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Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double‐blind, placebo‐controlled randomized trial

2014; Elsevier BV; Volume: 12; Issue: 4 Linguagem: Inglês

10.1111/jth.12521

1538-7933

J. A. Kline, Kristen E. Nordenholz, D. Mark Courtney, Christopher Kabrhel, Alan E. Jones, Matthew T. Rondina, Deborah B. Diercks, James R. Klinger, Jackeline Hernandez,

Atrial Fibrillation Management and Outcomes

Journal of Thrombosis and HaemostasisVolume 12, Issue 4 p. 459-468 Original ArticleFree Access Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial J. A. Kline, Corresponding Author J. A. Kline Departments of Emergency Medicine and Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA Correspondence: Jeffrey A. Kline, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Regenstrief R2200, 1050 Wishard Blvd, Indianapolis, IN 46202, USA. Tel.: +1 317 287 3007; E-mail: jefkline@iupui.eduSearch for more papers by this authorK. E. Nordenholz, K. E. Nordenholz Department of Emergency Medicine, School of Medicine, University of Colorado, Aurora, CO, USASearch for more papers by this authorD. M. Courtney, D. M. Courtney Department of Emergency Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USASearch for more papers by this authorC. Kabrhel, C. Kabrhel Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USASearch for more papers by this authorA. E. Jones, A. E. Jones Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, USASearch for more papers by this authorM. T. Rondina, M. T. Rondina Department of Internal Medicine, University of Utah, Salt Lake City, UT, USASearch for more papers by this authorD. B. Diercks, D. B. Diercks Department of Emergency Medicine, University of California, Davis, Sacramento, CA, USASearch for more papers by this authorJ. R. Klinger, J. R. Klinger Department of Internal Medicine, Alpert Medical School of Brown University, Providence, RI, USASearch for more papers by this authorJ. Hernandez, J. Hernandez Department of Emergency Medicine, Carolinas, Charlotte, NC, USASearch for more papers by this author J. A. Kline, Corresponding Author J. A. Kline Departments of Emergency Medicine and Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA Correspondence: Jeffrey A. Kline, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Regenstrief R2200, 1050 Wishard Blvd, Indianapolis, IN 46202, USA. Tel.: +1 317 287 3007; E-mail: jefkline@iupui.eduSearch for more papers by this authorK. E. Nordenholz, K. E. Nordenholz Department of Emergency Medicine, School of Medicine, University of Colorado, Aurora, CO, USASearch for more papers by this authorD. M. Courtney, D. M. Courtney Department of Emergency Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USASearch for more papers by this authorC. Kabrhel, C. Kabrhel Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USASearch for more papers by this authorA. E. Jones, A. E. Jones Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, USASearch for more papers by this authorM. T. Rondina, M. T. Rondina Department of Internal Medicine, University of Utah, Salt Lake City, UT, USASearch for more papers by this authorD. B. Diercks, D. B. Diercks Department of Emergency Medicine, University of California, Davis, Sacramento, CA, USASearch for more papers by this authorJ. R. Klinger, J. R. Klinger Department of Internal Medicine, Alpert Medical School of Brown University, Providence, RI, USASearch for more papers by this authorJ. Hernandez, J. Hernandez Department of Emergency Medicine, Carolinas, Charlotte, NC, USASearch for more papers by this author First published: 31 January 2014 https://doi.org/10.1111/jth.12521Citations: 159 Manuscript handled by: P. de Moerloose Final decision: F. R. Rosendaal, 26 January 2014 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summary Background Acute pulmonary embolism (PE) can worsen quality of life due to persistent dyspnea or exercise intolerance. Objective Test if tenecteplase increases the probability of a favorable composite patient-oriented outcome after submassive PE. Methods Normotensive patients with PE and right ventricular (RV) strain (by echocardiography or biomarkers) were enrolled from eight hospitals. All patients received low-molecular-weight heparin followed by random assignment to either a single weight-based bolus of tenecteplase or placebo, administered in a double-blinded fashion. The primary composite outcome