Is there data supporting use of tenecteplase for massive or submassive PE?

What is the data for tenecteplase in pulmonary embolism?

Comment by InpharmD Researcher

While guidelines favor the use of thrombolytic therapy in pulmonary embolism (PE) with hemodynamic instability, there is no consensus on a specific agent, and tenecteplase is not currently approved for the treatment of PE. Evidence shows a reduction in mortality with thrombolytics in high-risk PE, and a recent meta-analysis found tenecteplase led to a significantly increased 30-day survival rate for patients with massive PE compared to anticoagulation without major concern for bleeding complications. However, this mortality benefit was not observed in patients with intermediate-risk PE. Tenecteplase used in the treatment of massive and submassive PE has shown benefits in reduced hospital stay and hemodynamic decompensation in addition to an increased rate of right ventricular function improvement. Due to the lack of head-to-head comparative trials and similar efficacy observed in meta-analyses between alteplase and tenecteplase in the treatment of PE, there is limited evidence to support the use of one agent over another.

Background

According to 2020 American Society of Hematology (ASH) guidelines, thrombolysis therapy in addition to anticoagulation is a reasonable consideration in submassive pulmonary embolism (PE), defined as right ventricular dysfunction without hemodynamic instability. Patients with low bleeding risk, such as younger age, or high decompensation risk due to concurrent cardiopulmonary disease are potential candidates. The guideline does not provide further data or recommendations on different thrombolytic agents being used in practice. In general, systemic thrombolysis is preferred over catheter-directed therapy unless in patients with a high risk of bleeding, contraindications to systemic thrombolytic therapy, and/or persistent hemodynamic instability despite systemic thrombolysis. [1]

The ASH panel reviewed 29 systematic reviews and 26 randomized controlled trials (RCTs; n = 2,787) and concluded that the use of thrombolytic agents in patients with PE and hemodynamic compromise (systolic blood pressure <90 mm Hg or a decrease in systolic blood pressure ≥ 40 mm Hg from baseline) was associated with lower mortality (relative risk [RR] 0.61; 95% confidence interval [CI] 0.40 to 0.94; absolute risk reduction [ARR] 58 fewer per 1.000 patients; 95% CI 9 fewer to 90 fewer). In addition, patients receiving systemic thrombolysis had a lower risk of subsequent PE (RR 0.56; 95% CI 0.35 to 0.91; ARR 7 fewer per 1,000 patients; 95% CI 10 fewer to 2 fewer), but the relative risk of deep vein thrombosis (DVT) was not significantly improved. [1]

The 2019 European Society of Cardiology guidelines recommends rescue thrombolytic therapy for patients who deteriorate hemodynamically (Class I). Detailed definition of hemodynamic instability is listed as follows: cardiac arrest (cardiopulmonary resuscitation needed), obstructive shock (systolic blood pressure [SBP] <90 mmHg or vasopressors required to achieve a BP ≥ 90 mmHg despite adequate filing status and end-organ hypoperfusion), and persistent hypotension (SBP <90 mmHg or SBP drop ≥ 40 mmHg, lasting longer than 15 min and not caused by new-onset arrhythmia, hypovolaemia, or sepsis). The 2019 guideline states that in patients with high-risk PE, mostly in cardiogenic shock, thrombolytic agents are associated with a significant reduction in mortality and recurrent PE combined. However, this favorable outcome is accompanied by a 9.9% rate of severe bleeding and a 1.7% rate of intracranial hemorrhage. In an intermediate-risk PE population with normal BP at presentation, thrombolytic therapy greatly reduces the risk of hemodynamic decompensation or further clinical collapse. Still, the risks of severe intracranial and extracranial bleeding are significantly higher. [2]

Overall, thrombolytic therapy improves pulmonary obstruction, pulmonary artery pressure (PAP), and pulmonary vascular resistance (PVR) compared with heparin alone. The greatest effects are seen if treatment is initiated within 48 hours of symptom onset, but the therapy can still be considered within 6-14 days of symptom onset. Intravenous administration of recombinant tissue-type plasminogen activator (rtPA; 100 mg infused over 2 hours) remains the preferable agent and strategy. On the other hand, tenecteplase even investigated in clinical trials, has not yet been approved for this indication. The authors state the impact of early thrombolysis for (intermediate or high-risk) acute PE on long-term benefits on clinical symptoms, functional limitation, or chronic thromboembolic pulmonary hypertension (CTEPH) is still unclear. [2]

According to 2016 CHEST guidelines, a systemically administered thrombolytic regimen is recommended in patients with acute PE associated with hypotension (e.g., systolic blood pressure <90 mm Hg) who do not have a high bleeding risk. On the other hand, in patients with acute PE without hypotension, the guideline does not recommend thrombolytic therapy. In selected patients with acute PE who continue to deteriorate regardless of the underlying anticoagulant therapy but have yet to develop hypotension and have a low bleeding risk, the panel suggests systemically administered thrombolytic therapy over no such therapy. Preference for a specific agent is not addressed (i.e., tenecteplase or alteplase). [3]

