Accepted Article

Received Date : 06-Mar-2014 Revised Date

: 14-Apr-2014

Accepted Date : 08-May-2014 Article type

: Original Article - Clinical Haemostasis and Thrombosis

Impact of the Efficacy of Thrombolytic Therapy on the Mortality of Patients with Acute Submassive Pulmonary Embolism: A Meta-Analysis

Short title: Nakamura, Thrombolysis and Pulmonary Embolism

Shunichi Nakamura, MD, Hitoshi Takano, MD, Yoshiaki Kubota, MD, Kuniya Asai, MD, Wataru Shimizu, MD, PhD Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan

Address for correspondence: Shunichi Nakamura, MD Department of Cardiovascular Medicine, Nippon Medical School 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-0022, Japan Phone number: +81-3-3822-2131(Ext 4018) Fax number: +81-3-5685-0987 Email address: [email protected]

Abstract Background: The efficacy of thrombolytic therapy in patients with submassive pulmonary embolism (PE) remains unclear. Previous meta-analyses have not separately reported the proportion of patients with submassive PE. Objective: We assessed the effect of thrombolytic therapy on mortality, recurrent PE, clinical deterioration

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requiring treatment escalation, and bleeding in patients with submassive PE. Methods: The MEDLINE, EMBASE, and Cochrane Library databases were queried to identify all relevant randomized controlled trials comparing adjunctive thrombolytic therapy with heparin alone as initial treatments in patients with acute submassive PE, and reported 30-day mortality or in-hospital clinical outcomes. Results: A total of 1510 patients were enrolled in this meta-analysis. No significant differences were apparent in the composite endpoint of all-cause death or recurrent PE between the adjunctive thrombolytic therapy arm and the heparin-alone arm (3.1% vs 5.4%; RR, 0.64 [0.32–1.28]; P = 0.2). Adjunctive thrombolytic therapy significantly reduced the incidence of the composite endpoint of all-cause death or clinical deterioration (3.9% vs 9.4%; RR, 0.44; P < 0.001). There were no statistically significant associations for major bleeding when adjunctive thrombolytic therapy was compared with heparin therapy alone (6.6% vs 1.9%; P = 0.2). Conclusions: This meta-analysis shows that adjunctive thrombolytic therapy does not significantly reduce the risk of mortality or recurrent PE in patients with acute submassive PE but that adjuvant thrombolytic therapy prevents clinical deterioration requiring the escalation of treatment in patients with acute submassive PE. Bleeding risk assessment might be the most successful approach for improving clinical outcomes and patient-specific benefit.

Keywords: pulmonary embolism, heparin, thrombolytic therapy, mortality, prognosis

Introduction Acute pulmonary embolism (PE) is a common and often fatal disease. The established treatment for acute PE is anticoagulant therapy with unfractionated or low-molecular-weight heparin, followed by warfarin treatment for at least 3 to 6 months, and patients who present with normal blood pressure and normal right ventricular (RV) function have excellent prognoses [1-5]. Thrombolytic therapy in hemodynamically unstable patients with so-called massive PE is recommended in the current clinical guidelines [4-6]. Patients who present with acute PE, and RV dysfunction or myocardial damage detected by echocardiography, computed tomography, and cardiac biomarkers, tend to have poor prognoses [7, 8]. Hemodynamically stable patients who present with these clinical manifestations are diagnosed with submassive PE [4], and although some investigators call this condition intermediate-risk PE [5], the 2 conditions are virtually equivalent. The efficacy of thrombolytic therapy in submassive PE remains unclear. Previous meta-analyses have not separately reported on patients who

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have submassive PE [9-11]. Therefore, we assessed the impacts of thrombolytic therapy on the risks and benefits to patients with submassive PE, which included mortality, recurrent PE, clinical deterioration, and bleeding.

