treated with heparin, and on days 5 and 14 and at one year follow‐up there was no clear effect of urokinase. A second study comparing rt‐PA versus heparin (Goldhaber 1993), in which perfusion defects were expressed as the proportion of lung not perfused, also showed a small effect in favour of rt‐PA at day 1 (MD 0.13%, 95% CI 0.05 to 0.21; 101 participants; Analysis 5.1). However, results must be interpreted with caution due to high risk of bias in Goldhaber 1993.

Dalla‐Volta 1992 compared alteplase plus heparin versus heparin alone, showing no clear effect on total lung score between the two groups at day 7 (MD 1.70, 95% CI −1.04 to 4.44; 21 participants; Analysis 5.4); however, results show a small difference in favour of alteplase at day 30 after treatment (MD 2.80, 95% CI 0.35 to 5.25; 22 participants; Analysis 5.6). Comparison of scores by change from baseline in both groups provides no clear evidence to support a difference between the two groups at day 7 or at day 30 (day 7: MD 1.80, 95% CI −0.51 to 4.11; 21 participants; Analysis 5.4; day 30: MD 0.70, 95% CI −1.37 to 2.77; 22 participants; Analysis 5.6). These results show that alteplase plus heparin and heparin alone may improve total lung scores with similar effect, but by day 30 the score in the alteplase‐plus‐heparin group was higher than the score in the heparin‐alone group. Due to the small number of participants involved, the results should be interpreted with caution.

Levine 1990 compared rt‐PA plus heparin versus placebo plus heparin, showing no clear difference in the number of participants with greater than 50% improvement on lung scan at 24 hours after treatment (OR 3.84, 95% CI 0.94 to 15.73; 57 participants; Analysis 6.1). We could not estimate this in the PIOPED 1990 study.

Pulmonary angiogram assessment

Researchers evaluated pulmonary angiograms using the Miller index (Miller 1971). The overall total score for pulmonary angiograms in Dalla‐Volta 1992 shows a small reduction in the alteplase‐plus‐heparin group (MD −3.4, 95% CI −4.72 to −2.08; 36 participants; Analysis 7.1).

Ly 1978 and Tibbutt 1974 compared streptokinase versus heparin, and, when pooled, results show a small difference in angiographic score changes from baseline to 72 hours in favour of streptokinase (MD −9.3, 95% CI −12.81 to −5.78; 47 participants, 2 studies; Analysis 7.2). This indicates that changes in angiographic score from baseline to 72 hours after treatment were greater in participants treated with streptokinase than in those treated with heparin. These results must be interpreted with caution, because both studies carried high risk of bias according to our review criteria.

Echocardiograms

Eight studies performed echocardiograms (Ahmed 2018; Becattini 2010; Fasullo 2011; Goldhaber 1993; Kucher 2014; Sinha 2017; Taherkhani 2014; Zhang 2018). Goldhaber 1993 compared rt‐PA plus heparin versus heparin alone; panellists decided by consensus whether right ventricular wall motion was normal or mildly (1+), moderately (2+), or severely (3+) hypokinetic. Tricuspid regurgitation was visually assessed according to the size of the largest colour doppler jet as absent, mild (1+), moderate (2+), or severe (3+). This study showed that the rt‐PA group had increased numbers of participants with improved right ventricular wall movement (OR 2.90, 95% CI 0.98 to 8.60 at 3 hours; OR 3.20, 95% CI 1.20 to 8.57 at 24 hours; 89 participants; Analysis 8.1) and tricuspid regurgitation (OR 6.35, 95% CI 1.90 to 21.17 at 3 hours; OR 3.20, 95% CI 1.20 to 8.57 at 24 hours; 89 participants; Analysis 8.2). Sinha 2017, comparing tenecteplase plus heparin versus placebo plus heparin, also reported that the thrombolytic group had a higher rate of right ventricular function improvement at 7 days after treatment (OR 3.46, 95% CI 1.42 to 8.42; 86 participants; Analysis 8.1).

Fasullo 2011 compared alteplase plus heparin versus heparin alone, assessing inferior vena cava, doppler acceleration time, paradoxical systolic septal motion, tricuspid annular plane systolic excursion, and B‐type natriuretic peptide (BNP) values (at baseline; at 24, 48, and 72 hours; at six days; at discharge; and at three months and six months). Investigators found earlier improvement in the thrombolytics group compared with the placebo group, with evident differences after 24 hours that lasted throughout hospitalisation and during the follow‐up period. Another study compared USAT (rt‐PA) plus heparin versus heparin alone (Kucher 2014), reporting the right‐to‐left ventricular dimension (RV/LV) ratio at 24 hours and at three months as a primary outcome. Results show a difference between the two groups at 24 hours, but at three months they show no clear effect for the rt‐PA group (P = 0.36). This study also shows that USAT (rt‐PA) had better outcomes at 24 hours than at three months for tricuspid annular systolic excursion, right ventricular‐to‐left ventricular pressure gradient, and minimum inferior vena cava diameter. Taherkhani 2014 compared alteplase or streptokinase plus enoxaparin versus enoxaparin alone. This study reported no clear differences between the two groups in normalisation of the RV. Zhang 2018 compared rt‐PA plus enoxaparin versus enoxaparin alone, and reported that the thrombolytics group had more reduction in RV/LV ratio at 24 hours after treatment.

In this review, we found that after treatment, most echocardiogram parameters in individual studies were better in the thrombolytics group than in the control group. For example, Fasullo 2011 reported the paradoxical systolic septal motion (OR 0.24, 95% CI 0.07 to 0.82 at 24 hours; OR 0.35, 95% CI 0.13 to 0.92 at 48 hours; OR 0.29, 95% CI 0.10 to 0.88 at 72 hours; OR 0.12, 95% CI 0.01 to 2.49 at six days; 72 participants; Analysis 8.3); Fasullo 2011, Kucher 2014 and Zhang 2018 reported right‐to‐left ventricular ratio at 24 hours after treatment (MD −0.16, 95% CI −0.21 to −0.11; 197 participants; 3 studies; Analysis 8.4); and Fasullo 2011 with 72 participants, reported additional time points: 48 hours (MD −0.19, 95% CI −0.20 to −0.18), 72 hours (MD −0.14, 95% CI −0.15 to −0.13), six days (MD −0.22, 95% CI −0.23 to −0.21), discharge (MD −0.33, 95% CI −0.34 to −0.32), three months (MD −0.14, 95% CI −0.34 to 0.05; 131 participants; pooled Fasullo 2011 and Kucher 2014), and six months (MD −0.21, 95% CI −0.22 to −0.20; 72 participants) (see Analysis 8.4).

Researchers reported similar time points for tricuspid annular plane systolic excursion: 24 hours (MD 0.45, 95% CI −1.18 to 2.07; 131 participants; pooled Fasullo 2011 and Kucher 2014), 48 hours (MD 1.00, 95% CI −0.13 to 2.13; 1 study, 72 participants), 72 hours (MD 1.80, 95% CI 0.67 to 2.93; 1 study, 72 participants), six days (MD 2.50, 95% CI 1.57 to 3.43; 1 study, 72 participants), discharge (MD 2.00, 95% CI 0.75 to 3.25; 1 study, 72 participants), three months (MD 0.33, 95% CI −3.18 to 3.85; 131 participants, 2 studies; pooled Fasullo 2011 and Kucher 2014), and six months (MD 1.30, 95% CI 0.28 to 2.32; 1 study, 72 participants; see Analysis 8.5). Kucher 2014 reported the right ventricular‐to‐right atrial pressure gradient (MD −6.30, 95% CI −13.06 to 0.46 at 24 hours; MD 3.20, 95% CI −4.77 to 11.17 at three months; Analysis 8.6) and the minimum inferior vena cava diameter (MD −6.60, 95% CI −9.36 to −3.84 at 24 hours; MD −0.50, 95% CI −2.79 to 1.79 at three months; 1 study, 59 participants; Analysis 8.7).