According to a systematic review published in 2016, intravenous thrombolysis or mechanical thrombectomy can be used to treat hemodynamically unstable PE patients. Being a third-generation thrombolytic, tenecteplase is approved for the treatment of acute coronary syndromes. It has also been evaluated in patients with acute PE. While there were no head-to-head comparison trials between thrombolytic agents, there were eight clinical trials that evaluated the effectiveness of thrombolytic agents including tenecteplase in patients with intermediate-risk PE. Overall, thrombolytic agents were found to be associated with lower all-cause mortality compared with anticoagulants (2.17% versus 3.89%, respectively), but they increased the risk of major bleeding (9.24% versus 3.42%) and intracranial hemorrhage (1.46% versus 0.19%). [4]

A recent meta-analysis assessed the efficacy and safety of tenecteplase in patients with PE. A total of six studies (4 RCTs and two cohort studies; N= 2,201) were included in the analysis. Tenecteplase was found to increase the 30-day survival rate for patients with high-risk (i.e., massive) PE compared to anticoagulation (16.6% vs. 6; p= 0.005) without increasing the incidence of bleeding (6% vs. 5%; p= 0.73). For patients with intermediate-risk PE (i.e., submassive), tenecteplase reduced right ventricular insufficiency at 24 hours, and the incidence of hemodynamic failure without affecting mortality in the short- (<30 days; risk ratio [RR] 0.83; 95% CI 0.47 to 1.46) or long-term (≥ 30 days; RR 1.04; 95% CI 0.88 to 1.22). Tenecteplase was, however, associated with higher bleeding risk compared to anticoagulation at <30 days (RR 1.79; 95% CI 1.61 to 2.00). Based on these results, tenecteplase is suggested to be a promising candidate for patients with massive PE. However, tenecteplase is not recommended for patients with intermediate-risk PE due to the higher bleeding risk compared to standard anticoagulation. This meta-analysis is limited by the small number of trials included, indicating a need for further large-scale studies evaluating the safety and efficacy of tenecteplase for massive and submassive PE. [5]

A 2021 Cochrane systematic review and meta-analysis assessing the effects of thrombolytic therapy for acute pulmonary embolism states people in the PEITHO trial treated with tenecteplase for submassive PE had less hemodynamic decompensation, but an increased risk of major hemorrhage and stroke. Additionally, tenecteplase treatment did not affect long-term mortality rates compared to placebo and heparin. Pooled data from two studies comparing tenecteplase plus heparin versus placebo plus heparin found tenecteplase to result in more hemorrhagic stroke compared to heparin following treatment (odds ratio [OR] 7.59, 95% CI 1.38 to 41.72). [6]

Pooled analyses show that fewer hemodynamic decompensation events occurred after thrombolytic therapy (OR 0.26, 95% CI 0.13 to 0.53), which included a study comparing tenecteplase versus heparin. In this same study, the tenecteplase 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). Tenecteplase also was found to reduce echocardiography parameters with small differences in decreases in both the right ventricle end-diastolic dimension and the right-to-left end-diastolic dimension ratio at 24 hours. However, an additional report found no difference in D‐dimer concentrations between the tenecteplase group and the control group at three‐month follow‐up (p= 0.05). A pooled analysis of five studies including one comparing tenecteplase to heparin found evidence to support the thrombolytics group having a shorter hospital stay (mean difference -1.4 days, 95% CI -2.69 to -0.11). Low-certainty evidence suggests that thrombolytics may reduce death following acute pulmonary embolism compared with heparin, but may be helpful in reducing the recurrence of pulmonary emboli. Additionally, thrombolytic therapy may cause more major and minor hemorrhagic events. [6]

In a systematic review and meta-analysis, fifteen randomized controlled studies were reviewed in 2015. The studies compared systemic thrombolytic therapy including tenecteplase plus anticoagulation with anticoagulation alone in patients with acute PE. Thrombolytic therapy was associated with a statistically significant reduction of overall mortality compared with heparin (OR 0.59, 95% CI 0.36 to 0.96). Overall mortality was not statistically significant after the exclusion of studies including patients with high-risk PE (OR 0.64, 95% CI 0.35 to 1.17). [7]

Relevant Prescribing Information

Indication:
TNKase® (Tenecteplase) is indicated for use in the reduction of mortality associated with acute myocardial infarction (AMI). [8]

Pharmacology:
Tenecteplase is a modified form of human tissue plasminogen activator (tPA) that binds to fibrin and converts plasminogen to plasmin. In the presence of fibrin, in vitro studies demonstrate that tenecteplase conversion of plasminogen to plasmin is increased relative to its conversion in the absence of fibrin. Following administration of 30, 40, or 50 mg of TNKase, there are decreases in circulating fibrinogen (4%-15%) and plasminogen (11%-24%). The clinical significance of fibrin-specificity on safety (e.g., bleeding) or efficacy has not been established. Tenecteplase was cleared from the plasma with an initial half-life of 20 to 24 minutes. The terminal phase half-life of Tenecteplase was 90 to 130 minutes. [8]

Adverse Reactions:
The most frequent adverse reaction associated with TNKase is bleeding. For TNKase-treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9% and any stroke was 1.8%. Major bleeding, defined as bleeding requiring blood transfusion or leading to hemodynamic compromise, and minor bleeding had an incidence of 4.7% and 21.8%, respectively, in the ASSENT-2 trial. [8]

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the data for tenecteplase in pulmonary embolism?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-6 for your response.

Comparative Efficacy and Safety of Thrombolytic Agents for Pulmonary Embolism: A Bayesian Network Meta-Analysis
Design	Bayesian network meta-analysis
Objective	To evaluate the efficacy and safety of different thrombolytic agents in the treatment of all types of acute pulmonary embolism (PE): hemodynamically unstable PE (massive PE) and hemodynamically stable PE (submassive PE and low-risk PE)
Included Studies	29 RCTs
Patient Population	N= 3,067
Patient Characteristics	Patients with any type of acute PE treated with thrombolytic and anticoagulant therapy
Outcome Measures	Primary: mortality, recurrent PE, and pulmonary artery systolic pressure (PASP) Secondary: bleeding
Results	Endpoint	RR or mean difference* (95% credible interval)	Alteplase SUCRA	Tenecteplase SUCRA
	Mortality	1.36 (0.34 to 5.41)	38.84	29.89
	Recurrent PE	1.70 (0.29 to 17.62)	74.47	49.46
	PASP	5.99 (-13.60 to 26.02)	69.03	39.78
	Major Bleeding	3.00 (0.77 to 9.17)	64.36	10.49
	Minor Bleeding	1.84 (0.62 to 5.27)	40.01	9.53
	*Tenecteplase vs. alteplase CI, confidence interval; RR, risk ratio; SUCRA, surface under the cumulative ranking curve
Study Author Conclusions	For patients with acute PE, four thrombolytic agents (alteplase, reteplase, streptokinase, and urokinase) appeared to be superior in efficacy compared with anticoagulant alone due to a reduction in mortality and no increase in major and minor bleeding risk. Alteplase may be a better choice compared with anticoagulant alone because it not only reduced mortality but also reduced PE recurrence rate and treated PASP. Tenecteplase did not reduce mortality compared with anticoagulants alone and may not be a good choice of thrombolytic agents due to an increase in minor bleeding compared with streptokinase and anticoagulants alone
InpharmD Researcher Critique	The included studies had a short-term follow-up and did not look into any long-term outcomes in PE patients. Furthermore, a subgroup analysis was not performed for the thrombolytic dose due to the small number of included studies.

References:

Li HY, Wang YB, Ren XY, Wang J, Wang HS, Jin YH. Comparative Efficacy and Safety of Thrombolytic Agents for Pulmonary Embolism: A Bayesian Network Meta-Analysis. Pharmacology. 2023;108(2):111-126. doi:10.1159/000527668

Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism
Design	Randomized, double-blind trial, multicenter N= 1,005
Objective	To compare tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism
Study Groups	Tenecteplase (n= 506) Placebo (n= 499)
Inclusion Criteria	Age of 18 years or older, objectively confirmed acute pulmonary embolism with an onset of symptoms 15 days or less before randomization, right ventricular dysfunction confirmed by echocardiography or spiral computed tomography (CT) of the chest, and myocardial injury confirmed by a positive test for troponin I or troponin T
Exclusion Criteria	Hemodynamic decompensation (or collapse) at presentation; known significant bleeding risk (recent exposure to aspirin or any other antiplatelet therapy was not considered an exclusion criterion); administration of thrombolytic agents within the previous 4 days; vena cava filter insertion or pulmonary thrombectomy within the previous 4 days; uncontrolled hypertension defined as systolic blood pressure >180 mm Hg and/or diastolic blood pressure >110 mm Hg at randomization; known hypersensitivity to tenecteplase, alteplase, unfractionated heparin, or to any of the excipients; pregnancy, lactation or parturition within the previous 30 days; known coagulation disorder (including treatment with vitamin K antagonists and a platelet count lower than 100,000/mm3)
Methods	A single weight-based intravenous bolus (given over a period of 5 to 10 seconds) of the fibrinolytic agent tenecteplase was given. The dose ranged from 30 mg to 50 mg, depending on body weight (< 60 kg 30 mg; ≥ 60 to < 70 kg 35 mg; ≥ 70 to < 80 kg 40 mg; ≥ 80 to < 90 kg 45 mg; ≥ 90 kg 50 mg). The administration of unfractionated heparin (UFH) was started as an intravenous bolus immediately after randomization in both groups. The initial bolus of UFH was omitted in patients receiving a therapeutic dose of low-molecular-weight heparin or fondaparinux, and the start of the infusion was delayed until 12 hours after the last injection of low-molecular-weight heparin or until 24 hours after the last injection of fondaparinux. The heparin infusion rate was adjusted to achieve and maintain an activated partial thromboplastin time that was 2.0 to 2.5 times the upper limit of the normal range, corresponding to therapeutic heparin levels (equivalent to factor Xa inhibition of 0.3 to 0.7 IU per milliliter). The use of anticoagulant agents other than UFH was not allowed until 48 hours after randomization.
Duration	From November 2007 through July 2012 30 days
Outcome Measures	Primary outcome: death or hemodynamic decompensation (or collapse) within 7 days after randomization Secondary outcomes: death within 7 days after randomization, hemodynamic decompensation within 7 days, confirmed symptomatic recurrence of pulmonary embolism within 7 days, death within 30 days, and major adverse events within 30 days Safety outcomes: ischemic or hemorrhagic stroke (including hemorrhagic conversion of ischemic stroke) within 7 days after randomization, extracranial major (moderate or severe) bleeding within 7 days, and serious adverse events within 30 days
Baseline Characteristics		Tenecteplase (n= 506)		Placebo (n= 499)
	Age, years	66.5 ± 14.7		65.8 ± 15.9
	Male	242 (47.8%)		231 (46.3%)
	Weight, kg	82.5 ± 17.9		82.6 ± 18.2
	Clinical Status Systolic blood pressure, mm Hg Heart rate, beats/min Respiratory rate, breaths/min Oxygen treatment	130.8 ± 18.3 94.5 ± 17.1 21.8 ± 5.8 436 (86.2%)		131.3 ± 18.5 92.3 ± 16.7 21.6 ± 5.7 421 (84.4%)
	Medical History Previous venous thromboembolism Immobilization Active cancer Chronic pulmonary disease	126 (24.9%) 55 (10.9%) 41 (8.1%) 26 (5.1%)		147 (29.5%) 56 (11.2%) 32 (6.4%) 34 (6.8%)
Results		Tenecteplase (n= 506)	Placebo (n= 499)	Odds Ratio (95% CI)	p-value
	Primary outcome	13 (2.6%)	28 (5.6%)	0.44 (0.23-0.87)	0.02
	Death from any cause	6 (1.2%)	9 (1.8%)	0.65 (0.23-1.85)	0.42
	Hemodynamic decompensation	8 (1.6%)	25 (5%)	0.30 (0.14-0.68)	0.002
	Time between randomization and primary efficacy outcome, days	1.54 ± 1.71	1.79 ± 1.60
	Recurrent pulmonary embolism between randomization and primary day 7 Fatal Nonfatal	1 (0.2%) 0 1 (0.2%)	5 (1%) 3 (0.6%) 2 (0.4%)	0.20 (0.02-1.68) -- --	0.12 -- --
	Other in-hospital complications and procedures Mechanical ventilation Surgical embolectomy Catheter thrombus fragmentation vena cava interruption Thrombolytic treatment other than study medication	8 (1.6%) 1 (0.2%) 1 (0.2%) 5 (1.0%) 4 (0.8%)	15(3%) 2(0.4%) 0 1(0.2%) 23(4.6%)	--	--
	Death from any cause between randomization and day 30	12 (2.4%)	16 (3.2%)	0.73 (0.34-1.57)	0.42
Adverse Events	Bleeding between randomization and day 7: Major extracranial bleeding: 6.3% vs. 1.2% (odds ratio 5.55; 95% CI 2.3 to 13.39; p < 0.001) Minor bleeding: 32.6% vs. 8.6% Major bleeding: 11.5% vs. 2.4% Stroke between randomization and day 7: 2.4% vs. 0.2% (odds ratio 12.10; 95% CI 1.57 to 93.39; p= 0.003) Hemorrhagic stroke: 2% vs. 0.2%
Adverse Events	Serious adverse events between randomization and day 30: 10.9% vs. 11.8% (odds ratio 0.91; 95% CI 0.62 to 1.34; p= 0.63)
Study Author Conclusions	In normotensive patients with intermediate-risk pulmonary embolism, the composite primary outcome of early death or hemodynamic decompensation was reduced after treatment with a single intravenous bolus of tenecteplase. However, tenecteplase was also associated with a significant increase in the risk of intracranial and other major bleeding. Therefore, great caution is warranted when considering fibrinolytic therapy for hemodynamically stable patients with pulmonary embolism, right ventricular dysfunction, and a positive cardiac troponin test.
InpharmD Researcher Critique	The study was not powered to detect differences in rates of death, which occurred relatively infrequently in the two treatment groups. Moreover, the definition of hemodynamic decompensation or collapse included a persistent, isolated drop in systolic blood pressure, which could be of questionable clinical significance. A lower-dose strategy, reduced by 50% in patients ≥ 75 years, utilized in one published trial in patients with ST-segment elevation myocardial infarction could be potentially implemented in this study to decrease the risk of severe bleeding.

References:

Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. doi:10.1056/NEJMoa1302097

Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism (PE)
Design	Multi-center, double-blind, placebo-controlled, randomized trial N= 709
Objective	To investigate the long-term prognosis of patients with intermediate-risk pulmonary embolism (PE) and the effect of thrombolytic treatment on the persistence of symptoms or the development of late complications
Study Groups	Tenecteplase (n= 359) Placebo (n= 350)
Inclusion Criteria	Age 18 years or older, objectively confirmed with acute PE with first symptoms 15 days or less before randomization, right ventricular (RV) dysfunction confirmed by echocardiography or spiral computed tomography of the chest, myocardial injury confirmed by a positive troponin I or T test result
Exclusion Criteria	Hemodynamic collapse at presentation, known significant bleeding risk, administration of thrombolytic agents within the previous 4 days, uncontrolled hypertension defined as systolic blood pressure >180 mm Hg and/or diastolic blood pressure >110 mm Hg at randomization
Methods	Patients were randomized (1:1) to receive tenecteplase or placebo. Patients randomized to tenecteplase received a single weight-based intravenous bolus (administered over 5 to 10 seconds). Patients randomized to placebo received a single intravenous bolus of the same volume and appearance. Unfractionated heparin was started in both arms as an intravenous bolus followed by infusion at a rate adjusted to achieve and maintain an activated partial thromboplastin time of 2.0 to 2.5 times that of control. Treatment with anticoagulant agents was allowed 48 hours after randomization.
Duration	November 2007 through July 2012 Follow-up: 30 days
Outcome Measures	Primary outcome: clinical composite of all-cause death or hemodynamic decompensation (or collapse) at day 30 Secondary outcome: death from hemodynamic collapse, bleeding, stroke, PE recurrence at day 30
Baseline Characteristics		Tenecteplase (n= 359)	Placebo (n= 350)
	Age, years	66.7 ± 15.1	66.4 ± 16
	Male	169 (47.1 %)	159 (45.4 %)
	Weight, kg	82.6 ± 18.7	81 ± 17.1
	Systolic blood pressure, mm Hg	130.6 ± 17.9	132.3 ± 18.4
	Heart rate, beats/min	94.9 ± 17.2	91.5 ± 16.7
	Respiratory rate, respirations/min	21.8 ± 5.8	21.7 ± 5.6
	Oxygen treatment	315 (87.7 %)	298 (85.1 %)
	Chronic pulmonary disease	20 (5.6 %)	21 (6 %)
	Chronic heart failure	18 (5 %)	20 (5.7 %)
	Previous venous thromboembolism	84 (23.4 %)	93 (26.6 %)
	Surgery or major trauma in the previous month	26 (7.2 %)	21 (6 %)
Results	Endpoint	Tenecteplase (n= 359)	Placebo (n= 350)	p-value
	Clinical composite of all-cause death between randomization and day 30 Hemodynamic collapse Stroke Recurrent pulmonary embolism Respiratory failure Extracranial bleeding	8 (2.2 %) 1 (0.3 %) 4 (1.1 %) 0 (0 %) 0 (0 %) 1 (0.3 %)	10 (2.9 %) 1 (0.3 %) 0 (0 %) 2 (0.6 %) 2 (0.6 %) 0 (0 %)	0.595 N/A N/A N/A N/A N/A
	Death from any cause between day 30 and long-term follow up Stroke Acute myocardial infarction Respiratory failure Bleeding Chronic heart failure	65 (18.1 %) 1 (0.3 %) 0 (0 %) 2 (0.6 %) 0 (0 %) 1 (0.3 %)	53 (15.1 %) 2 (0.6 %) 1 (0.3 %) 1 (0.3 %) 1 (0.3 %) 0 (0 %)
	Long-term follow-up did not reveal significant differences between the 2 treatment arms regarding the presence of residual pulmonary hypertension or RV dysfunction.
Adverse Events	Common Adverse Events: N/A
	Serious Adverse Events: N/A
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	Thrombolytic treatment with tenecteplase did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea, functional limitation, or persisting RV dysfunction, which were mostly mild in both treatment arms. These results suggest that future trials investigating advanced reperfusion regimens and modalities for acute PE should primarily focus on early efficacy and, particularly, safety outcomes while also prospectively including an adequately long period of prospective follow-up that will permit the assessment of the patients’ clinical and hemodynamic course as well as their functional status and quality of life.
InpharmD Researcher Critique	Long-term follow-up was conducted in only 28 out of the 76 sites (approximately two-thirds of the entire randomized population), the causes of late death (beyond the first 30 days) were not determined in all cases, and clinical and echocardiographic examinations could not be performed in all survivors.

References:

Konstantinides SV, Vicaut E, Danays T, et al. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol. 2017;69(12):1536-1544. doi:10.1016/j.jacc.2016.12.039

Treatment of Submassive Pulmonary Embolism with Tenecteplase or Placebo: Cardiopulmonary Outcomes at 3 months: Multicenter Double-blind, Placebo-controlled Randomized trial
Design	Multicenter, double-blind, placebo-controlled randomized trial N= 83
Objective	To test if tenecteplase increases the probability of a favorable composite patient-oriented outcome after submassive pulmonary embolism (PE)
Study Groups	Treatment (n= 40) Placebo (n= 43)
Inclusion Criteria	Age > 17 years with PE diagnosed on computed tomographic pulmonary angiography performed within 24 hours and normal arterial systolic blood pressure with evidence of right ventricular strain manifested by hypokinesis on echocardiography, elevated troponin I or T using local thresholds (values exceeding the 99 percentile with a coefficient of variability < 10%) or brain natriuretic peptide (BNP) measurement > 90 pg/mL to NT-proBNP > 900 pg/mL (not more than 6 hours prior to CT angiography and not more than 30 hours before enrollment)
Exclusion Criteria	Patients with systolic blood pressure <90 mmHg, a do not resuscitate or do not intubate order, systemic fibrinolytic treatment within previous 7 days, documented GI bleeding within previous 30 days, or active hemorrhage in any of the following sites at the time of enrollment: intraperitoneal, retroperitoneal, pulmonary, uterine, bladder, or nose; head trauma causing loss of consciousness within previous 7 days, any history of hemorrhagic stroke, ischemic stroke within the past year, prior history of heparin-induced thrombocytopenia, history of intraocular hemorrhage, intracranial metastasis, known inherited bleeding disorder (i.e. hemophilia, platelet count < 50,000/uL, prothrombin time abnormal [INR > 1.7]); chest, abdominal, intracranial, or spinal surgery within the previous 14 days; current treatment with fondaparinux, direct thrombin inhibitor or administration of a glycoprotein inhibitor within the previous 48 hours *Note, exclusion criteria came from a 2013 study: “Rationale and methodology for a multicentre randomized trial of fibrinolysis for pulmonary embolism that includes quality of life outcomes.”
Methods	After informed consent, all patients were treated with full-dose low-molecular-weight heparin (LMWH), 1 mg/kg enoxaparin, or dalteparin 200 units/kg subcutaneously prior to injection of study drug or placebo. If the patient was receiving unfractionated heparin, it was discontinued and LMWH was started. Study group assignment occurred by a predetermined, blocked permuted 1:1 randomization to either placebo or tenecteplase in 0.9% saline in an opaque syringe. Patients received tiered dose tenecteplase. LMWH was continued for the remainder of the hospital stay. Depending on the site, the clinical care team could unblind the randomization assignment by either opening the envelope or calling the research pharmacy only if absolutely necessary for emergent treatment decisions. After discharge, all patients without active cancer were treated with warfarin, and patients with cancer were treated with low-molecular-weight heparin. At 90 days, all survivors returned for measurements.
Duration	August 2008 to December 2013
Outcome Measures	Five-day adverse outcomes from PE: death, circulatory shock, or need for intubation Five-day adverse outcomes from treatment: death from hemorrhage, any intracranial or intraspinal hemorrhage, active bleeding with >2 g/dL drop in hemoglobin within 24 hours requiring transfusion, and any bleeding that required surgery, endoscopic or intravascular treatment
Baseline Characteristics		Placebo (n= 43)	Tenecteplase (n= 40)	p-value
	Male	29 (67%)	20 (50%)	0.09
	White	26 (60%)	28 (70%)	0.37
	Surgery within the previous 6 weeks	4 (9%)	1 (3%)	0.21
	Prior history of PE or DVT	9 (21%)	6 (15%)	0.41
	Active malignancy	4 (9%)	9 (23%	0.08
	Malignancy under chemotherapy treatment	0 (0%)	5 (12.5%)	0.01
	Pulse rate > 110 beats min-1	12 (28%)	9 (23%)	0.47
	Systolic blood pressure < 100 mmHg	11 (26%)	10 (25%)	0.99
	Troponin elevated	21 (49%)	20 (50%)	0.99
	Brain natriuretic peptide elevated	26 (60%)	26 (60%)	0.28
	Right ventricular dysfunction on echocardiography	21 (49%)	18 (45%)	0.66
Results	Endpoint	Placebo (n= 43)	Treatment (n= 40)
	Within 5 days
	Death	1	1
	Shock/intubation	2	0
	At 90-day follow-up
	VTE and poor functional capacity and low perception of wellness	1	0
	Poor functional capacity and low perception of wellness	5	1
	Recurrent VTE and low perception of wellness	2	0
	Poor functional capacity only	2	3
	Recurrent VTE only	1	1
	Low perception of wellness only	2	0
	None	27	34
Adverse Events	Common Adverse Events: 30% placebo group developed a study-defined adverse outcome and 5% treated with tenecteplase within 5 days. 37% placebo group and 15% had an adverse outcome (this includes the within 5 days groups).
	Serious Adverse Events: 2 patients in the placebo and two patients in the treatment group had serious Adverse Events which needed unbinding.
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	Patients with submassive PE treated with single bolus of tenecteplase had a modestly increased probability of a good functional outcome.
InpharmD Researcher Critique	The authors suggest that although there are good outcomes, the sample size is too small in assessing whether tenecteplase increases the risk of intracranial hemorrhage. This study was terminated early, which makes the final results not very trustworthy. The authors stated that they should have measured right ventricular pressure during exercise since their original prediction was that quality of life improvements would be associated with improved right ventricular function, but no difference was made. This shows that some of these hypotheses and tests were not well thought out ahead of time.

References:

Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost. 2014;12(4):459-468. doi:10.1111/jth.12521

Efficacy and Safety of Thrombolytic Therapy in Acute Submassive Pulmonary Embolism: Follow-Up Study
Design	Single-center, prospective, randomized study N= 86
Objective	To study the impact of thrombolytic therapy in acute submassive pulmonary embolism (PE) in terms of mortality, hemodynamic status, improvement in right ventricular function, and safety in terms of major and minor bleeding
Study Groups	Group I (n=45) received a single weight-adjusted does of tenecteplase over five to ten seconds Group II (n= 41) received the same volume of normal saline placebo
Inclusion Criteria	Patients 18 to 75 years old with acute PE symptoms occurring within 14 days of presentation that had evidence of right ventricular dysfunction (diagnosed by echocardiography) and/or biochemical evidence of myocardial injury confirmed by contrast-enhanced computed tomography pulmonary angiogram
Exclusion Criteria	Symptoms of PE occurring greater than 14 days before presentation, age less than 18 or greater than 75 years, known hypersensitivity to streptokinase, tenecteplase, or heparin, uncontrolled hypertension (defined as systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 110 mmHg at presentation), systolic blood pressure < 90 mmHg for more than 15 minutes at presentation, known coagulation disorder or use of a vitamin K antagonist, platelet count < 100,000/mm³, known intracranial neoplasm, history of hemorrhagic stroke, or history of ischemic stroke in the past year, and/or active peptic ulcer or bleeding excluding menstruation
Methods	Patients who met the inclusion criteria were enrolled and evaluated using ECG, cardiac enzyme analysis, VIVID 2D echocardiogram, and CT pulmonary angiogram for diagnosis. To assess for pulmonary artery systolic pressures (PASPs) and right ventricular (RV) function, echocardiograms were repeated on day 7 after enrollment. Within one hour of presentation, patients were randomized to Group I (n=45) who received a single weight-adjusted does of tenecteplase over five to ten seconds or Group II (n= 41) received the same volume of normal saline placebo. Both groups received unfractionated heparin (UFH), with group I receiving only infusion UFH and group II received a bolus dose and infusion UFH to maintain a partial activated thromboplastin time (APTT) of 2.0-2.5 times the upper limit of normal. Patients were discharged when they were asymptomatic, with systolic blood pressure over 100 mmHg, and with no active bleeding.
Duration	January 2012 and July 2015
Outcome Measures	Primary efficacy outcome: Composite of death from any cause and hemodynamic decompensation (need for cardiopulmonary resuscitation, SBP < 90 mmHg or >40 mmHg for 15 minutes of more with end-organ hypoperfusion or need for vasopressors) or collapse within 7 days of randomization Secondary outcomes: Composite of the primary outcome and symptomatic reoccurrence of PE within seven days, and/or death or hospitalization within 30 days Safety outcomes: Ischemic or hemorrhagic stroke within seven days of randomization or extracranial major bleeding within seven days of randomization
Baseline Characteristics		Group I (n= 45)	Group II (n= 41)	p-Value
	Age, years	54.35 ± 12.1	55.12 ± 11.7	0.2
	Female	14	12	0.4
	Risk factors Smoking Immobilization Surgery/Major Trauma	13 (28%)	12 (29%)	0.32
		11 (24%)	11 (26%)	0.22
		7 (16%)	6 (14%)	0.5
	Mean RV/LV size ratio	1.14 ± 0.11	1.16 ± 0.14	0.08
	Troponin T elevation	34 (75%)	28 (70%)	0.2
	Troponin I elevation	25 (55%)	26 (65%)	0.4
	PASP, mmHg	48.90 ± 3.0	49.21 ± 3.09	0.6
	No baseline characteristics differed among the groups. However, more males were in the study than females.
Results	Endpoint	Group I (n= 45)	Group II (n= 41)	p-Value
	Primary composite outcome within 7 days	2 (4.5%)	8 (20%)	0.04
	All-cause death	2 (4.5%)	2 (5%)	0.3
	Hemodynamic decompensation	2 (4.5%)	8 (20%)	0.04
	Mean PASP at day seven, mmHg	32.80 ± 4.02	38.13 ± 4.49	0.04
	Mean ↓ in PASP from baseline, mmHg	14.10 ± 3.95	11.08 ± 4.23	0.003
	Improvement in RV function	31 (70%)	16 (40%)	0.001
	Mean days of hospital stay	8.1 ± 2.51	11.1 ± 2.14	0.001
	Minor bleeding within 7 days	7 (16%)	5 (12%)	0.04
	No other outcomes differed significantly among the groups.
Adverse Events	Common Adverse Events: N/A
	Serious Adverse Events: N/A
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	Patients with acute submassive PE do not derive overall mortality benefit, recurrent PE and rehospitalization with thrombolytic therapy but had improved clinical course in form of decrease in hemodynamic decompensation, mean hospital stay, PASP and improvement of RV function at the cost of increased minor bleeding.
InpharmD^TM Researcher Critique	This study was small, with a sample size of only 86 patients, and primarily evaluated the effects of tenecteplase in male patients with PE. The researchers found clinical improvements with reduction of hemodynamic decompensation and shorter hospital stay in the group treated with tenecteplase, but the generalizability of these findings is limited because of its study population and small sample size.

References:

Sinha SK, Sachan M, Goel A, et al. Efficacy and Safety of Thrombolytic Therapy in Acute Submassive Pulmonary Embolism: Follow-Up Study. J Clin Med Res. 2017;9(2):163-169. doi:10.14740/jocmr2829w

Tenecteplase compared with streptokinase and heparin in the treatment of pulmonary embolism (PE): an observational study
Design	Single-center, observational study N= 103
Objective	To compare the efficacy and safety of tenecteplase with streptokinase and heparin
Study Groups	Tenecteplase (n= 62) Streptokinase (n= 17) Heparin (n= 24)
Inclusion Criteria	Age >18 years of age, diagnosed with PE, treated with tenecteplase, streptokinase, or heparin were included for analysis.
Exclusion Criteria	Patients with active visceral bleeding or spontaneous intracranial hemorrhage or those with a history of cardiopulmonary resuscitation, chronic pulmonary hypertension, or severe COPD, patients with minimally controlled severe hypertension or diabetic hemorrhagic retinopathy
Methods	Tenecteplase was given as an intravenous weight-adjusted bolus over 5 seconds at a dose ranging from 30 to 50 mg (0.5 mg/kg), with a 5 mg step-up for every 10 kg increase from 60 to 90 kg. Streptokinase was infused as a loading dose of 250,000 units into a peripheral vein over 30 min followed by 100,000 units/h for 24 h (72 h if concurrent deep vein thrombosis [DVT] was suspected). Unfractionated heparin was administered intravenously as an initial bolus of 80 U/kg or 5,000 U followed by an infusion of 18 U/kg/h or 1,300 U/h until the patient's condition was stabilized. Patients with a confirmed diagnosis of PE were classified as massive if there was evidence of hemodynamic compromise (defined as systolic blood pressure < 90mmHg) and as submassive if there was right ventricular dysfunction on echocardiography with no hemodynamic compromise. Patients without any evidence of these features were labeled as minor PE cases. Bleeding was classified as major if there was any intracranial bleeding or overt bleeding with a decrease in hemoglobin ≥ 3 g/dL.
Duration	January 2008 through December 2014 Follow up: 180 days
Outcome Measures	Primary efficacy outcome: death from any cause within 7 days of treatment Secondary outcome: death within 180 days, changes in prognostic factors after the therapy such as dyspnoea, blood pressure, heart rate, right bundle branch block (RBBB), and oxygen saturation (SaO₂) at 7 days and 180 days
Baseline Characteristics		Tenecteplase (n= 62)	Streptokinase (n= 17)	Heparin (n= 24)
	Age, years	50.17 ± 14.74	47.11 ± 15.33	52.83 ± 19
	Male	40 (64.5 %)	12 (70.5 %)	14 (58.3 %)
	Body mass index, kg/m²	30.18 ± 5.7	24.06 ± 2.64	26.11 ± 3.33
	Predisposing factors History of DVT Smoking Surgery Hospitalization Malignancy	29 (46.77 %) 7 (11.2 %) 9 (14.5 %) 31 (50 %) 6 (9.6 %)	8 (47.06 %) 3 (17.6 %) 2 (11.76 %) 6 (35.29 %) 0 (0 %)	13 (54.17 %) 3 (12.5 %) 3 (12.5 %) 15 (62.5%) 5 (20.83)
Results	Endpoint	Tenecteplase (n= 62)	Streptokinase (n= 17)	Heparin (n= 24)
	Death from any cause Within 7 days Within 180 days	3 (4.84 %) 6 (9.67 %)	1 (5.88 %) 2 (11.76 %)	2 (8.33 %) 3 (12.5 %)
	Dyspnea Pre Post Day 7 6 months	60 (96.77 %) 35 (56.45 %) 0 (0 %) 3 (4.84 %)	15 (88.23 %) 9 (52.94 %) 1 (5.88 %) 2 (11.76 %)	22 (91.67 %) 16 (66.67 %) 1 (4.17 %) 2 (8.33 %)
	RBBB Pre Post Day 7	11 (17.74 %) 1 (1.61 %) 0 (0 %)	6 (35.29 %) 2 (11.76 %) 2 (11.76 %)	1 (4.17 %) 0 (0 %) 1 (4.17 %)
	Heart rate, beat/min Pre Post Day 7 6 months	108.34 ± 22.12 84.21 ± 18.10 79.45 ± 10.04 78.11 ± 7.02	107.56 ± 17.32 98.54 ± 7.23 92.08 ± 10.34 89.32 ± 11.21	101.41 ± 23.91 90.77 ± 16.21 90.23 ± 10.08 87.58 ± 8.32
	Systolic blood pressure, mmHg Pre Post Day 7 6 months	118.01 ± 23.21 128.41 ± 20.05* 129.30 ± 13.45 * 128.31 ± 13.98*	124.46 ± 16.10 127.31 ± 17.97 126.02 ± 16.54 122.58 ± 16.21	126.21 ± 27.78 124.43 ± 24.05 126.91 ± 21.04 124.44 ± 18.23
	Diastolic blood pressure, mmHg Pre Post Day 7 6 months	79.05 ± 14.23 79.68 ± 11.68 80.01 ± 9.41 81.28 ± 10.56	77.06 ± 10.53 79.57 ± 10.99 78.33 ± 10.54 80.45 ± 13.87	80.07 ± 11.23 86.34 ± 8.09 82.78 ± 9.45 80.77 ± 10.24
	SaO_2^* Pre Post Day 7 6 months	88.79 ± 10.03 96.90 ± 4.10 97.46 ± 2.00* 97.91 ± 1.70*	91.90 ± 4.10 94.90 ± 2.31 92.72 ± 2.00 90.09 ± 8.50	91.4 ± 3.38 92.75 ± 2.75 90.25 ± 1.65 91.83 ± 1.74
	* p < 0.05 compared to baseline value Primary outcome: The difference between treatment groups was non-significant (p > 0.05) at both time points. Seconday outcome: All three treatment groups showed significant improvement in the rate of dyspnea at all evaluations compared with baseline data (p < 0.05).
Adverse Events	Common Adverse Events: Bleeding complications were noted on day 7 after treatment. The incidence of overall bleeding in the three groups was comparable: tenecteplase (3.2%), streptokinase (5.88%), and heparin (4.17%).
	Serious Adverse Events: No intracranial bleeding or fatal bleeding episode was observed in either group.
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	Tenecteplase was found to be effective in patients with PE irrespective of their clinical status and no major adverse events were noted.
InpharmD Researcher Critique	Due to the observational nature of the study, there was no control on treatment assignment or on the number of patients in each treatment group. There was an unequal number of patients in each treatment group and impacted the results of the study.

References:

Agrawal A, Kamila S, Donepudi A, Premchand R. Tenecteplase compared with streptokinase and heparin in the treatment of pulmonary embolism: an observational study. J Drug Assess. 2017;6(1):33-37. Published 2017 Jan 3. doi:10.1080/21556660.2017.1419957