Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: Rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial

doi:10.1016/j.ahj.2011.10.003

American Heart Journal

Volume 163, Issue 1, January 2012, Pages 33-38.e1

https://doi.org/10.1016/j.ahj.2011.10.003 Get rights and content

Background

In acute pulmonary embolism (PE), overt right ventricular (RV) failure with cardiogenic shock indicates a poor prognosis. However, normotensive patients with acute RV dysfunction on echocardiography or computed tomography and with myocardial troponin elevation may also have an adverse outcome. Thrombolysis rapidly reverses RV pressure overload in PE, but it remains unclear whether it may improve the early and long-term clinical outcome of selected normotensive patients.

Design

The Pulmonary EmbolIsm THrOmbolysis (PEITHO) trial is a prospective, multicenter, international, randomized (1:1), double-blind comparison of thrombolysis with tenecteplase vs placebo in normotensive patients with confirmed PE, an abnormal right ventricle on echocardiography or computed tomography, and a positive troponin I or T test result. Both treatment groups receive standard anticoagulation. The primary efficacy outcome is the composite of death from any cause or hemodynamic collapse within 7 days of randomization. Safety outcomes include ischemic/hemorrhagic strokes and other major bleeding episodes. In addition, 180-day clinical and echocardiographic follow-up will be performed. The study is expected to enroll approximately 1,000 patients.

Conclusions

By determining the benefits vs risks of thrombolysis in submassive or intermediate-risk PE, this trial is expected to answer a long-standing query on the management of this patient population.

Section snippets

Background and rationale

Acute venous thromboembolism occurs frequently and causes death and disability.¹ Registries conducted 2 decades ago reported an incidence ranging between 23 and 69 cases per 100,000 patients per year.2, 3 More recently, an epidemiologic model derived from data across 6 European countries with a total population of 310.4 million yielded a pulmonary embolism (PE) attack rate of 98 cases per 100,000 person-years.⁴ The estimated number of fatalities related to venous thromboembolism was 370,000, or

Objectives of the trial

The primary objective of the PEITHO trial is to demonstrate the superiority (ie, the clinical benefit) of thrombolysis with tenecteplase as opposed to placebo in normotensive patients with acute PE, if they have evidence of RV dysfunction on echocardiography or computed tomography of the chest and, in addition, evidence of myocardial injury/necrosis as indicated by a positive cardiac troponin I or T test result. All patients receive standard anticoagulation as indicated.15, 22

The secondary

Patient population and study design

The inclusion and exclusion criteria of the PEITHO trial (ClinicalTrials.gov identifier NCT00639743) are listed in Table I; the flow diagram is displayed in Figure 1. In a patient with confirmed acute PE, randomization should occur no later than 2 hours after the diagnosis of RV dysfunction and myocardial injury. A single intravenous bolus of tenecteplase (fibrinolytic treatment arm; group A) or placebo (reference treatment arm; group B), adapted for known or estimated body weight, is

Outcomes

The primary efficacy outcome is the composite of death from any cause or hemodynamic collapse within 7 days of randomization. Hemodynamic collapse is defined as at least 1 of the following: (i) the need for cardiopulmonary resuscitation; (ii) systolic blood pressure <90 mm Hg for at least 15 minutes, or drop of systolic blood pressure by at least 40 mm Hg for at least 15 minutes, with signs of end-organ hypoperfusion (cold extremities, or urinary output <30 mL/h, or mental confusion); (iii) the

Long-term follow-up

The patient's vital status will be recorded 6 months after randomization. This may be done by an appointment at the clinic or, in case of death, by contact (via telephone or mail) with the patient's family or physician. The follow-up can be done between days 180 and 210, but the status must be given for day 180 after randomization. If follow-up is done earlier, a repeated contact with the patient must be made on or after day 180. Recorded data include the following: (1) in case of death, the