BNP values showed faster reduction in the thrombolytics group than in the placebo group during hospitalisation at six days after admission. Becattini 2010 also reported reduction in echocardiography parameters and found small differences in decreases in both right ventricle end‐diastolic dimension and the right‐to‐left end‐diastolic dimension ratio at 24 hours in favour of tenecteplase, but the difference was not maintained during the seven‐day follow‐up period (data were unavailable). These figures indicate that treatment with thrombolytics plus heparin possibly results in more participants with improved right ventricular wall movement and tricuspid regurgitation than treatment with heparin alone.

Chronic thromboembolic pulmonary hypertension

Six studies compared thrombolytic therapy plus heparin versus heparin alone for pulmonary hypertension (Ahmed 2018; Fasullo 2011; Sharifi 2013; Sinha 2017; Taherkhani 2014; Zhang 2018). Fasullo 2011 and Zhang 2018 reported that participants in the thrombolytics group had lower pulmonary hypertension than participants in the heparin group at 24 hours (MD −11.28, 95% CI −16.80 to −5.76; 2 studies, 138 participants). Fasullo 2011 and Sharifi 2013 reported the outcome at 48 hours (MD −7.37, 95% CI −9.20 to −5.53; 2 studies, 193 participants), and Fasullo 2011 and Ahmed 2018 reported the outcome at 72 hours (MD −7.65, 95% CI −10.03 to −5.28; 2 studies, 124 participants). Fasullo 2011 and Taherkhani 2014 reported at six days (MD −5.69, 95% CI −9.37 to −2.02; 2 studies, 122 participants); Sinha 2017 at seven days (MD −5.33, 95% CI −7.14 to −3.52; 1 study, 86 participants); Fasullo 2011 at discharge (MD −8.00, 95% CI −9.78 to −6.22; 1 study, 72 participants) and at three months (MD −7.00, 95% CI −17.18 to 3.18; 1 study, 72 participants); Fasullo 2011 and Sharifi 2013 at six months (MD −11.95, 95% CI −23.71 to −0.19; 2 studies, 193 participants); and Sharifi 2013 at 28 months (MD −15.00, 95% CI −17.32 to −12.68; 1 study, 128 participants) (see Analysis 8.8).

Differences in coagulation parameters over time

Fibrinogen

Two studies (Dalla‐Volta 1992; PIOPED 1990) comparing thrombolytic versus heparin treatment at less than three hours after treatment show a small difference in fibrinogen levels in favour of thrombolytics (total MD −2.68 g/L, 95% CI −4.36 to −1.00; 2 studies, 45 participants; Analysis 9.1). However, we found no clear evidence to support a difference between the two groups at 24 hours (MD −1.61 g/L, 95% CI −3.99 to 0.76; 2 studies, 114 participants), nor at 48 hours (MD −0.60 g/L, 95% CI −1.40 to 0.20; 1 study, 83 participants) after treatment (see Analysis 9.1). This may indicate that thrombolytic treatment results in a lower level of fibrinogen than heparin treatment. Levine 1990 also reported this comparison, but we could not extract the data from this study, as it reported changes in mean fibrinogen levels in a figure, showing that the thrombolytics group had a lower level of fibrinogen than the placebo group within 24 hours after treatment. In this update, an additional report of Kline 2014 stated that the fibrinogen levels between the two groups showed no evident difference at three‐month follow‐up (P = 0.862).

D‐dimer

As a molecular marker of haemostatic activation, D‐dimer indicates fibrin turnover both from intravascular fibrin formation and from subsequent lysis of a fibrin clot. Dalla‐Volta 1992 and PIOPED 1990 both reported a difference between participants treated with thrombolytics plus heparin and those treated with heparin alone at two hours after treatment. We used a random‐effects method to pool as heterogeneity was very high (I² = 86%), which was reflected in the pooled analysis (MD 21.04, 95% CI −4.60 to 46.69; 2 studies, 45 participants; Analysis 9.2). Dalla‐Volta 1992 reported a difference between two groups at 24 hours after treatment (MD 5.30 µg/mL, 95% CI 2.12 to 8.48; 31 participants; Analysis 9.2). These results show that D‐dimer concentrations may be higher in the thrombolytics‐plus‐heparin group than in the heparin‐alone group. However, an additional report from Kline 2014 for this update reports no clear difference in D‐dimer concentrations between the tenecteplase group and the control group at three‐month follow‐up (P = 0.05).

Plasminogen

Dalla‐Volta 1992 reported a difference in concentrations of plasminogen at two hours (MD −60.30%, 95% CI −71.92 to −48.68; 22 participants) and at 24 hours (MD −36.00%, 95% CI −48.06 to −23.94; 21 participants) after treatment in favour of alteplase (see Analysis 9.3). This shows that treatment with alteplase plus heparin may result in a lower plasminogen concentration than treatment with heparin alone.

Post‐thrombotic syndrome

No data were available for this outcome. If data become available, we will include them in future updates.

Escalation of treatment

Two studies reported the number of participants who needed escalation of treatment after receiving thrombolytics versus heparin (Konstantinides 2002; Taherkhani 2014). Konstantinides 2002 compared alteplase plus heparin versus heparin alone, finding that fewer participants in the alteplase‐plus‐heparin group needed escalation of treatment for in‐hospital events compared with the heparin‐alone group. Pooling these data with data from alteplase or streptokinase plus enoxaparin versus enoxaparin alone (Taherkhani 2014), we found a small difference in favour of alteplase (OR 0.32, 95% CI 0.16 to 0.64; 2 studies, 306 participants; Analysis 10.1).This indicates that fewer participants required rescue thrombolysis in the thrombolytic‐plus‐heparin group than in the heparin‐alone group.

Hospital stay

Five studies that compared thrombolytics versus heparin reported length of hospital stay (Ahmed 2018; Kucher 2014; Sharifi 2013; Sinha 2017; Taherkhani 2014). Analyses show that statistical heterogeneity between included studies was at a considerable level (I² = 93%), and given the heterogeneity of the interventions, we used a random‐effects model for the pooled analysis. For delivery technique for the thrombolytic drug, one study used the USAT system (Kucher 2014), and another study delivered a 'safe dose' of rt‐PA through intravenous injection (Sharifi 2013). The other three studies respectively used alteplase or streptokinase (Taherkhani 2014), streptokinase (Ahmed 2018) and tenecteplase (Sinha 2017). Pooled analysis of the five studies yielded clear evidence to support the thrombolytics group having a shorter hospital stay compared with the heparin group (MD −1.40 days, 95% CI −2.69 to −0.11; 5 studies, 368 participants; Analysis 10.2). After we excluded the studies at high risk of bias (Ahmed 2018; Kucher 2014; Taherkhani 2014) as part of the sensitivity analysis, we still found evidence to support a difference between the two groups for hospital stay (MD −2.72 days, 95% CI −2.95 to −2.49; 2 studies, 207 participants; Analysis 11.1).

Survival time

Duration of follow‐up varied, and researchers reported deaths up to 72 hours (Tibbutt 1974), 10 days (Levine 1990), 14 days (Goldhaber 1993; Ly 1978; UPETSG 1970), 19 days (PIOPED 1990), 30 days (Dalla‐Volta 1992; Konstantinides 2002), and 180 days after randomisation (Fasullo 2011). Fasullo 2011 and Konstantinides 2002 show a beneficial effect of thrombolytics over control in clinical event‐free survival time. The other studies did not report this outcome. However, we could not extract data from the two studies to conduct a pooled analysis because they provided only a figure for survival time. Thus we cannot draw a specific conclusion about survival time nor about thrombolytic effects on death.