included: (i) death, circulatory shock, intubation or major bleeding within 5 days or (ii) recurrent PE, poor functional capacity (RV dysfunction with either dyspnea at rest or exercise intolerance) or an SF36® Physical Component Summary (PCS) score < 30 at 90-day follow-up. Results Eighty-three patients were randomized; 40 to tenecteplase and 43 to placebo. The trial was terminated prematurely. Within 5 days, adverse outcomes occurred in three placebo-treated patients (death in one and intubation in two) and one tenecteplase-treated patient (fatal intracranial hemorrhage). At 90 days, adverse outcomes occurred in 13 unique placebo-treated patients and five unique tenecteplase-treated patients Thus, 16 (37%) placebo-treated and six (15%) tenecteplase-treated patients had at least one adverse outcome (exact two-sided P = 0.017). Conclusions Treatment of patients with submassive pulmonary embolism with tenecteplase was associated with increased probability of a favorable composite outcome. Introduction The adjunctive use of fibrinolysis to treat acute submassive pulmonary embolism (PE) remains controversial. In patients without contraindications, published clinical guidelines consistently recommend fibrinolysis for massive PE, defined as PE that causes systolic arterial hypotension 1-3. However, the same guidelines conflict in their recommendations for fibrinolysis for submassive PE, defined as PE that does not cause systolic arterial hypotension, but does cause right ventricular strain. Some of the conflict arises from a dearth of randomized clinical trials that precludes ability to assess a number needed to treat for survival in this subgroup 4, 5. Mortality as a primary outcome hampers clinical trials of submassive PE because the short-term mortality rate directly attributable to PE is below 2% 6, 7. This implies the need for an impractically large sample size, compelling the need for a composite endpoint, which is more likely to have larger differences between treatment groups 8, 9. In addition to risk of death, patients with submassive PE may suffer persistent right ventricular dysfunction that can impair their quality of life by causing dyspnea and exercise intolerance 10-16. If associated with deep vein thrombosis, their quality of life can be further degraded by the post-thrombotic syndrome 17, 18. We therefore designed a primary composite outcome from the perspective of the patient: to survive the PE without need for life supporting interventions in hospital and on follow-up, and at 90 days to have good functional capacity (defined as normal right ventricular function on echocardiography, a New York Heart Association functional class better than 3, and adequate exercise tolerance on 6-min walk test) and perception of wellness on the physical component portion of the SF-36 no worse than two standard deviations below normal 9. In the present investigation, all patients received standard therapy with low-molecular-weight heparin followed by random assignment to either a weight-based, single bolus of placebo or tenecteplase. We hypothesized that a larger proportion of patients who received tenecteplase would have a favorable composite outcome. Methods Study design and regulatory controls This was a multicenter, double-blinded, intention to treat, placebo-controlled, randomized controlled efficacy trial. The rationale and methodology are described in more detail in a separate publication 9. The trial was registered on clinicaltrials.gov (NCT00680628) in 2008 and conducted under IND100274 from the US Food and Drug Administration (FDA). The clinical trial was named by the investigators as Tenecteplase or Placebo: Cardiopulmonary Outcomes at Three months (TOPCOAT). The protocol was approved by the Institutional Review Boards at each participating site. All patients signed written informed consent in the physical presence of a site investigator. The study was monitored for safety by an independent Data Safety and Monitoring Committee. Study setting and population Prospective enrollment occurred at eight academic medical centers in the US where the authors practice. The inclusion criteria were: (i) age > 17 years; (ii) PE diagnosed on computed tomographic pulmonary angiography performed within 24 h; and (iii) normal arterial systolic blood pressure with evidence of right ventricular strain, manifested by (a) hypokinesis on echocardiography, (b) elevated troponin I or T using local