Statistical analysis

The PEITHO trial is a prospective, multicenter, international, randomized (1:1), double-blind, parallel group comparison. The aim is to demonstrate the superiority of tenecteplase over placebo with regard to the primary composite end point, that is, death or hemodynamic collapse at 7 days. Null and alternative hypotheses are as follows: H₀: 7-day-death-hemcol_tenect = 7-day-death-hemcol_placebo vs H₁: 7day-death-hemcol_tenect ≠ 7day-death-hemcol_placebo (where hemcol stands for hemodynamic

Measures against bias

A computer-generated randomization scheme is used. Randomization is stratified by center and, within the centers, performed in blocks of 4 to ensure balanced distribution of the treatment groups. Randomization is performed centrally via the Internet, and treatment allocation is concealed from all investigators. In the ITT analysis, missing data for the primary outcome will be imputed according to the worst-case principle (end point reached). In case of large differences between per-protocol and

Sample size/power calculations

Based on a meta-analysis of previous thrombolysis trials²¹ and on the largest randomized PE trial to date,²³ it is estimated that the primary end point (death or hemodynamic collapse within 7 days) in the control group will be approximately 7%. A 2-group χ² test (not continuity recorded) with a .047 2-sided significance level will have 80% power to detect the difference between a group placebo proportion, π₁, of 0.070 and a group tenecteplase proportion, π₂, of 0.030 (odds ratio of 0.411) when

Administrative organization

The PEITHO is an independent, investigator-initiated trial with an academic sponsor (Département de la Recherche Clinique, Assistance Publique-Hôpitaux de Paris, France). The Steering Committee (listed in the online Appendix) consists of the study chairperson, the co-chairperson, and the principal investigators who act as national coordinators for each of the participating countries. Furthermore, nonvoting members include a representative of the Sponsor and representatives of the market

Sources of funding

The study is being supported by public funding, specifically by grants from the French Government (Ministry of Health) and the German Government (Federal Ministry of Education and Research). In addition, the Sponsor has obtained the study drug (tenecteplase and placebo) and a grant from the MAH. The MAH is also involved in safety reporting to local authorities as per regulations (except for France, where this is entirely the responsibility of the Sponsor). According to the study protocol and as

Conclusions

With an expected enrollment of approximately 1,000 patients, PEITHO will be the largest thrombolysis trial ever performed in patients with acute PE. As of September 30, 2011, 793 patients have been enrolled in the study. A confirmation of the study hypothesis will help to expand the use of thrombolysis to normotensive patients who present with findings of acute RV dysfunction and myocardial injury. This increased use of thrombolysis may reduce the number of deaths or complications from PE. In

Disclosures

The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.

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Cited by (108)