Composite clinical outcome

Four studies reported the important composite clinical outcome (Kline 2014; Meyer 2014; Sinha 2017; Zhang 2018). Meyer 2014, Sinha 2017 and Zhang 2018 reported all‐cause death or haemodynamic decompensation. Pooled analysis shows fewer composite events of death or haemodynamic decompensation occurred in the thrombolytics group than in the control group (OR 0.36, 95% CI 0.20 to 0.66; 3 studies, 1157 participants; Analysis 10.3). For this update, we identified an additional report for Meyer 2014, which gave the composite outcome of chronic thromboembolic pulmonary hypertension (CTEPH) or post‐PE impairment (Barco 2019). Kline 2014 reported recurrent venous thromboembolism (VTE), poor functional capacity, and low perception of wellness as measured by the 36‐item Short Form Health Survey (SF‐36). However, we found no clear evidence to support a difference between the two groups for these outcomes. As these composite clinical outcomes are different, it is not appropriate to pool them.

Quality of life

One study reported participants' quality of life (QoL) in the follow‐up period. Kline 2014 reported the number of participants who remained in the intensive care unit on day 2 and the QoL as measured by the VEINES QoL score and SF‐36. This study showed that QoL measured by both VEINES QoL and SF‐36 at 90 days follow‐up was similar between the two treatment groups (P = 0.40 and P = 0.67, respectively).

Healthcare cost comparison

None of the included trials reported cost comparisons. If data become available, we will report this information in future updates.

Discussion

Summary of main results

We have described the main results in summary of findings Table 1.

Outcomes analysed

Overall, results for included outcomes were somewhat unsatisfactory and susceptible to bias, due to the fact that most outcomes in the subgroups were extracted from only one or two studies. Most studies had small sample sizes, and some were of low methodological quality. For this update we found only three studies with four or more 'Risk of bias' domains assessed as being at low risk of bias (Fasullo 2011; Meyer 2014; UPETSG 1970). However, Meyer 2014 received funds from several companies, which may have caused conflicts of interest. In addition, some trials did not assess the most important outcomes defined in this review or did not evaluate the potential complications of thrombolytic therapy.

Clinical interpretation of the data

Thrombolytic agents showed possible benefit for death compared with heparin (OR 0.58, 95% CI 0.38 to 0.88; 19 studies, 2319 participants; low‐certainty evidence) and recurrence of PE (OR 0.54, 95% CI 0.32 to 0.91; 12 studies, 2050 participants; low‐certainty evidence). However, after excluding six studies at high risk of bias, we found no clear evidence to support a difference between the two groups for risk of death (OR 0.71, 95% CI 0.45 to 1.13; 13 studies, 2046 participants). We also found no clear effect of thrombolytics on recurrence of PE comparing with heparin after removing one study at high risk of bias (OR 0.60, 95% CI 0.35 to 1.04; 11 studies, 1949 participants).

Results indicate more major haemorrhagic events in the thrombolytics group than in the control group (OR 2.84, 95% CI 1.92 to 4.20; 15 studies, 2101 participants; moderate‐certainty evidence); and more minor haemorrhagic events in the thrombolytics group than in the control group (OR 2.97, 95% CI 1.66 to 5.30; 13 studies, 1757 participants; low‐certainty evidence). The treatment effect was not changed after exclusion of trials at high risk of bias for these outcomes.

The total number of deaths was 87 among 2319 participants, and the total number of major haemorrhagic events was 136 among 2101 participants over all studies. From the confidence intervals, we can see a relatively precise estimate of treatment effect for recurrence of PE and for major and minor haemorrhagic events. However, the treatment effect for mortality was influenced by exclusion of studies at high risk of bias in a sensitivity analysis, even only slight alterations in the confidence intervals were evident. Thus, additional high‐quality studies are needed before firm conclusions can be drawn.

Two studies reported on haemorrhagic stroke, which occurred more often in the thrombolytics group than in the control group (OR 7.59, 95% CI 1.38 to 41.72) (Meyer 2014; Sinha 2017). Both studies compared tenecteplase with heparin. However, we cannot draw a strong conclusion from this result, due to the limited numbers of included studies and participants involved.

Many of the results for the remaining secondary outcome measures of this review are based on only one or two studies. In addition, studies used different follow‐up periods and interventions, resulting in unavoidable heterogeneity. The very limited results appear to suggest that thrombolytic therapy may be better than heparin for improving haemodynamic outcomes, perfusion lung scanning, pulmonary angiogram assessment, echocardiograms, pulmonary hypertension, coagulation parameters, composite clinical outcomes, need for escalation and survival time to a greater extent than heparin alone. However, the heterogeneity of the studies and the small number of participants involved warrant caution when interpreting results.

Thrombolytic therapy showed a probable advantage over heparin for length of hospital stay. Participants treated with thrombolytics had a shorter stay than with heparin before (MD −1.40 days, 95% CI −2.69 to −0.11) and after (MD −2.72 days, 95% CI −2.95 to −2.49) excluding the study at high risk of bias. However, substantial heterogeneity (I² = 93%) between the studies and the small number of participants (368 participants) involved in this analysis warrant caution when results are interpreted.

None of the included studies provided data on post‐thrombotic syndrome or on cost comparison. Given the risks of bias in the included studies and the inconsistent results, we cannot draw any strong conclusions about the benefit of thrombolytic agents versus heparin in this review.

Overall completeness and applicability of evidence

We assessed the effectiveness and safety of thrombolytic therapy for people with acute PE. We found that thrombolytic therapy was probably better than comparison treatments in reducing the odds ratio of death and recurrence of PE, and it may improve some composite clinical outcomes and haemodynamic parameters (perfusion lung scanning, pulmonary angiogram assessment, and echocardiograms). All participants in the included studies were adults aged 18 or over, with a mean age of about 60. However, the included trials did not include strict subgroups of elderly participants. Only Meyer 2014 included a subgroup for participants over 75, and results of this study provide no clear evidence to support a difference between the two groups in their composite outcome 'death or haemodynamic decompensation' (OR 0.63, 95% CI 0.24 to 1.66). Possible differences between adults and elderly people therefore need further investigation.

Based on data from Konstantinides 2002, Perlroth 2007 highlighted that the heparin group required treatment escalation approximately three times more often than the thrombolytics group, but the researchers observed no difference in the risk of death from PE. Investigators also found that treatment with heparin alone was more effective and less costly than treatment with alteplase plus heparin among participants with submassive PE and right ventricular dysfunction. However, we were not able to investigate any differences between thrombolytic therapy and the comparison treatment by healthcare costs and post‐thrombotic syndrome, as no included studies reported on these outcomes. In clinical practice, haemodynamic parameters and the age of people with PE must be considered, especially for haemodynamically‐unstable people and those aged over 75.

The included studies involved different types of thrombolytics, including alteplase, urokinase, streptokinase, rt‐PA, ultrasound‐assisted catheter‐directed thrombolysis systems, and tenecteplase, usually followed by heparin. The control intervention was heparin alone or placebo plus heparin. No studies compared thrombolytics versus surgical intervention; surgical thrombectomy in massive PE will probably not lend itself to a prospective analysis (Duffett 2020). The test for subgroup differences indicates no clear difference between the types of thrombolytic used and death from all causes, recurrence of PE, major or minor haemorrhagic events. Pooled data from two studies indicate that tenecteplase may increase the odds ratio of haemorrhagic stroke (OR 7.59, 95% CI 1.38 to 41.72, 1091 participants). Possible differences between different types of thrombolytics need further investigation. Catheter‐directed administration may have theoretical advantages (e.g. low dose and more targeted) (Stewart 2020), but data are too scarce to make any judgement.

In Meyer 2014, researchers followed about 70% of participants over two years (median 37.8 months) and found that tenecteplase treatment did not affect long‐term mortality among participants with intermediate‐risk PE. This report also provided echocardiographic data for only about 30% of participants (144/506 (28.5%) in the tenecteplase group and 146/499 (28.9%) in the control group) with long‐term follow‐up (at least 24 months), showing that tenecteplase treatment did not reveal clear differences in residual pulmonary hypertension nor in RV dysfunction. In addition, another report of Meyer 2014 included in this update revealed that among 219 follow‐up participants with six‐month and 37‐month echocardiographic results, the composite outcome of CTEPH or post‐PE impairment at 37 months in two groups was 14.3% and 12.1% respectively, showing no obvious difference (Barco 2019). We could not use these data in our meta‐analysis because the other included studies reported only short‐term mortality (follow‐up period less than three months for most studies). Using data from this report in the meta‐analysis would have further increased heterogeneity. Future studies should therefore further investigate the effect on mortality of thrombolytic treatment with long‐term follow‐up.

Thrombolytics for massive PE (haemodynamically‐unstable patients)

It is clinically very important to differentiate haemodynamically‐stable and unstable patients (massive PE). However, we have identified only one study to date that compared thrombolytic therapy versus heparin in people with massive PE (Jerjes‐Sánchez 1995). Four studies included both massive and unknown PE types (Dotter 1979; Ly 1978; Tibbutt 1974; UPETSG 1970). The proportion of massive PE varied, at 8% in Ly 1978, 9% in UPETSG 1970, 23% in Tibbutt 1974, and 71% in Dotter 1979. As we did not know the types of PE for all participants included in these studies, we decided to include these four studies in the 'type of PE unknown' group. In PIOPED 1990, all included participants had an unclear PE type. We therefore included this study in the same group.

Jerjes‐Sánchez 1995 shows unbalanced allocation in the two groups at onset of PE, so we judged this study as having high risk of bias due to the high risk of selective reporting and the very small sample size. In this RCT, eight participants received 1,500,000 IU of streptokinase in one hour through a peripheral vein followed by heparin, or heparin alone. The four participants who were randomised to streptokinase (mean time of onset of symptoms of the first event of PE: 2½ hours) improved in the first hour after treatment, survived, and over two years of follow‐up did not present with pulmonary arterial hypertension. All four participants treated with heparin alone (mean time of onset of symptoms for the first event of PE: 34¾ hours) died within one to three hours after arrival at the emergency department. We excluded this study along with another five studies at high risk of bias from the sensitivity analysis (Goldhaber 1993; Kucher 2014; Ly 1978; Taherkhani 2014; Tibbutt 1974), and this appreciably influenced the results for death from all causes between the two groups. Thus, the data from Jerjes‐Sánchez 1995 had an influence on the pooled analysis. Even though we performed a subgroup analysis according to different types of PE (massive/submassive/unknown types of PE) for the primary outcomes, these results cannot be extrapolated to massive PE due to the limitations of Jerjes‐Sánchez 1995.

Quality of the evidence

We have described the main results in summary of findings Table 1.

Randomisation and blinding

Only three studies reported both appropriate random sequence generation and allocation concealment (Goldhaber 1993; Meyer 2014; UPETSG 1970), and seven reported satisfactory blinding (Fasullo 2011; Kline 2014; Konstantinides 2002; Levine 1990; Meyer 2014; PIOPED 1990; UPETSG 1970). Goldhaber 1993 and Ahmed 2018 reported no blinding, and Taherkhani 2014 indicated that blinding was broken. Although two studies used the appropriate method to generate the random sequence, Ly 1978 included five participants who were not randomised, and Jerjes‐Sánchez 1995 reported unbalanced numbers between intervention and control groups at the onset of PE. The remaining trials did not provide clear details about random sequence generation, allocation concealment, or blinding. Three studies were of high risk of performance bias but low risk of detection bias (Kucher 2014; Sharifi 2013; Tibbutt 1974). One study was unclear in all items for 'Risk of bias' assessment (Marini 1988), and in one study, all 'Risk of bias' domains were at unclear or high risk (Dotter 1979). This could have biased study results in favour of treatment.

Sample size

Many of the outcome measures were only reported in one or two studies, so some effect sizes have wide confidence intervals (such as for incidence of haemorrhagic stroke). Many of the included studies involved small numbers of participants. For some outcomes, we may not have been able to detect any real effects of thrombolytics because of small sample size.

Conflicts of interest

Four included studies were funded by related pharmaceutical companies (Dotter 1979; Kline 2014; Kucher 2014; Meyer 2014), and some study authors worked for these companies (Meyer 2014). This could potentially result in conflicts of interest in drafting and reporting results of the study, even though study authors stated there was no influence over the whole study period.

Heterogeneity

Heterogeneity in responses did not appear to result from differences in methods used for most of the primary outcomes (including overall mortality, recurrence of pulmonary emboli, and major haemorrhagic events), nor for some of the secondary outcomes (mean pulmonary arterial pressure improvement, pulmonary angiogram assessment (72 hours after treatment), and echocardiograms). We obtained dynamic measurements from studies comparing thrombolytics versus heparin, showing a similar effect on those outcomes listed above. We found no dose‐related or time‐related relationships in these dynamic analyses.

We noted moderate heterogeneity in dynamic analysis of minor bleeding in studies comparing thrombolytics versus heparin (Ahmed 2018; Becattini 2010; Dalla‐Volta 1992; Fasullo 2011; Kucher 2014; Levine 1990; Ly 1978; Meyer 2014; Sinha 2017; Taherkhani 2014; Tibbutt 1974; UPETSG 1970; Zhang 2018), and we found a difference between the two therapies. We took this into consideration for assessing the certainty of the evidence. A great degree of heterogeneity was present in the dynamic analysis for D‐dimer concentration at two hours after treatment (Dalla‐Volta 1992; PIOPED 1990), pulmonary artery systolic pressure (Ahmed 2018; Fasullo 2011; Sharifi 2013; Sinha 2017; Taherkhani 2014; Zhang 2018), and right ventricle‐to‐left ventricle ratio (Fasullo 2011; Kucher 2014; Zhang 2018), showing differences between the two treatment groups. This may be a consequence of the different types of thrombolytics and heparin used in the two studies (see Characteristics of included studies table). We performed subgroup analysis for various thrombolytic agents. However, given the lack of data on different thrombolytic strategies, such as routes, doses and durations, we could not perform further subgroup analysis. Future updates should include subgroup analyses for different treatment strategies once more relevant studies are published.

Due to the above issues, we downgraded the overall certainty of the evidence presented in this review by one or two levels to moderate or low, because of concerns over risks of bias and inconsistency.

Potential biases in the review process

We analysed outcomes on an ITT basis, using a random‐effects model for pooled analysis of heterogeneous data (I² = 40% to 100%). We did this to reduce the bias of estimated intervention effects.

We classified studies as having high risk of overall bias if two or more 'Risk of bias' domains carried a high risk of bias. We conducted a sensitivity analysis by excluding these studies to assess the effects of this exclusion on the estimated intervention effect.

Agreements and disagreements with other studies or reviews

Individually, almost all studies show that thrombolytic therapy may reduce the primary outcomes defined by the study, especially echocardiographic parameters. Our meta‐analysis of all included studies shows probable beneficial results for thrombolysis for death from all causes. However, the sensitivity analysis, when studies labelled as having high risk of bias were removed, provides no clear evidence to support a difference between the two groups in terms of death (OR 0.71, 95% CI 0.45 to 1.13). Results from Jerjes‐Sánchez 1995 show an apparent benefit for the thrombolytics group, and removing this study from the sensitivity analysis may explain the changes in results. For this update, we added two studies (Sinha 2017; Zhang 2018) with a total of 152 participants to the outcome of all‐cause death, and the result is consistent with the review of Chatterjee 2014. However, Chatterjee 2014 did not use the GRADE criteria to assess the certainty of the evidence.

In the meta‐analysis by Chatterjee 2014, study authors reported that theirs was the first analysis of thrombolysis in PE with sufficient statistical power to detect associations with a meaningful mortality reduction. However, these investigators included the data from Jerjes‐Sánchez 1995, which we labelled as carrying a high risk of bias, Furthermore, Chatterjee 2014 did not perform a sensitivity analysis according to the methodological quality of included studies and did not assess conflicts of interest in the included trials, which may introduce bias to the review process. According to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), the Peto OR works well when individual odds ratios are close to one (i.e. intervention effects are small), and when events are not particularly common (the ideal event rate is below 1%). In Chatterjee 2014, the range of the OR was 0.03 to 5.80 and the maximum event rate was 100% (4/4) in the control group. Thus, the Peto OR method used by Chatterjee 2014 to pool data may not be the most appropriate way to analyse it.

Our review included different subgroup analyses compared with Chatterjee 2014 and with evidence‐based guidelines (NICE 2012). In our review, we placed studies that included participants with unclear types of PE into the 'type of PE unknown' group, which was more precise than the subgroups used by Chatterjee 2014 and NICE 2012 (namely, unstable/massive and stable/submassive). The National Institute for Health and Clinical Excellence (NICE) guideline did not reveal obvious reductions in overall mortality in the unstable/massive and stable/submassive PE subgroups (OR 0.52, 95% CI 0.24 to 1.15; OR 0.67, 95% CI 0.30 to 1.51, respectively). Four other reviews did not report obvious reductions in overall mortality, especially for participants with submassive PE or haemodynamically‐stable participants (Cao 2014; Liu 2014; Marti 2014; Nakamura 2014). Larger clinical trials focusing on this association are therefore needed.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1: Thrombolytic therapy versus heparin: primary outcome measures, Outcome 1: Death from all causes

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Analysis 1.2

Comparison 1: Thrombolytic therapy versus heparin: primary outcome measures, Outcome 2: Recurrence of pulmonary emboli

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Analysis 1.3

Comparison 1: Thrombolytic therapy versus heparin: primary outcome measures, Outcome 3: Major haemorrhagic events

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Analysis 1.4

Comparison 1: Thrombolytic therapy versus heparin: primary outcome measures, Outcome 4: Haemorrhagic stroke

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Analysis 1.5

Comparison 1: Thrombolytic therapy versus heparin: primary outcome measures, Outcome 5: Minor haemorrhagic events

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Analysis 2.1

Comparison 2: Thrombolytic therapy versus heparin: primary outcome measures (sensitivity analysis according to study quality), Outcome 1: Death from all causes

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Analysis 2.2

Comparison 2: Thrombolytic therapy versus heparin: primary outcome measures (sensitivity analysis according to study quality), Outcome 2: Recurrence of pulmonary emboli

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Analysis 2.3

Comparison 2: Thrombolytic therapy versus heparin: primary outcome measures (sensitivity analysis according to study quality), Outcome 3: Major haemorrhagic events

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Analysis 2.4

Comparison 2: Thrombolytic therapy versus heparin: primary outcome measures (sensitivity analysis according to study quality), Outcome 4: Minor haemorrhagic events

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Analysis 3.1

Comparison 3: Thrombolytic therapy versus heparin: primary outcome measures (subgroup analysis according to types of PE), Outcome 1: Death from all causes

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Analysis 3.2

Comparison 3: Thrombolytic therapy versus heparin: primary outcome measures (subgroup analysis according to types of PE), Outcome 2: Recurrence of pulmonary emboli

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Analysis 3.3

Comparison 3: Thrombolytic therapy versus heparin: primary outcome measures (subgroup analysis according to types of PE), Outcome 3: Major haemorrhagic events

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Analysis 3.4

Comparison 3: Thrombolytic therapy versus heparin: primary outcome measures (subgroup analysis according to types of PE), Outcome 4: Minor haemorrhagic events

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Analysis 4.1

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 1: Pulmonary arterial systolic pressure improvement (mmHg)

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Analysis 4.2

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 2: Mean pulmonary arterial pressure improvement (mmHg)

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Analysis 4.3

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 3: Right ventricular end‐diastolic pressure improvement (mmHg)

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Analysis 4.4

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 4: Total pulmonary resistance improvement (dyn·s·cm^‐5)

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Analysis 4.5

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 5: Cardiac index improvement (L/min/m²)

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Analysis 4.6

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 6: Right ventricular systolic pressure improvement (mmHg) at 24 hours

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Analysis 4.7

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 7: Right arterial mean pressure improvement (mmHg) at 24 hours

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Analysis 4.8

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 8: Arterial‐venous oxygen difference (vol %) at 24 hours

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Analysis 4.9

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 9: Arterial PO₂ (mmHg) improvement at 24 hours

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Analysis 4.10

Comparison 4: Thrombolytic therapy versus heparin: haemodynamic outcomes, Outcome 10: Haemodynamic decompensation

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Analysis 5.1

Comparison 5: Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution), Outcome 1: Day 1

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Analysis 5.2

Comparison 5: Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution), Outcome 2: Day 2

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Analysis 5.3

Comparison 5: Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution), Outcome 3: Day 5

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Analysis 5.4

Comparison 5: Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution), Outcome 4: Day 7

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Analysis 5.5

Comparison 5: Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution), Outcome 5: Day 14

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Analysis 5.6

Comparison 5: Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution), Outcome 6: Day 30

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Analysis 5.7

Comparison 5: Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution), Outcome 7: Absolute resolution (1‐year follow‐up)

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Analysis 6.1

Comparison 6: Thrombolytic therapy versus heparin: number of patients with greater than 50% improvement on lung scan, Outcome 1: Day 1

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Analysis 6.2

Comparison 6: Thrombolytic therapy versus heparin: number of patients with greater than 50% improvement on lung scan, Outcome 2: Day 7

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Analysis 7.1

Comparison 7: Thrombolytic therapy versus heparin: pulmonary angiogram assessment, Outcome 1: Change from baseline at 2 hours

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Analysis 7.2

Comparison 7: Thrombolytic therapy versus heparin: pulmonary angiogram assessment, Outcome 2: Change from baseline at 72 hours

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Analysis 8.1

Comparison 8: Thrombolytic therapy versus heparin: echocardiograms, Outcome 1: Right ventricular wall movement improvement

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Analysis 8.2

Comparison 8: Thrombolytic therapy versus heparin: echocardiograms, Outcome 2: Tricuspid regurgitation improvement

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Analysis 8.3

Comparison 8: Thrombolytic therapy versus heparin: echocardiograms, Outcome 3: Paradoxical systolic septal motion

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Analysis 8.4

Comparison 8: Thrombolytic therapy versus heparin: echocardiograms, Outcome 4: Right ventricle‐to‐left ventricle ratio

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Analysis 8.5

Comparison 8: Thrombolytic therapy versus heparin: echocardiograms, Outcome 5: Tricuspid annular plane systolic excursion

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Analysis 8.6

Comparison 8: Thrombolytic therapy versus heparin: echocardiograms, Outcome 6: Right ventricular‐to‐right atrial pressure gradient

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Analysis 8.7

Comparison 8: Thrombolytic therapy versus heparin: echocardiograms, Outcome 7: Minimum inferior vena cava diameter

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Analysis 8.8

Comparison 8: Thrombolytic therapy versus heparin: echocardiograms, Outcome 8: Pulmonary hypertension

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Analysis 9.1

Comparison 9: Thrombolytic therapy versus heparin: haemocoagulation variables, Outcome 1: Fibrinogen (g/L)

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Analysis 9.2

Comparison 9: Thrombolytic therapy versus heparin: haemocoagulation variables, Outcome 2: D‐dimer (µg/mL)

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Analysis 9.3

Comparison 9: Thrombolytic therapy versus heparin: haemocoagulation variables, Outcome 3: Plasminogen (%)

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Analysis 10.1

Comparison 10: Thrombolytic therapy versus heparin: other outcomes, Outcome 1: Escalation of treatment

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Analysis 10.2

Comparison 10: Thrombolytic therapy versus heparin: other outcomes, Outcome 2: Hospital stay

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Analysis 10.3

Comparison 10: Thrombolytic therapy versus heparin: other outcomes, Outcome 3: Composite clinical outcome

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Analysis 11.1

Comparison 11: Thrombolytic therapy versus heparin: other outcomes (sensitivity analysis according to study quality), Outcome 1: Hospital stay