Methods Data sources and search strategy The MEDLINE, EMBASE, and Cochrane Library databases were queried to identify all relevant published and unpublished randomized controlled trials comparing adjunctive thrombolytic therapy with heparin administered alone in the initial treatment of patients with acute submassive PE. We searched the databases for the following keywords:

“pulmonary

embolism”,

“pulmonary

thromboembolism”,

“PE”,

“PTE”,

“thrombolytic”,

“thrombolytic therapy”, “thrombolysis”, “fibrinolytic”, “fibrinolytic therapy”, “tissue type plasminogen activator”, “tissue plasminogen activator”, “tPA”, “alteplase”, “streptokinase”, “urokinase”, “lanoteplase”, “tenecteplase”, “reteplase”, “right ventricular dysfunction”, “right ventricular”, “right ventricle dysfunction”, “right ventricle”, “submassive”, “intermediate risk”, “normotensive”, and “normotension”. We also acquired abstracts from major international meetings. The search was limited to original articles written in English and studies presented at major international congresses between January 1980 and January 2014. Reference lists within selected articles were reviewed for other potentially relevant citations. In addition, authors of the reports selected were contacted to obtain further information, if required. The abstracts were selected by 2 investigators (S.N. and A.K.) following discussion. We selected studies that included (1) patients with acute submassive PE, defined as hemodynamically stable patients with submassive PE presenting with either RV dysfunction or myocardial injury detected by echocardiography, computed tomography, or cardiac biomarkers, (2) at least 20 study participants, (3) a control group of patients who were treated with heparin alone, (4) a follow-up duration that lasted at least the length of the hospital stay or 30 days, and (5) randomized trials. Reviews, editorials, animal studies, and case reports were excluded from this analysis. Following retrieval of the reports, further studies were excluded if there were overlaps in populations participating in 2 studies, in which case the study with the larger sample size was included. Data extraction and quality assessment Study data from the selected trials, including the baseline clinical characteristics of the study population and the outcome measures, were extracted using the prepared standardized extraction database. The quality of the study in relation to the analysis of the efficacy of thrombolysis was assessed using the Cochrane Collaboration’s

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tool for assessing risk of bias. These steps were performed independently by 2 investigators (S.N. and A.K.). Endpoints Four outcomes were assessed to determine the efficacy and safety of thrombolytic therapy in acute submassive PE: (1) all-cause death, (2) the composite endpoint of all-cause death or recurrent PE, (3) the composite endpoint of all-cause death or clinical deterioration, defined as that requiring least one of the following: emergency surgical embolectomy; thrombus fragmentation by catheter, or “rescue” thrombolysis; catecholamine administration because of sustained hypotension and shock, cardiopulmonary resuscitation, vital signs indicating hypotension and shock, endotracheal intubation, or hypotension, defined as a drop in systolic blood pressure ≥ 40 mmHg with organ hypoperfusion, (4) major bleeding, defined as fatal, intracranial, or requiring intervention with transfusion or surgery. Statistical analysis The data collected from all of the studies were collated to estimate the pooled impact of the efficacy of adjunctive thrombolytic therapy compared with heparin therapy alone, and this was expressed as the risk ratio (RR). The calculations were based on a random-effects model. When no events occurred within a group, continuity corrections were used to enable the calculation of an RR. Heterogeneity among the trials was quantified using Higgins and Thompson’s I2. The I2 statistic can be interpreted as the percentage of variability caused by heterogeneity between studies rather than that caused by sampling errors. A value of I2 < 25% was considered to indicate moderate heterogeneity. All results are presented as point estimates, and the corresponding 95% confidence intervals (CIs) are presented in parentheses. To assess the effect of individual studies on the summary estimate of effects, we performed an influence analysis using a jackknife procedure where pooled estimates were recalculated by omitting one study at a time. Meta-regression analysis was performed based on the trial data. Potential publication bias was assessed using the Egger test and represented graphically using Begg’s funnel plots of the natural log of the RR versus its standard error of the mean. All analyses were performed using Review Manager (RevMan) Version 5.2. (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata Version 13 (StataCorp LP, College Station, Texas, USA).