thresholds (values exceeding the 99 percentile with coefficient of variability < 10%) or (c) brain natriuretic peptide (BNP) measurement > 90 pg mL−1 or NT proBNP > 900 pg mL−1 (not more than 6 h prior to CT angiography and not more than 30 h before enrollment). The initial echocardiography had to be ordered as part of standard care. Severity criteria initially included a pulse oximetry reading < 95% within the previous 2 hours in all locations except Aurora, CO, and Salt Lake City, UT, but this criterion was dropped after 15 patients were enrolled 19. The study had 24 exclusion criteria listed in a previous publication 9. In summary, exclusions included systolic hypotension (< 90 mmHg), inability to walk, contraindications to fibrinolysis, and end-stage conditions. Treatment protocol After informed consent, all patients were treated with full-dose low-molecular-weight heparin (LMWH), 1 mg kg−1 enoxaparin, or weight-based dalteparin, 200 units kg−1, administered subcutaneously prior to injection of study drug or placebo. If the patient was receiving unfractionated heparin, this was discontinued and LMWH was started. A venous blood specimen was obtained for baseline studies. Study group assignment occurred by a predetermined, blocked permuted 1 : 1 randomization sequence that was prepared by the study statistician and linked to a unique study ID number used by a research pharmacist to prepare placebo or tenecteplase in 0.9% saline in an opaque syringe. Patients received tiered dose tenecteplase in accordance with the TNKase® insert (Genentech Inc., San Francisco, CA, USA). A site investigator injected the syringe contents as soon as practicable. A study-specific order form was placed on the chart to continue low-molecular-weight heparin for the remainder of their hospital stay. Depending upon the site, the clinical care team could unblind the randomization assignment by either opening the envelope or calling the research pharmacy. The envelope had clear language indicating that unblinding was to occur only if absolutely necessary to make emergent treatment decisions. Decisions about long-term anticoagulant therapy were at the discretion of the clinical care team. Measurements and outcomes Five-day adverse outcomes were PE related or treatment related. Adverse outcomes from PE were death, circulatory shock (hypotension requiring vasopressor infusion), or need for intubation. Adverse outcomes from treatment were death from hemorrhage, any intracranial or intraspinal hemorrhage, active bleeding with > 2 g dL−1 drop in hemoglobin within 24 h requiring transfusion, and any bleeding that required surgery, endoscopic or intravascular treatment. All patients had a complete blood count and fibrinogen concentration measured at enrollment and on days 1 and 2. On each day, a study coordinator personally visited each patient to record any bleeding episodes, including minor bleeding, using a standardized case report form. After discharge, all patients without active cancer were treated with warfarin sodium with a target international normalized ratio (INR) for the prothrombin time between 2 and 3. Patients with active cancer were treated with low-molecular-weight heparin injections. We assessed quality of anticoagulation by the time in therapeutic range (TTR), defined as the percentage of INR measurements that were found to be between 2 and 3 in the time-frame of 1 week after discharge and 90-day follow-up. At 90 days, all survivors returned for measurements to assess for adverse outcomes in the form of venous thromboembolism recurrence, poor functional capacity or poor physical health-related quality of life. All patients had study-funded transthoracic echocardiography, conducted with a specific protocol to assess for right ventricular size, pressure and systolic function. Echocardiograms were interpreted by a board-certified cardiologist who was blinded to treatment and outcome. We assessed for the following adverse outcomes within 90 days: Venous thromboembolism recurrence required image-proven evidence of a new pulmonary arterial filling defect observed on repeat CT pulmonary angiography, or a new deep venous thrombosis observed on compression ultrasound. Poor functional capacity outcome required two components. (i) Right ventricular hypokinesis or dilation (right ventricle > left ventricle in apical four chamber view), or an estimated right ventricular systolic pressure > 45 mmHg, assessed on transthoracic echocardiography. (ii) Exercise intolerance or dyspnea at rest. Exercise intolerance was defined as inability to walk 330 m using the 6-min walk test, performed in accordance with American Thoracic Society guidelines. Severe dyspnea was defined by a New York Heart Association functional class of 3 or 4, assessed by the questionnaire of Kubo et al. 20, 21 Poor physical health-related quality of life outcome required a normalized Physical Component Summary score from the Standard Form 36 (SF 36™) below 30 (i.e. < 2 standard deviations below the normative score of 50) 10, 22. Impact of post-thrombotic syndrome was assessed with the VEINES QOL survey (we planned for a score < 40 to be considered a poor physical health-related outcome) 23. Secondary outcomes measured within 5 days included dependence upon intensive care services, rate of unblinding, rate of hospital discharge, hemoglobin and fibrinogen concentrations, total number of days of minor bleeding, and frequency of all-cause Good Clinical Practice-defined adverse events. Secondary outcomes measured at 90 days included the proportion with a New York Heart Association functional class ≥ 3, and the mean 6-min walk distance, change in pulse oximetry with walking, the mental health component score from the SF-36, the VEINES-QOL score, and the patients' self-assessment of their overall health status on a 1–10 scale, with 1 indicating the worst possible and 10 the best possible health. Summary of the composite criterion standard for an adverse outcome (i) Any PE-related or treatment-related serious adverse outcomes within 5 days of enrollment. (ii) Image-confirmed recurrent PE or deep venous thrombosis within 3 months. (iii) Poor functional capacity at 3 months. (iv) A normalized Physical Component Summary score < 30 from the SF-36. (v) A VEINES QOL score < 40 in patients with known deep venous thrombosis. Patients with an adverse outcome within 5 days were invited to follow-up at 90 days, but each patient was only counted once in the summation of patients with an adverse outcome. Data analysis and sample size Means of continuous data were compared with an unpaired t-test or a paired t-test. Proportions were compared with 95% confidence intervals and P values from the Exact test. Frequencies were tested with Fisher's exact test. The sample size was estimated at 82 per group with complete data to show a 20% increase in the proportion of patients who reach the composite endpoint of a good outcome, with α = 0.05 at a power of 80%. For analysis of the component scale, SF-36 values are presented as raw data and the Mental Component Summary and Physical Component Summary scores are normalized to a mean of 50 with a standard deviation of 10. SF-36 component scores were compared with a two-sided P value for the Z distribution with α = 0.01 to account for multiple comparisons 24. The study was monitored for stopping criteria of harm or benefit using the Lan and DeMets alpha-spending approach 25. Results We recruited patients from August 2008 until October 2012. The database was completed and locked on 15 December 2013, at which time unblinding occurred. Figure 1 shows the Consort diagram for the study. Six hundred and forty-three patients with inclusion criteria were screened and informed consent was obtained in 87 (13.5%). No patient withdrew after informed consent. Randomization allocated 40 patients to tenecteplase and 43 to placebo. Table 1 shows the clinical characteristics of the study population, including the demographic data, frequency of co-morbid conditions and data that indicate the severity of the PE, stratified by treatment group. None of the variables were significantly different between groups, although the data suggest a trend (P < 0.20) with gender, Hispanic ethnicity, malignancy and COPD. Table 1 shows the percentage of the sample who had abnormal echocardiography, and the percentage with abnormal biomarkers BNP and troponin I. The frequency with which these screening tests for severity were performed was: echocardiography in 54 (65%), BNP in 69 (83%) and troponin in 83 (100%). Table 2 shows the breakdown of concomitant limb venous thrombosis stratified by treatment group. There were no significant differences in the frequency or location of deep venous thrombosis between the two groups. Regarding quality of anticoagulation during the 3 months after discharge, patients randomized to tenecteplase had a mean TTR of 48% (SD 24%) and a median TTR of 50% (1st–3rd quartiles, 33–67%). Patients randomized to placebo had a mean TTR of 49% (SD 20%) and a median TTR of 50% (1st–3rd quartiles, 33–60%). Table 1. Patient demographic data, comorbid conditions and severity criteria Clinical finding Placebo Tenecteplase P N = 43 N = 40 Male gender 29 67% 20 50% 0.09 Caucasian race 26 60% 28 70% 0.37 Black race 17 40% 11 28% 0.26 Other race 1 2% 1 3% 0.99 Hispanic ethnicity 5 12% 1 3% 0.11 Surgery within the previous 6 weeks 4 9% 1 3% 0.21 Trauma within the previous 6 weeks 2 5% 3 8% 0.42 Coronary artery disease without myocardial infarction 1 2% 1 3% 0.99 Prior myocardial infarction 2 5% 0 0% 0.24 Systolic heart failure 2 5% 1 3% 0.99 Prior history of PE or DVT 9 21% 6 15% 0.41 Active malignancy* PE, pulmonary embolism; DVT, deep venous thrombosis. *Patient report of ongoing care by an oncologist. †Above the 99th percentile for normal with imprecision coefficient of variability < 10%, 83 patients had troponin performed; ‡> 90 pg mL−1 for brain natriuretic peptide or > 900 pg mL−1 for pro-brain natriuretic peptide, 69 patients had either test performed; §right ventricular hypokinesis on echocardiography, 54 had echocardiography. 4 9% 9 23% 0.08 Malignancy under chemotherapy treatment 0 0% 5 12.5% 0.01 Chronic obstructive pulmonary disease 3 7% 0 0% 0.12 History of asthma 6 14% 4 10% 0.52 Any connective tissue disease 4 9% 4 10% 0.99 Diabetes mellitus 6 14% 4 10% 0.52 Prior stroke 1 2% 0 0% 0.99 Human immunodeficiency virus 0 0% 1 3% 0.99 Body mass index > 40 kg m−2 6 14% 6 15% 0.99 Age > 75 years 4 9% 4 10% 0.99 Pulse oximetry < 94% 30 70% 27 68% 0.99 Pulse rate > 110 beats min−1 12 28% 9 23% 0.47 Systolic blood pressure < 100 mmHg 11 26% 10 25% 0.99 Troponin elevateda PE, pulmonary embolism; DVT, deep venous thrombosis. *Patient report of ongoing care by an oncologist. †Above the 99th percentile for normal with imprecision coefficient of variability < 10%, 83 patients had troponin performed; ‡> 90 pg mL−1 for brain natriuretic peptide or > 900 pg mL−1 for pro-brain natriuretic peptide, 69 patients had either test performed; §right ventricular hypokinesis on echocardiography, 54 had echocardiography. 21 49% 20 50% 0.99 Brain natriuretic peptide elevated‡ PE, pulmonary embolism; DVT, deep venous thrombosis. *Patient report of ongoing care by an oncologist. †Above the 99th percentile for normal with imprecision coefficient of variability < 10%, 83 patients had troponin performed; ‡> 90 pg mL−1 for brain natriuretic peptide or > 900 pg mL−1 for pro-brain natriuretic peptide, 69 patients had either test performed; §right ventricular hypokinesis on echocardiography, 54 had echocardiography. 26 60% 20 50% 0.28 Right ventricular dysfunction on echocardiography§ PE, pulmonary embolism; DVT, deep venous thrombosis. *Patient report of ongoing care by an oncologist. †Above the 99th percentile for normal with imprecision coefficient of variability < 10%, 83 patients had troponin performed; ‡> 90 pg mL−1 for brain natriuretic peptide or > 900 pg mL−1 for pro-brain natriuretic peptide, 69 patients had either test performed; §right ventricular hypokinesis on echocardiography, 54 had echocardiography. 21 49% 18 45% 0.66 Age (years, mean and SD) 54 (14) 57 (14) 0.38 Body mass index (kg m−2) 34 (9) 33 (9) 0.46 Pulmonary arterial systolic pressure (mmHg) 55 (11) 58 (11) 0.36 PE, pulmonary embolism; DVT, deep venous thrombosis. *Patient report of ongoing care by an oncologist. †Above the 99th percentile for normal with imprecision coefficient of variability < 10%, 83 patients had troponin performed; ‡> 90 pg mL−1 for brain natriuretic peptide or > 900 pg mL−1 for pro-brain natriuretic peptide, 69 patients had either test performed; §right ventricular hypokinesis on echocardiography, 54 had echocardiography. Table 2. Frequency and location of concomitant deep venous thrombosis Most proximal location of thrombosis Placebo Tenecteplase Any deep venous thrombosis 21 49% 19 48% Femoral vein 12 28% 8 20% Popliteal vein 8 19% 11 28% Calf vein 6 14% 4 10% Saphenous vein 0 0% 1 3% Axillary vein 2 5% 0 0% Figure 1Open in figure viewerPowerPoint Flow diagram of study enrollment and outcomes. Exclusions (in order of frequency observed): (i) contraindications to fibrinolysis or frailty precluding the 6-min walk test (228, 41%), (ii) investigator unavailable (144, 26%); (iii) clinical care team decided to give fibrinolytics (139, 25%), (iv) creatinine clearance < 30 mL min−1 (22, 4%), (v) other situation precluding follow-up (22, 4%). Table 3 and Fig. 2 show the main results of the study. Three patients treated with placebo had an adverse outcome within 5 days, including one who died from cardiac arrest that was directly attributed to PE, and two who required endotracheal intubation, vasopressor support and catheter thrombectomy. One patient treated with tenecteplase died from intracranial hemorrhage that occurred 5 h after drug administration, representing the only patient with a major bleed that occurred during the 5-day period of surveillance. No patient died in the period between hospital discharge and 90 days. We obtained complete follow-up data on 39/43 survivors from the placebo group (90%) and 37/39 (94%) of the tenecteplase group. Table 3. Breakdown of all adverse outcomes in each treatment group Treatment Within 5 days At 90-day follow-up Death Shock/intubation Recurrent VTE* *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfunction on echocardiography plus either a New York Heart Association functional score ≥ 3 21 or < 330 m walked in 6 min 20). ‡Low perception of wellness by the Physical Component Summary score < 30 from the SF36 survey 22). §None indicates the number of patients with no predefined adverse endpoint at 90-day follow-up. and poor functional capacitya *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfunction on echocardiography plus either a New York Heart Association functional score ≥ 3 21 or < 330 m walked in 6 min 20). ‡Low perception of wellness by the Physical Component Summary score < 30 from the SF36 survey 22). §None indicates the number of patients with no predefined adverse endpoint at 90-day follow-up. and low perception of wellness‡ *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfunction on echocardiography plus either a New York Heart Association functional score ≥ 3 21 or < 330 m walked in 6 min 20). ‡Low perception of wellness by the Physical Component Summary score < 30 from the SF36 survey 22). §None indicates the number of patients with no predefined adverse endpoint at 90-day follow-up. Poor functional capacity† *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfunction on echocardiography plus either a New York Heart Association functional score ≥ 3 21 or < 330 m walked in 6 min 20). ‡Low perception of wellness by the Physical Component Summary score < 30 from the SF36 survey 22). §None indicates the number of patients with no predefined adverse endpoint at 90-day follow-up. and low perception of wellness‡ *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfunction on echocardiography plus either a New York Heart Association functional score ≥ 3 21 or < 330 m walked in 6 min 20). ‡Low perception of wellness by the Physical Component Summary score < 30 from the SF36 survey 22). §None indicates the number of patients with no predefined adverse endpoint at 90-day follow-up. Recurrent VTE* *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfunction on echocardiography plus either a New York Heart Association functional score ≥ 3 21 or < 330 m walked in 6 min 20). ‡Low perception of wellness by the Physical Component Summary score < 30 from the SF36 survey 22). §None indicates the number of patients with no predefined adverse endpoint at 90-day follow-up. and low perception of wellness‡ *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfunction on echocardiography plus either a New York Heart Association functional score ≥ 3 21 or < 330 m walked in 6 min 20). ‡Low perception of wellness by the Physical Component Summary score < 30 from the SF36 survey 22). §None indicates the number of patients with no predefined adverse endpoint at 90-day follow-up. Poor functional capacity† *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfunction on echocardiography plus either a New York Heart Association functional score ≥ 3 21 or < 330 m walked in 6 min 20). ‡Low perception of wellness by the Physical Component Summary score < 30 from the SF36 survey 22). §None indicates the number of patients with no predefined adverse endpoint at 90-day follow-up. only Recurrent VTE only Low perception of wellness‡ *VTE, recurrent venous thromboembolism (two with pulmonary embolism, one with deep venous thrombosis and one with both in the placebo arm and one with deep venous thrombosis in the tenecteplase arm). †Poor functional capacity (right ventricular dysfu