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Summary of findings 1. Thrombolytic therapy versus heparin: primary outcome measures for pulmonary embolism

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
Thrombolytic therapy versus heparin: primary outcome measures for pulmonary embolism
Patient or population: people with acute PE Setting: hospital Intervention: thrombolytic therapy Comparison: heparin
Outcomes	Risk with heparin	Risk with thrombolytic therapy	Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
Death from all causes (duration of follow‐up: from 7 days to 12 months)	Study population		OR 0.58 (0.38 to 0.88)	2319 (19)	⊕⊕⊝⊝ low^b
	47 per 1000	28 per 1000 (19 to 42)
	Moderate^a
	49 per 1000	29 per 1000 (19 to 43)
Recurrence of pulmonary emboli (duration of follow‐up: from 7 days to 12 months)	Study population		OR 0.54 (0.32 to 0.91)	2050 (12)	⊕⊕⊝⊝ low^b
	39 per 1000	21 per 1000 (13 to 36)
	Moderate^a
	42 per 1000	23 per 1000 (14 to 38)
Major haemorrhagic events (duration of follow‐up: from 7 days to 12 months)	Study population		OR 2.84 (1.92 to 4.20)	2101 (15)	⊕⊕⊕⊝ moderate^c
	35 per 1000	94 per 1000 (65 to 133)
	Moderate^a
	24 per 1000	66 per 1000 (46 to 95)
Minor haemorrhagic events (duration of follow‐up: from 7 days to 12 months)	Study population		OR 2.97 (1.66 to 5.30)	1757 (13)	⊕⊕⊝⊝ low^c,d
	96 per 1000	239 per 1000 (149 to 359)
	Moderate^a
	86 per 1000	219 per 1000 (135 to 333)
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The risk in the intervention group* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence CI: confidence interval; OR: odds ratio;PE: pulmonary embolism; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effectGRADE Working Group grades of evidence.
^aMedian control group risk from the studies included in this meta‐analysis. ^bDowngraded by two levels for very serious risk of bias (due to serious risk of selection, performance and other bias in most included studies). ^cDowngraded by one level for serious risk of bias (due to serious risk of selection, performance and other bias in some included studies). ^dDowngraded by one level for inconsistency (due to moderate heterogeneity; I² = 55%).

Summary of findings 1. Thrombolytic therapy versus heparin: primary outcome measures for pulmonary embolism

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Table 1. American Heart Association definitions of massive, submassive, and low‐risk PE

Risk classification	Definition	Short‐term mortality
Massive PE	Acute PE with haemodynamically‐unstable manifestations such as sustained hypotension (systolic blood pressure < 90 mmHg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolaemia, sepsis, or left ventricular dysfunction), lack of pulse, or persistent profound bradycardia (heart rate < 40 beats per minute (bpm) with signs or symptoms of shock)	25% to 65%
Submassive PE	Haemodynamically stable (without systemic hypotension (systolic blood pressure > 90 mmHg)) people who present with either right ventricular dysfunction or myocardial necrosis (RV dysfunction (CT, BPN/proBNP, ECG changes) or myocardial necrosis (elevated troponins))	3%
Low‐risk PE	Absence of hypotension, RV dysfunction, and myocardial necrosis	< 1%
BPN: B‐type natriuretic peptide CT: computed tomography ECG: electrocardiography PE: pulmonary embolism RV: right ventricular

Table 1. American Heart Association definitions of massive, submassive, and low‐risk PE

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Comparison 1. Thrombolytic therapy versus heparin: primary outcome measures

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Death from all causes Show forest plot	19	2319	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.38, 0.88]

1.1.1 rt‐PA vs heparin	5	359	Odds Ratio (M‐H, Fixed, 95% CI)	0.57 [0.16, 2.06]
1.1.2 Streptokinase vs heparin	4	94	Odds Ratio (M‐H, Fixed, 95% CI)	0.24 [0.06, 0.93]
1.1.3 Urokinase vs heparin	1	160	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.26, 2.50]
1.1.4 Tenecteplase vs heparin	4	1233	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.38, 1.45]
1.1.5 Alteplase vs heparin	3	364	Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.23, 1.65]
1.1.6 USAT (rt‐PA) vs heparin	1	59	Odds Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 7.96]
1.1.7 Streptokinase or alteplase vs enoxaparin heparin	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	0.13 [0.01, 2.58]
1.2 Recurrence of pulmonary emboli Show forest plot	12	2050	Odds Ratio (M‐H, Fixed, 95% CI)	0.54 [0.32, 0.91]

1.2.1 rt‐PA vs heparin	4	346	Odds Ratio (M‐H, Fixed, 95% CI)	0.18 [0.04, 0.84]
1.2.2 Urokinase vs heparin	1	160	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.31, 1.65]
1.2.3 Tenecteplase vs heparin	3	1149	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.16, 1.92]
1.2.4 Alteplase vs heparin	3	364	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.25, 2.30]
1.2.5 Streptokinase vs heparin	1	31	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.83]
1.3 Major haemorrhagic events Show forest plot	15	2101	Odds Ratio (M‐H, Fixed, 95% CI)	2.84 [1.92, 4.20]

1.3.1 rt‐PA vs heparin	4	238	Odds Ratio (M‐H, Fixed, 95% CI)	2.90 [0.43, 19.30]
1.3.2 Streptokinase vs heparin	3	107	Odds Ratio (M‐H, Fixed, 95% CI)	1.64 [0.34, 8.07]
1.3.3 Urokinase vs heparin	1	160	Odds Ratio (M‐H, Fixed, 95% CI)	2.23 [1.00, 4.99]
1.3.4 Tenecteplase vs heparin	4	1232	Odds Ratio (M‐H, Fixed, 95% CI)	4.64 [2.59, 8.30]
1.3.5 Alteplase vs heparin	3	364	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.23, 2.16]
1.4 Haemorrhagic stroke Show forest plot	2	1091	Odds Ratio (M‐H, Fixed, 95% CI)	7.59 [1.38, 41.72]

1.5 Minor haemorrhagic events Show forest plot	13	1757	Odds Ratio (M‐H, Random, 95% CI)	2.97 [1.66, 5.30]

1.5.1 rt‐PA vs heparin	2	124	Odds Ratio (M‐H, Random, 95% CI)	14.38 [3.19, 64.78]
1.5.2 Streptokinase vs heparin	3	107	Odds Ratio (M‐H, Random, 95% CI)	0.64 [0.17, 2.43]
1.5.3 Urokinase vs heparin	1	160	Odds Ratio (M‐H, Random, 95% CI)	1.52 [0.64, 3.63]
1.5.4 Tenecteplase vs heparin	3	1149	Odds Ratio (M‐H, Random, 95% CI)	4.49 [1.35, 14.95]
1.5.5 Alteplase vs heparin	2	108	Odds Ratio (M‐H, Random, 95% CI)	2.90 [1.26, 6.66]
1.5.6 USAT (rt‐PA) vs heparin	1	59	Odds Ratio (M‐H, Random, 95% CI)	3.11 [0.30, 31.79]
1.5.7 Streptokinase or Alteplase vs enoxaparin heparin	1	50	Odds Ratio (M‐H, Random, 95% CI)	2.09 [0.18, 24.61]

Comparison 1. Thrombolytic therapy versus heparin: primary outcome measures

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Comparison 2. Thrombolytic therapy versus heparin: primary outcome measures (sensitivity analysis according to study quality)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Death from all causes Show forest plot	13	2046	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.45, 1.13]

2.1.1 rt‐PA vs heparin	4	258	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.18, 3.30]
2.1.2 Streptokinase vs heparin	1	31	Odds Ratio (M‐H, Fixed, 95% CI)	0.50 [0.04, 6.17]
2.1.3 Urokinase vs heparin	1	160	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.26, 2.50]
2.1.4 Tenecteplase vs heparin	4	1233	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.38, 1.45]
2.1.5 Alteplase vs heparin	3	364	Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.23, 1.65]
2.2 Recurrence of pulmonary emboli Show forest plot	11	1949	Odds Ratio (M‐H, Fixed, 95% CI)	0.60 [0.35, 1.04]

2.2.1 rt‐PA vs heparin	3	245	Odds Ratio (M‐H, Fixed, 95% CI)	0.26 [0.04, 1.61]
2.2.2 Urokinase vs heparin	1	160	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.31, 1.65]
2.2.3 Tenecteplase vs heparin	3	1149	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.16, 1.92]
2.2.4 Alteplase vs heparin	3	364	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.25, 2.30]
2.2.5 Streptokinase vs heparin	1	31	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.83]
2.3 Major haemorrhagic events Show forest plot	11	1893	Odds Ratio (M‐H, Fixed, 95% CI)	2.91 [1.92, 4.39]

2.3.1 rt‐PA vs heparin	3	137	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [0.05, 47.52]
2.3.2 Urokinase vs heparin	1	160	Odds Ratio (M‐H, Fixed, 95% CI)	2.23 [1.00, 4.99]
2.3.3 Tenecteplase vs heparin	4	1232	Odds Ratio (M‐H, Fixed, 95% CI)	4.64 [2.59, 8.30]
2.3.4 Alteplase vs heparin	3	364	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.23, 2.16]
2.4 Minor haemorrhagic events Show forest plot	8	1541	Odds Ratio (M‐H, Random, 95% CI)	3.82 [2.06, 7.09]

2.4.1 rt‐PA vs heparin	2	124	Odds Ratio (M‐H, Random, 95% CI)	14.38 [3.19, 64.78]
2.4.2 Urokinase vs heparin	1	160	Odds Ratio (M‐H, Random, 95% CI)	1.52 [0.64, 3.63]
2.4.3 Tenecteplase vs heparin	3	1149	Odds Ratio (M‐H, Random, 95% CI)	4.49 [1.35, 14.95]
2.4.4 Alteplase vs heparin	2	108	Odds Ratio (M‐H, Random, 95% CI)	2.90 [1.26, 6.66]

Comparison 2. Thrombolytic therapy versus heparin: primary outcome measures (sensitivity analysis according to study quality)

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Comparison 3. Thrombolytic therapy versus heparin: primary outcome measures (subgroup analysis according to types of PE)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Death from all causes Show forest plot	19	2319	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.38, 0.88]

3.1.1 Submassive PE	12	1993	Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.37, 1.02]
3.1.2 Submassive PE (USAT (rt‐PA) vs heparin)	1	59	Odds Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 7.96]
3.1.3 Massive PE	1	8	Odds Ratio (M‐H, Fixed, 95% CI)	0.01 [0.00, 0.77]
3.1.4 Type of PE unknown	5	259	Odds Ratio (M‐H, Fixed, 95% CI)	0.68 [0.28, 1.62]
3.2 Recurrence of pulmonary emboli Show forest plot	12	2050	Odds Ratio (M‐H, Fixed, 95% CI)	0.54 [0.32, 0.91]

3.2.1 Submassive PE	10	1859	Odds Ratio (M‐H, Fixed, 95% CI)	0.45 [0.22, 0.92]
3.2.2 Type of PE unknown	2	191	Odds Ratio (M‐H, Fixed, 95% CI)	0.68 [0.31, 1.52]
3.3 Major haemorrhagic events Show forest plot	15	2101	Odds Ratio (M‐H, Fixed, 95% CI)	2.84 [1.92, 4.20]

3.3.1 Submassive PE	11	1873	Odds Ratio (M‐H, Fixed, 95% CI)	3.24 [2.01, 5.21]
3.3.2 Type of PE unknown	4	228	Odds Ratio (M‐H, Fixed, 95% CI)	2.07 [1.03, 4.18]
3.4 Minor haemorrhagic events Show forest plot	13	1757	Odds Ratio (M‐H, Random, 95% CI)	2.97 [1.66, 5.30]

3.4.1 Submassive PE	9	1483	Odds Ratio (M‐H, Random, 95% CI)	4.34 [2.46, 7.66]
3.4.2 Submassive PE (USAT (rt‐PA) vs heparin)	1	59	Odds Ratio (M‐H, Random, 95% CI)	3.11 [0.30, 31.79]
3.4.3 Type of PE unknown	3	215	Odds Ratio (M‐H, Random, 95% CI)	1.18 [0.57, 2.44]

Comparison 3. Thrombolytic therapy versus heparin: primary outcome measures (subgroup analysis according to types of PE)

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Comparison 4. Thrombolytic therapy versus heparin: haemodynamic outcomes

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Pulmonary arterial systolic pressure improvement (mmHg) Show forest plot	4		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.1.1 Urokinase vs heparin at 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1.2 Streptokinase vs heparin at 72 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1.3 rt‐PA vs heparin at 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1.4 Tenecteplase vs heparin at 7 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.2 Mean pulmonary arterial pressure improvement (mmHg) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.2.1 Urokinase vs heparin at 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.2.2 Streptokinase vs heparin at 72 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.2.3 rt‐PA vs heparin at 1.5 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.3 Right ventricular end‐diastolic pressure improvement (mmHg) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.3.1 Urokinase vs heparin at 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.3.2 Streptokinase vs heparin at 72 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4 Total pulmonary resistance improvement (dyn·s·cm^‐5) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.4.1 Urokinase vs heparin at 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4.2 Streptokinase vs heparin at 72 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.4.3 rt‐PA vs heparin at 1.5 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.5 Cardiac index improvement (L/min/m²) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.5.1 Streptokinase vs heparin at 72 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.5.2 Urokinase vs heparin at 24 hours	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.6 Right ventricular systolic pressure improvement (mmHg) at 24 hours Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.7 Right arterial mean pressure improvement (mmHg) at 24 hours Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.8 Arterial‐venous oxygen difference (vol %) at 24 hours Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.9 Arterial PO₂ (mmHg) improvement at 24 hours Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.10 Haemodynamic decompensation Show forest plot	3	1157	Odds Ratio (M‐H, Fixed, 95% CI)	0.26 [0.13, 0.53]

4.10.1 rt‐PA vs heparin at 3 months	1	66	Odds Ratio (M‐H, Fixed, 95% CI)	0.13 [0.01, 2.62]
4.10.2 Tenecteplase vs heparin at 7 days	2	1091	Odds Ratio (M‐H, Fixed, 95% CI)	0.28 [0.13, 0.57]

Comparison 4. Thrombolytic therapy versus heparin: haemodynamic outcomes

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Comparison 5. Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Day 1 Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.1.1 Urokinase vs heparin	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.1.2 rt‐PA vs heparin	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.2 Day 2 Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.2.1 Urokinase vs heparin	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.3 Day 5 Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.3.1 Urokinase vs heparin	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.4 Day 7 Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.4.1 Alteplase vs heparin (total lung score)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.4.2 Change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.5 Day 14 Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.5.1 Urokinase vs heparin	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.6 Day 30 Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.6.1 Alteplase vs heparin (total lung score)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.6.2 Change from baseline	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.7 Absolute resolution (1‐year follow‐up) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.7.1 Urokinase vs heparin	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 5. Thrombolytic therapy versus heparin: perfusion lung scanning (absolute resolution)

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Comparison 6. Thrombolytic therapy versus heparin: number of patients with greater than 50% improvement on lung scan

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Day 1 Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.1.1 rt‐PA vs heparin	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.2 Day 7 Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.2.1 rt‐PA vs heparin	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 6. Thrombolytic therapy versus heparin: number of patients with greater than 50% improvement on lung scan

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Comparison 7. Thrombolytic therapy versus heparin: pulmonary angiogram assessment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Change from baseline at 2 hours Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.1.1 Alteplase vs heparin (overall total score)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.1.2 Alteplase vs heparin (left lung)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.1.3 Alteplase vs heparin (right lung)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.2 Change from baseline at 72 hours Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7.2.1 Streptokinase vs heparin	2	47	Mean Difference (IV, Fixed, 95% CI)	‐9.30 [‐12.81, ‐5.78]

Comparison 7. Thrombolytic therapy versus heparin: pulmonary angiogram assessment

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Comparison 8. Thrombolytic therapy versus heparin: echocardiograms

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Right ventricular wall movement improvement Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8.1.1 3 hours after treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.2 24 hours after treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.1.3 7 days after treatment	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.2 Tricuspid regurgitation improvement Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8.2.1 3 hours after treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.2.2 24 hours after treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.3 Paradoxical systolic septal motion Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8.3.1 24 hours after treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.3.2 48 hours after treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.3.3 72 hours after treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.3.4 6 days after treatment	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8.4 Right ventricle‐to‐left ventricle ratio Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.4.1 24 hours after treatment	3	197	Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.21, ‐0.11]
8.4.2 48 hours after treatment	1	72	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.20, ‐0.18]
8.4.3 72 hours after treatment	1	72	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.15, ‐0.13]
8.4.4 6 days after treatment	1	72	Mean Difference (IV, Random, 95% CI)	‐0.22 [‐0.23, ‐0.21]
8.4.5 Discharge after treatment	1	72	Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.34, ‐0.32]
8.4.6 3 months after treatment	2	131	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.34, 0.05]
8.4.7 6 months after treatment	1	72	Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.22, ‐0.20]
8.5 Tricuspid annular plane systolic excursion Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.5.1 24 hours after treatment	2	131	Mean Difference (IV, Random, 95% CI)	0.45 [‐1.18, 2.07]
8.5.2 48 hours after treatment	1	72	Mean Difference (IV, Random, 95% CI)	1.00 [‐0.13, 2.13]
8.5.3 72 hours after treatment	1	72	Mean Difference (IV, Random, 95% CI)	1.80 [0.67, 2.93]
8.5.4 6 days after treatment	1	72	Mean Difference (IV, Random, 95% CI)	2.50 [1.57, 3.43]
8.5.5 Discharge after treatment	1	72	Mean Difference (IV, Random, 95% CI)	2.00 [0.75, 3.25]
8.5.6 3 months after treatment	2	131	Mean Difference (IV, Random, 95% CI)	0.33 [‐3.18, 3.85]
8.5.7 6 months after treatment	1	72	Mean Difference (IV, Random, 95% CI)	1.30 [0.28, 2.32]
8.6 Right ventricular‐to‐right atrial pressure gradient Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8.6.1 24 hours after treatment	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.6.2 3 months after treatment	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.7 Minimum inferior vena cava diameter Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8.7.1 24 hours after treatment	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.7.2 3 months after treatment	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.8 Pulmonary hypertension Show forest plot	6		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.8.1 24 hours after treatment	2	138	Mean Difference (IV, Random, 95% CI)	‐11.28 [‐16.80, ‐5.76]
8.8.2 48 hours after treatment	2	193	Mean Difference (IV, Random, 95% CI)	‐7.37 [‐9.20, ‐5.53]
8.8.3 72 hours after treatment	2	124	Mean Difference (IV, Random, 95% CI)	‐7.65 [‐10.03, ‐5.28]
8.8.4 6 days after treatment	2	122	Mean Difference (IV, Random, 95% CI)	‐5.69 [‐9.37, ‐2.02]
8.8.5 7 days after treatment	1	86	Mean Difference (IV, Random, 95% CI)	‐5.33 [‐7.14, ‐3.52]
8.8.6 Discharge after treatment	1	72	Mean Difference (IV, Random, 95% CI)	‐8.00 [‐9.78, ‐6.22]
8.8.7 3 months after treatment	1	72	Mean Difference (IV, Random, 95% CI)	‐7.00 [‐17.18, 3.18]
8.8.8 6 months after treatment	2	193	Mean Difference (IV, Random, 95% CI)	‐11.95 [‐23.71, ‐0.19]
8.8.9 28 months after treatment	1	121	Mean Difference (IV, Random, 95% CI)	‐15.00 [‐17.32, ‐12.68]

Comparison 8. Thrombolytic therapy versus heparin: echocardiograms

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Comparison 9. Thrombolytic therapy versus heparin: haemocoagulation variables

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Fibrinogen (g/L) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1.1 Less than 3 hours after treatment	2	45	Mean Difference (IV, Random, 95% CI)	‐2.68 [‐4.36, ‐1.00]
9.1.2 24 hours after treatment	2	114	Mean Difference (IV, Random, 95% CI)	‐1.61 [‐3.99, 0.76]
9.1.3 48 hours after treatment	1	83	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.40, 0.20]
9.2 D‐dimer (µg/mL) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.2.1 Less than 3 hours after treatment	2	45	Mean Difference (IV, Random, 95% CI)	21.04 [‐4.60, 46.69]
9.2.2 24 hours after treatment	1	31	Mean Difference (IV, Random, 95% CI)	5.30 [2.12, 8.48]
9.3 Plasminogen (%) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

9.3.1 2 hours after treatment	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9.3.2 24 hours after treatment	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 9. Thrombolytic therapy versus heparin: haemocoagulation variables

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Comparison 10. Thrombolytic therapy versus heparin: other outcomes

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Escalation of treatment Show forest plot	2	306	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.16, 0.64]

10.2 Hospital stay Show forest plot	5	368	Mean Difference (IV, Random, 95% CI)	‐1.40 [‐2.69, ‐0.11]

10.2.1 USAT (rt‐PA) vs heparin	1	59	Mean Difference (IV, Random, 95% CI)	0.30 [‐1.57, 2.17]
10.2.2 rt‐PA vs heparin	1	121	Mean Difference (IV, Random, 95% CI)	‐2.70 [‐2.94, ‐2.46]
10.2.3 Streptokinase or alteplase vs enoxaparin heparin	1	50	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.83, 0.83]
10.2.4 Streptokinase vs heparin	1	52	Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.96, ‐0.24]
10.2.5 Tenecteplase vs heparin	1	86	Mean Difference (IV, Random, 95% CI)	‐3.00 [‐3.98, ‐2.02]
10.3 Composite clinical outcome Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.3.1 All‐cause death or haemodynamic decompensation	3	1157	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.20, 0.66]
10.3.2 Recurrent VTE and poor functional capacity and low perception of wellness	1	83	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.84]
10.3.3 Poor functional capacity and low perception of wellness	1	83	Odds Ratio (M‐H, Fixed, 95% CI)	0.19 [0.02, 1.75]
10.3.4 Recurrent VTE and low perception of wellness	1	83	Odds Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.40]
10.3.5 Chronic thromboembolic pulmonary hypertension or post‐PE impairment	1	219	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.55, 2.64]

Comparison 10. Thrombolytic therapy versus heparin: other outcomes

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Comparison 11. Thrombolytic therapy versus heparin: other outcomes (sensitivity analysis according to study quality)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Hospital stay Show forest plot	2	207	Mean Difference (IV, Random, 95% CI)	‐2.72 [‐2.95, ‐2.49]

11.1.1 rt‐PA vs heparin	1	121	Mean Difference (IV, Random, 95% CI)	‐2.70 [‐2.94, ‐2.46]
11.1.2 Tenecteplase vs heparin	1	86	Mean Difference (IV, Random, 95% CI)	‐3.00 [‐3.98, ‐2.02]

Comparison 11. Thrombolytic therapy versus heparin: other outcomes (sensitivity analysis according to study quality)

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Cochrane Review language

Website language

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

PICOs

PICOs

Population

Intervention

Comparison

Outcome

Plain language summary

Drugs to dissolve pulmonary embolism (blood clot in the lungs)

Visual summary

Authors' conclusions

Implications for practice

Implications for research

Summary of findings

Background

Description of the condition

Description of the intervention

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other bias

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

Included studies

Design

Participants

Interventions

Outcome measures

Ongoing studies

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Primary outcome measures

Death from all causes

Recurrence of pulmonary emboli

Major and minor haemorrhagic events

Major haemorrhagic events