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Results Selection and characteristics of the studies We screened the titles or abstracts of 696 potentially eligible trials. Of these, 690 trials were excluded because they were either irrelevant or they were duplicates (Figure 1). Consequently, 6 randomized trials comparing adjuvant thrombolytic therapy with heparin therapy alone in patients with acute submassive PE were included in this analysis after the complete text of the papers was analyzed [12-18]. Table 1 and Table 2 present the characteristics and the quality assessments of the studies included in the meta-analysis. A total of 1510 patients were enrolled in this meta-analysis. Of these, 747 patients received adjuvant thrombolytic therapy with alteplase (3 trials, 173 patients), or tenecteplase (3 trials, 574 patients) and 763 patients were treated with heparin only (Table 1). The dose of alteplase in all 3 trials comprised a 100-mg infusion in total which was administered over 2 h as an initial 10-mg bolus, followed by a 90-mg infusion in 2 out of 3 trials, and in the remaining trial alteplase was administered as a 100-mg infusion. In the 3 other trials analyzed, tenecteplase was administered as a 30- to 50-mg bolus, adjusted according to body weight. The patients within the adjuvant thrombolytic therapy groups in all of the trials were also administered heparin, as were the patients in the control groups. The thrombolytic agents were administered intravenously. Unfractionated heparin or low-molecular-weight heparin were administered in both thrombolytic therapy group and control group of the included trials. In 5 of the 6 trials selected [12-17], major bleeding was defined as fatal bleeding requiring transfusion, or hemodynamic deterioration requiring intervention, and in the remaining trial major bleeding was defined as fatal bleeding, hemorrhagic stroke, or a drop in the hemoglobin concentration by at least 4 g/dL, with or without transfusion. We enrolled all of the patients from 5 of the trials selected for analysis [12-17], and we only enrolled those patients who had experienced submassive PE from the remaining trial [18] selected for analysis, because it also included patients who had experienced nonmassive PE. All-cause death No significant differences were found in all-cause death between the adjuvant thrombolytic therapy study arm and the heparin therapy control arm (2.3% vs 3.7%; RR, 0.72 (0.39–1.31)) (Figure 2). A low level of heterogeneity existed among these trials (I2 = 0%). Subgroup analysis showed there were no differences in the efficacy between tenecteplase and alteplase (P = 0.5). Analysis using Egger’s test and rank correlation testing did not indicate a small study effect nor any evidence of publication bias (Egger test: P = 0.3; rank correlation test: P = 0.3).

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All-cause death and recurrent pulmonary embolism The benefit of adjuvant thrombolytic therapy compared with heparin alone on the composite endpoint of all-cause death or recurrent PE did not attain statistical significance (3.1% vs 5.4%; RR, 0.64 [0.32–1.28]) (Figure 2). A mild level of heterogeneity existed among these studies (I2 = 20%). Sub-analysis showed that recurrent PE in patients receiving adjuvant thrombolytic therapy was not significantly lower than in patients receiving heparin alone (0.8% vs 1.7%; RR, 0.60 [0.21–1.69]) (Figure 2). Subgroup analysis showed there were no differences in the efficacy between tenecteplase and alteplase (P = 0.7). Analysis using Egger’s test and rank correlation testing did not indicate a small study effect nor any evidence of publication bias (Egger test: P = 0.3; rank correlation test: P = 0.2). All-cause death and clinical deterioration Data regarding clinical deterioration were available in 4 of the trial reports selected for analysis [12, 13, 15-17]. Adjuvant thrombolytic therapy significantly reduced the composite endpoint of all-cause death or clinical deterioration in patients with acute submassive PE compared with heparin alone (3.9% vs 9.4%; RR, 0.44 [0.29–0.67]) (Figure 2). A low level of heterogeneity existed among these studies (I2 = 0%). Clinical deterioration only in patients receiving adjuvant thrombolytic therapy was also significantly lower than in patients receiving heparin alone (1.4% vs 6.5%; RR, 0.29 [0.15–0.55]) (Figure 2). Subgroup analysis showed there were no differences in the efficacy between tenecteplase and alteplase (P = 1.0). Analysis using Egger’s test and rank correlation testing did not indicate a small study effect nor any evidence of publication bias (Egger test: P = 0.7; rank correlation test: P = 0.5). Safety outcomes Major bleeding tended to be higher in the adjuvant thrombolytic therapy arm of the study compared with the control arm, but this difference was not statistically significant (6.6% vs 1.90%; RR, 2.07 [0.58–7.35]) (Figure 2). Subgroup analysis showed that intracranial bleeding was higher in the adjuvant thrombolytic therapy study arm than in the heparin control arm (1.7% vs 0.1%; RR, 5.2 [1.33–20.31]). Data relating to minor bleeding were available in the reports from 3 of the trials selected [12-14, 17], and minor bleeding was higher in the adjuvant thrombolytic therapy study arm that in the heparin control arm (33.1% vs 8.5%; RR, 3.79 [2.54–5.66]) (Figure 2). Analysis using Egger’s test and rank correlation testing did not indicate a small study effect nor any evidence of publication bias (Egger test: P = 0.2; rank correlation test: P = 1.0).

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Sensitivity analysis Subgroup analysis was undertaken for clinical outcomes in relation to baseline characteristics (Figure 3). We noted that the magnitude of the effect of the composite endpoint of all-cause death or recurrent PE was greater in trials that recorded a higher mean baseline age (P value for heterogeneity = 0.04) and a higher mean baseline systolic blood pressure (P value for heterogeneity = 0.03), and a large sample size exceeding 100 (P value for heterogeneity = 0.04). On univariate meta-regression analysis, patients with lower systolic blood pressures who were receiving adjuvant thrombolytic therapy tended to show a greater reduction in the composite outcome of all-cause death or recurrent PE than did patients receiving heparin therapy alone (Figure 4) (P = 0.1), but none of the trends showed associations between age or a large sample size, and the composite outcome of all-cause death or recurrent PE. Influence analysis of the composite endpoint of all-cause mortality or clinical deterioration involved omitting one of the 4 studies [12, 13, 15-17] in which data about clinical deterioration were available, and none of the studies influenced the overall result. Discussion This meta-analysis confirms that adjunctive thrombolytic therapy does not reduce the incidences of short-term all-cause mortality and recurrent PE in patients with acute submassive PE compared with heparin therapy administered alone. Furthermore, this meta-analysis shows that adjunctive thrombolytic therapy significantly reduces the incidences of the composite endpoint of mortality or clinical deterioration compared with heparin therapy administered alone. Regarding adverse effects, adjunctive thrombolytic therapy was associated with intracranial bleeding, but there were no statistically significant association for major bleeding when adjunctive thrombolytic therapy was compared with heparin therapy alone. This meta-analysis consisted of all of the trials available at the time of the analysis and did not overturn the accepted notion that adjunctive thrombolytic therapy does not significantly reduce the risk of mortality in patients with submassive PE. Recent publications report that the 30-day mortality rate in patients with submassive PE is 3.0% [19-21], and these rates are in line with the 30-day mortality rate of 3.0% determined in our meta-analysis. These results also suggest that if adjunctive thrombolytic therapy reduces the risk of mortality in patients with submassive PE compared with heparin alone by about 30%, which is similar to the result from our meta-analysis (28%), then the size effect of this treatment is only about 1%. This could explain why the survival benefit of adjunctive thrombolytic therapy in patients with submassive PE has been difficult to demonstrate.

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Interestingly, when all-cause death and clinical deterioration were analyzed together, a significant risk reduction in favor of adjuvant thrombolytic therapy was observed. The actual clinical benefits of adjuvant thrombolytic therapy are rapid symptomatic improvements that include alleviation of chest pain and dyspnea; hemodynamic and respiratory stabilization, which avoids the need for mechanical support and the use of catecholamines; and decrease in damage to the right side of the heart, which improves exercise tolerance. These benefits are often attributed to more rapid restoration of lung perfusion [13, 18, 22-24]. Although the present meta-analysis provides information that is limited to short-term outcomes, patients with acute PE who present with RV dysfunction and an increased systolic pulmonary artery pressure have been reported to be associated with persistent RV dysfunction, pulmonary artery hypertension, and poor outcomes at 6 weeks and 5 years [25, 26]. In a randomized trial, a significant early improvement in RV dysfunction was observed at the 6-month follow-up assessment in patients treated with adjunctive thrombolytic therapy compared with those administered heparin alone [14]. Therefore, reducing the risk of clinical deterioration through adjunctive thrombolytic therapy could be maintained in the long term. The major bleeding rate in the present meta-analysis was 4.2% over the course of the hospital stay or over 30 days. Although there was a trend of an increased risk of major bleeding in association with adjunctive thrombolytic therapy, the difference was not significant in comparison with patients treated with heparin alone. However, a significant increase in risk for intracranial bleeding was observed with thrombolytic therapy versus heparin alone. This harmful effect might be the trade-off for the benefit of a reduction in clinical deterioration. In this context, risk stratification of patients with submassive PE is of great clinical importance. There are no guidelines for the risk assessment of intracranial bleeding during thrombolytic therapy in patients with submassive PE; therefore, contraindications should be extrapolated from the current guidelines for acute myocardial infarction (Table 3) [27, 28]. To evaluate RV dysfunction, findings from investigations of RV hypokinesis, RV enlargement using echocardiography, and findings from the RV/left ventricular ratio using computed tomography are commonly used. Cardiac biomarkers of myocardial injury and necrosis, including cardiac troponin I or T, are other tools used to detect RV dysfunction [29, 30]. In a fictitious cohort of 1,000 patients from the present study, thrombolysis in patients with submassive PE could reduce the composite event of death or clinical deterioration by 55.3 patients and increase the intracranial bleeding by 16.1 patients compared with heparin therapy administered alone. From the perspective of beneficial effects on clinical deterioration, these studies indicate that the risk/benefit balance of this treatment may favor carefully selected patients with submassive PE who present with RV dysfunction or myocardial damage, and particularly those

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patients who do not have elevated risk of bleeding. Limitations This meta-analysis has several limitations that must be mentioned. First, each of the studies included in the meta-analysis had their own specific and general limitations. All of the studies differed with respect to their design, the patients’ characteristics, follow-up duration, the heparin therapy regimen, and the adjunctive thrombolytic therapy regimen, and inclusion criteria such as the definition of submassive PE and the time to enrollment from the onset of symptoms associated with PE, were different (Table 1). Although sensitivity analysis of this meta-analysis showed there were no statistically significant differences in these parameters, these differences may have influenced the results of this meta-analysis. As for the definition of major bleeding, the MSPPE3 trial included a definition of a decline in the hemoglobin concentration by at least 4 g/dL with or without transfusion as a major bleeding event. Furthermore, in one study, data about major bleeding were not available because it was impossible to separate the data relating to bleeding associated with submassive PE from those associated with non-massive PE or low-risk PE. This may explain why there was no statistical significance. The definition of clinical deterioration also includes various heterogeneous components, which makes this criterion difficult to generalize. Second, this meta-analysis was based on trial level data rather than individual patient data. Hence, we could not reliably analyze factors associated with the clinical outcomes because some of the background factors and co-morbidities were not available in some of the study reports included in the meta-analysis. Third, the number of the studies included in our meta-analysis was low despite collecting information from all of the trials available at the time. However, all of the studies included were prospective, randomized, and controlled, 5 of the 6 studies were double blind, and the remaining study was an open-labeled study (Table 1). Fourth, the present meta-analysis provides information that is limited to short-term outcomes. Therefore, further studies would need to carry out longer-term assessment of mortality, quality of life, and functional status. Another limitation to this work was that some of the studies were small, with the smallest study including only 36 patients. This study included participants with submassive PE and non-massive PE [18], and we only recruited patients with submassive PE from this study (adjuvant thrombolytic therapy arm: 18 patients; heparin arm: 18 patients). Finally, the trends in the use of PE therapeutic agents that have been occurring over the past decade include the use of tenecteplase and low-molecular-weight heparin use, and even though sensitivity analysis did not show significant differences except major bleeding between these agents, these newer agents may affect patient outcomes. As for the study selection, we did not included MOPPET trial [31] because the inclusion criteria in this study was simply determined by the extent of disturbed pulmonary

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blood flow irrespective of the existence of RV dysfunction or myocardial injury. MOPETT trial did not influence the overall results even if this trial was added in the selected studies (Supplementary file 2).We understand that our results were limited to the populations studied. However, despite these limitations, this study is as an important addition to the body of knowledge because it provides a compelling rationale for further research and represents the best available evidence until more data become accessible. Conclusions This is the first meta-analysis of randomized trials specifically designed to assess the clinical impact of thrombolytic therapy in patients with acute submassive PE. The results of the present meta-analysis demonstrate that adjunctive thrombolytic therapy does not significantly reduce the risk of mortality or recurrent PE in patients with acute submassive PE but that adjuvant thrombolytic therapy prevents clinical deterioration requiring the escalation of treatment in patients with acute submassive PE. Bleeding risk assessment might be a better approach for improving clinical outcomes and patient-specific benefit.

Addendum S. Nakamura: Study concept and design, analysis and interpretation of data, collection and assembly of data, drafting of the article, and critical revision of the article for important intellectual content. S. Nakamura takes responsibility for the manuscript as a whole. H. Takano: Study concept and design, analysis and interpretation of data, drafting of the article, and critical revision of the article for important intellectual content. Y. Kubota: Study concept and design, analysis and interpretation of data, collection and assembly of data, drafting of the article, and critical revision of the article for important intellectual content. K. Asai: drafting of the article, and critical revision of the article for important intellectual content. W. Shimizu: Study concept and design, drafting of the article, critical revision of the article for important intellectual content, and final approval of the article.

Funding sources: No financial support was received for this study. Disclosures None.

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359: 2804-13. 31

Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism

treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013; 111: 273-7.

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Accepted Article

Table 1 Characteristics of the included studies Study

Study

Sa

Me

Fe

Year

Design

mp

an

mal

le

Ag

e

size

e

(%

(y)

)

59

57

Treatment

Submassive PE Inclusion Criteria

Thrombolysis: Alteplase 100 mg/2 h

Symptoms or signs of

bel

Heparin: UFH 1000 U/h (aPTT at 1.5 to 2.5

PE ≤ 14 days

RCT

times the upper limit of normal)

SBP ≥ 90 mmHG

Goldhabe

Open-la

r 1993 (18)

36

RVD at ECG Thrombolysis: Alteplase 10 mg bolus,

Symptoms ≤ 4 days

-blind

followe by 90 mg/2 h infusion

SBP ≥ 90 mmHG

RCT

Heparin: UFH 1000 U/h (aPTT at 2.0 to 2.5

RVD at ECG or CT

MSPPE

Double

2002 (15)

256

62

52

times the upper limit of normal) Thrombolysis: Tenecteplase 30-50 mg

Symptoms ≤ 10 days

-blind

(weight-adjusted dose) bolus

SBP ≥ 100 mmHg

RCT

Heparin: UFH 80 U/kg bolus, followed by

RVD at ECG

TIPES

Double

2010 (13)

58

68

60

UFH 18 U/kg/h

(aPTT at 2.0 to 2.5 times

the upper limit of normal) Thrombolysis: Alteplase 10 mg bolus, 90

Symptoms ≤ 6 hours

-blind

mg/2 h infusion

SBP ≥ 100 mmHg

RCT

Heparin: UFH 5000U bolus, followed by

RVD at ECG

Fasullo

Double

2011 (14)

72

56

43

UFH 1000 U/h (the therapeutic range of aPTT was not stated) 83

55

41

Thrombolysis: Tenecteplase 30-50 mg

TOPCOA

Double

T 2014

-blind

(weight-adjusted dose) bolus

(16)

RCT

Heparin: LMWH (weight-adjusted dose)

Symptom duration: NA* SBP ≥ 90 mmHG RVDs on ECG, elevated cTn-T or I, or elevated BNP

PEITHO

Double

100

2014

-blind

5

(12) (17)

RCT

66

53

Thrombolysis: Tenecteplase 30-50 mg

Symptoms ≤ 15 days

(weight-adjusted dose) bolus

SBP ≥ 90 mmHg

Heparin: UFH bolus, followed by UFH

RVD at ECG or CT

infusion (aPTT at 2.0 to 2.5 times the upper

plus myocardial injury

limit of normal)

by cTn-T or I

Abbreviation: PE, pulmonary embolism; RCT, randomized controlled trial; UFH, unfractionated heparin; aPTT, activated partial thromboplastin time; SBP, systolic blood pressure; RVD, right ventricle dysfunction; ECG, echocardiography; CT, computed tomography; LMWH, low-molecular weighted heparin; cTn, cardiac troponin

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* TOPCOAT required entry within 24 h of CT pulmonary angiography, but had no lockout on symptom duration.

Table 2 Quality assessment of studies regarding the analysis of the efficacy of thrombolysis, according to

the Cochrane Risk of Bias Assessment

Sequence

Allocation

Blindin

Incomplete

Selective

generation

concealment

g

outcome data

reporting

Goldhaber

Yes

Yes

No

Yes

Yes

MSPPE

Yes

Yes

Yes

Yes

Yes

TIPES

Yes

Yes

Yes

Yes

Yes

Fasullo

Yes

Yes

Yes

Yes

Yes

TOPCOAT

Yes

Yes

Yes

Yes

Yes

PEITHO

Yes

Yes

Yes

Yes

Yes

Study/Year

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Table 3 Contraindications for thrombolytic therapy Absolute contraindications ¾

Hemorrhagic stroke or stroke of unknown origin at any time

¾

Ischemic stroke within 6 months

¾

Suspected aortic dissection

¾

Central nervous system damage or neoplasms

¾

Recent major trauma, surgery or head injury (within 3 weeks)

¾

Gastrointestinal bleeding within the last month

¾

Known bleeding

¾

Non-compressible punctures in the past 24hours

Relative contraindications ¾

Age > 75 years

¾

Transient ischemic attack within 6 months

¾

Current use of anticoagulant therapy

¾

Pregnancy or within 1 week post-partum

¾

Traumatic or prolonged cardiopulmonary resuscitation (10minutes)

¾

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

¾

Advanced liver disease

¾

Infective endocarditis

¾

Active peptic ulcer

¾

Major surgery within 3 weeks

¾

Dementia

Figure legends

Figure 1 The selection process for the inclusion of studies in the meta-analysis.

Figure 2 Forest plots of the efficacy of thrombolytic therapy on clinical endpoints in patients with acute submassive pulmonary embolism. The markers represent point estimates of risk ratios and the marker size represents the study weight in the random-effects meta-analysis. The horizontal bars represent the 95% confidence intervals. M-H, Mantel-Haenszel method; CI, confidence interval.

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Figure 3 Sensitivity analyses of treatment-effect modifications on clinical outcomes in the subgroups of interest. Risk ratios and 95% confidence intervals (95% CI) are used as summary statistics and are presented as plots, the center of which indicates the point estimate and the left and the right ends of the lines represent the 95% CI. The I2 statistic describes the heterogeneity across the trials, except where there was only one trial included within a subgroup. P values are given for the interaction between the treatment-effect and subgroups derived from meta-regression analysis; PE, pulmonary embolism; SBP, systolic blood pressure.

Figure 4 Meta-regression plots. Univariate meta-regression plot for all-cause death or recurrent pulmonary embolism according to the mean systolic blood pressure (P = 0.1, coefficient = 0.289). PE, pulmonary embolism.

Additional Figure (Supplementary file 2) Forest plots of the efficacy of thrombolytic therapy on clinical endpoints in patients with acute submassive pulmonary embolism. The markers represent point estimates of risk ratios and the marker size represents the study weight in the random-effects meta-analysis. The horizontal bars represent the 95% confidence intervals. M-H, Mantel-Haenszel method; CI, confidence interval.

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Accepted Article This article is protected by copyright. All rights reserved.

Accepted Article This article is protected by copyright. All rights reserved.