Inhibition of thrombin-activatable fibrinolysis inhibitor via DS-1040 to accelerate clot lysis in patients with acute pulmonary embolism: a randomized phase 1b study
2023, Journal of Thrombosis and Haemostasis
The optimal treatment of intermediate-risk pulmonary embolism (PE) in hemodynamically stable patients remains unknown. Fibrinolytics reduce the risk of hemodynamic deterioration but increase bleeding risk. DS-1040, an inhibitor of thrombin-activatable fibrinolysis inhibitor, enhanced endogenous fibrinolytic activity without increasing bleeding risk in preclinical studies.
To evaluate the tolerability and explore the efficacy of DS-1040 in patients with acute PE.
In this multicenter, randomized, double-blind, placebo-controlled study, ascending doses of intravenous DS-1040 (20-80 mg) or placebo were added to enoxaparin (1 mg/kg twice daily) in patients with intermediate-risk PE. The primary endpoint was the number of patients with major or clinically relevant nonmajor bleeding. The percentage change in thrombus volume and right-to-left ventricular dimensions, assessed using quantitative computed tomography pulmonary angiography, at baseline and after 12 to 72 hours were used to explore the efficacy of DS-1040.
Of 125 patients with all available data, 38 were randomized to placebo and 87 to DS-1040. The primary endpoint occurred in 1 patient in the placebo group (2.6%) and 4 patients who received DS-1040 (4.6%). One subject experienced major bleeding (DS-1040 80 mg group); no fatal or intracranial bleeding occurred. Thrombus volume was 25% to 45% lower after infusion, with no differences between the DS-1040 and placebo groups. There was no difference in the change from baseline right-to-left ventricular dimensions between the DS-1040 and placebo groups.
In patients with acute PE, adding DS-1040 to standard anticoagulation was not associated with an increase in bleeding but did not improve thrombus resolution or right ventricular dilation.
Evolving Management Trends and Outcomes in Catheter Management of Acute Pulmonary Embolism
2022, Journal of Cardiothoracic and Vascular Anesthesia
Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial
2021, The Lancet Haematology
Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe.
We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555).
Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0–78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210–224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1–5]) of 402 patients had at least one major bleeding event and 16 (4% [2–6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran.
A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation.
German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.
Meta-Analysis of Catheter Directed Ultrasound-Assisted Thrombolysis in Pulmonary Embolism
2019, American Journal of Cardiology
Ultrasound-assisted catheter directed thrombolysis (USAT) has been shown to improve hemodynamic function and reduce bleeding complications in patients with acute massive or submassive pulmonary embolism. We performed a meta-analysis to better evaluate the efficacy and safety of USAT. We conducted an extensive literature search in PUBMED, MEDLINE, and EMBASE databases from January 1, 2008 to December 31, 2018. Efficacy outcomes of interest were pulmonary artery systolic pressure, mean pulmonary pressure, ratio of right ventricular to left ventricular diameter, cardiac index, tricuspid annular plane systolic excursion, Miller Index Score, and Qanadli Score. Safety outcomes were in-hospital mortality, long-term mortality, major and minor bleeding complications, and recurrent pulmonary embolism. Meta-analysis was performed using Cochrane Collaboration Review Manager (version 5.1). Effect size was estimated using random effects model, with 95% confidence intervals (CIs). Twenty-eight studies (n = 2,135) met inclusion criteria. Compared with pretreatment parameters, post-USAT was associated with a reduction in the mean Miller Index Score and Qanadli Score by 10.55 (95% CI −12.98 to −8.12) and 15.64 (95% CI −19.08 to −12.20), respectively. Cardiac index and tricuspid annular plane systolic excursion improved by 0.68 L/m² (95% CI 0.49 to 0.87) and 3.68 mm (95% CI 2.43 to 4.93), respectively. Pulmonary artery systolic pressure and mean pulmonary pressure after therapy were reduced by a mean difference of 16.69 mm Hg (95% CI −19.73 to −13.65) and 12.13 mm Hg (95% CI −14.67 to −9.59) respectively. The right ventricular to left ventricular diameter dimension ratio decreased by 0.35 (95% CI −0.40 to −0.30) after therapy. In-hospital mortality in patients who underwent USAT was 2.9%, and total long-term mortality was 4.1%. Major and minor bleeding complications were seen in in 5.4% and 6.0% of patients, respectively. Recurrent events occurred in 0.2% of patients after USAT. In conclusion, USAT is a safe and effective procedure associated with significant hemodynamic and clinical improvement in patients with massive and submassive pulmonary embolism.
The Use of Thrombolysis for Acute Pulmonary Embolism in the United States: National Trends and Patient Characteristics from 2006 to 2011
2017, Journal of Emergency Medicine
Thrombolysis for the treatment of pulmonary embolism (PE) has received significant attention in the literature over the past 10 years.
Our primary objective was to examine the trend in thrombolysis use in the United States from 2006 to 2011. Secondary objectives include examining patient and hospital characteristics associated with receiving thrombolysis and rates of complications associated with thrombolysis.
In this retrospective cohort study, we used the Nationwide Inpatient Sample from 2006 to 2011 to identify patients with a diagnosis of PE who received or did not receive thrombolytic agents.
Examining the records of 47,911,414 hospital discharges identified a cohort of 1,317,329 patients with PE; of these patients, 10,617 received thrombolysis. During the study period, there was a 30% relative increase in the use of thrombolysis, from 0.68% (95% confidence interval [CI] 0.64–0.73%) to 0.89% (95% CI 0.83–0.95%; p < 0.01). After controlling for all factors in the model, factors associated with decreased access to thrombolysis were increasing age (odds ratio [OR] 0.981 [95% CI 0.980–0.982]; p < 0.01), female sex (OR 0.78 [95% CI 0.75–0.81]; p < 0.01), Black race (OR 0.86 [95% CI 0.81–0.91]; p < 0.01), Hispanic race (OR 0.78 [95% CI 0.71–0.86]; p < 0.01), other race (OR 0.72 [95% CI 0.59–0.88]; p = 0.02), and rural hospital location (OR 0.48 [95% CI 0.43–0.52]; p < 0.01).
The use of thrombolysis increased between 2006 and 2011 in the United States. Patients who receive thrombolysis tend to be white men, live in higher-income ZIP codes, and receive the therapy at large academic teaching hospitals.
Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism
2017, Journal of the American College of Cardiology
The long-term effect of thrombolytic treatment of pulmonary embolism (PE) is unknown.
This study investigated the long-term prognosis of patients with intermediate-risk PE and the effect of thrombolytic treatment on the persistence of symptoms or the development of late complications.
The PEITHO (Pulmonary Embolism Thrombolysis) trial was a randomized (1:1) comparison of thrombolysis with tenecteplase versus placebo in normotensive patients with acute PE, right ventricular (RV) dysfunction on imaging, and a positive cardiac troponin test result. Both treatment arms received standard anticoagulation. Long-term follow-up was included in the third protocol amendment; 28 sites randomizing 709 of the 1,006 patients participated.
Long-term (median 37.8 months) survival was assessed in 353 of 359 (98.3%) patients in the thrombolysis arm and in 343 of 350 (98.0%) in the placebo arm. Overall mortality rates were 20.3% and 18.0%, respectively (p = 0.43). Between day 30 and long-term follow-up, 65 deaths occurred in the thrombolysis arm and 53 occurred in the placebo arm. At follow-up examination of survivors, persistent dyspnea (mostly mild) or functional limitation was reported by 36.0% versus 30.1% of the patients (p = 0.23). Echocardiography (performed in 144 and 146 patients randomized to thrombolysis and placebo, respectively) did not reveal significant differences in residual pulmonary hypertension or RV dysfunction. Chronic thromboembolic pulmonary hypertension (CTEPH) was confirmed in 4 (2.1%) versus 6 (3.2%) cases (p = 0.79).
Approximately 33% of patients report some degree of persistent functional limitation after intermediate-risk PE, but CTEPH is infrequent. Thrombolytic treatment did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea or RV dysfunction in these patients. (Pulmonary Embolism Thrombolysis study [PEITHO]; NCT00639743)

View all citing articles on Scopus

: RCT reg # NCT00639743.

^a: On behalf of the PEITHO Investigators. See online Appendix for complete listing.

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Trial DesignSingle-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: Rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial

Background

Design

Conclusions

Section snippets

Background and rationale

Objectives of the trial

Patient population and study design

Outcomes

Long-term follow-up

Statistical analysis

Measures against bias

Sample size/power calculations

Administrative organization

Sources of funding

Conclusions

Disclosures

Lancet

J Am Coll Cardiol

Chest

Chest

Lancet

Thromb Res

Acting Surgeon General issues ‘call to action to prevent deep vein thrombosis and pulmonary embolism.’ September 2008

Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study

Arch Intern Med

A population-based perspective of the hospital incidence and case- fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study

Arch Intern Med

Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality

Thromb Haemost

Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Research Committee of the British Thoracic Society

Lancet

The clinical course of pulmonary embolism

N Engl J Med

Weekend versus weekday admission and mortality after acute pulmonary embolism

Circulation

Trial Design
Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: Rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial