PEITHO

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Meyer G, et al. "Fibrinolysis for patients with intermediate-risk pulmonary embolism". The New England Journal of Medicine. 2014. 370(15):1402-1411.
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Clinical Question

Among patients with submassive PE being treated with unfractionated heparin, does administration of tenecteplase reduce all-cause mortality or hemodynamic decompensation at 7 days when compared to placebo?

Bottom Line

Among patients with submassive PE being treated with unfractionated heparin, administration of tenecteplase reduces a composite endpoint of all-cause mortality or hemodynamic decompensation at 7 days when compared to placebo, though this was driven by reduced hemodynamic decompensation. Tenecteplase was associated with an increased rate of bleeding.

Major Points

Thrombolysis with intravenous tPA is a standard treatment for acute massive PE.[1] However, among patients with submassive PE, namely those who are hemodynamically stable but have signs of RV dysfunction, the selection of patients who may benefit from thrombolysis remains elusive. tPA has rarely been used in the latter population, where the benefit of thrombolysis has not clearly been demonstrated to outweigh the risk of major bleeding. The MAPPET-3 trial[2] (2002) compared heparin therapy with either tPA or placebo in patients with submassive PE and found that tPA reduced a composite endpoint of in-hospital all-cause mortality or clinical decompensation requiring further intervention. However, no survival benefit was seen, an observation attributed in part to the excess in bleeding risk associated with tPA. A low-dose tPA regimen was studied in the 2013 MOPETT trial,[3] which found reduction in pulmonary hypertension rates. However, the trial was limited by its open-label, single-center design, low rate of patients meeting the traditional definition of submassive PE, and questionable data collection practices.

The 2014 Pulmonary Embolism Thrombolysis (PEITHO) trial randomized 1,005 patients with a submassive PE (hemodynamic stability with RV strain and elevated troponins) to unfractionated heparin (UFH) with either tenecteplase or placebo. Groups were similar except for a higher rate of pre-randomization use of LMWH/fondaparinux in the tenecteplase group. At 7 days, tenecteplase was associated with a significant decrease in the primary endpoint of all-cause mortality or hemodynamic decompensation (2.6% vs. 5.6%; P=0.02; NNT 33), though this was driven by reduction in hemodynamic decompensation as there was no mortality benefit. Tenecteplase was associated with increased rates of major extracranial bleeding at 7 days (6.3% vs. 1.2%; P<0.001; NNH 20) and strokes at 7 days (2.4% vs. 0.2%; P=0.004; NNH 45).

Guidelines

As of April 2015, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, double-blind, placebo controlled trial
  • N=1,005
    • Tenecteplase (n=506)
    • Placebo (n=499)
  • Setting: 76 centers in 13 countries
  • Enrollment: 2007-2012
  • Follow-up: 30 days
  • Analysis: Intention-to-treat
  • Primary outcome: All-cause mortality or hemodynamic decompensation at 7 days

Population

Inclusion Criteria

  • Age ≥18 years
  • Pulmonary embolism with initial symptoms beginning in ≤15 days prior
    • Confirmation by VQ scan, CT angiogram, or pulmonary angiogram
  • RV dysfunction as defined by ≥1 of the following:
    • Echocardiogram - RV end-diastolic diameter >30mm on parasternal long-axis or short-axis views, right-to-left ventricular end-diastolic diameter >0.9 on apical or subcostal 4-chamber view, hypokinesis of RV free wall on any view, or tricuspid systolic velocity >2.6 m/sec on the apical or subcostal 4-chamber view
    • CT angiogram - Right-to-left ventricular internal diameter ratio >0.9 using the internal diameter/minor axis of RV and LV in the transverse plane
  • Myocardial injury defined by either of the following:
    • Troponin I >0.06 ug/L
    • Troponin T >0.01 ug/L

Exclusion Criteria

  • Hemodynamic collapse on presentation defined by any of the following:
    • Need for CPR
    • SBP <90 mmHg for ≥15 minutes
    • Drop in SBP by ≥40 mmHg for ≥15 min with findings of end organ hypoperfusion
    • Need for catecholamines to maintain organ perfusion and SBP >90 mmHg, including dopamine infused at >5 mcg/kg/min
  • Coagulopathy/significant bleeding risk excluding antiplatelet medication use
  • Use of thrombolytics in prior 4 days
  • IVC filter placement or pulmonary thrombectomy in prior 4 days
  • Uncontrolled HTN (SBP >180 mmHg or DBP >110 mmHg)
  • Treatment with another investigational medication in the prior week
  • Prior enrolment in PEITHO
  • Hypersensitivity to a tPA formulation, heparin, or any other study medications
  • Pregnancy, delivery in prior 30 days, lactation, women of childbearing age without negative pregnancy test or use of contraception
  • Any condition that would place a patient at increased risk with investigational therpay use

Baseline Characteristics

From the tenecteplase group. Groups were similar except where specified. Comparisons are tenecteplase vs. placebo.

  • Demographics: Age 66.5 years, male 47.8%
  • Baseline health data: Weight 82.5 kg, SBP 131 mmHg, HR 94 BPM, RR 22, receiving oxygen treatment 86.2%
  • PMH: Pulmonary disease 5.1%, HF 4.2%, prior VTE 24.9%, active cancer 8.1%, major trauma or surgery in prior month 6.1%, immobilization 10.9%
  • Medications: Estrogen 5.9%
  • Diagnosis of PE: CT scan 94.9%, V/Q scan 6.1%, pulmonary angiography 1.2%
  • Diagnosis of RV dysfunction: Echocardiography 54.9%, CT 14.6%, both 30.4%
  • Diagnosis of myocardial injury: Troponin I 71.9%, troponin T 32.4%, either 99.2%
  • LMWH/fondaparinux before randomization: 33.6% vs. 26.6% (P=0.02)

Interventions

  • Randomization to a group (stratification by center):
    • Tenecteplase - Tenecteplase 30-50 mg IV once over 5-10 seconds (dose varied by weight[4])
    • Placebo
  • Both groups were initiated on UFH immediately after randomization with goal ptt 2.0-2.5x ULN (factor Xa levels 0.3-0.7 units/mL)
    • UFH was bolused unless already given or if prior administration of therapeutic LMWH/fondaparinux
    • UFH initiation was delayed for 12 hours following the administration of any therapeutic LMWH or 24 hours following the administration of any fondaparinux
  • Other anticoagulants were disallowed until 48 hours after randomization

Outcomes

Comparisons are tenecteplase vs. placebo. Statistics presented when given.

Primary Outcome

All-cause mortality or hemodynamic decompensation at 7 days
2.6% vs. 5.6% (OR 0.44; 95% CI 0.23-0.87; P=0.02; NNT 33)
Hemodynamic decompensation defined by need for CPR, SBP <90 mmHg for ≥15 minutes, drop in SBP by ≥40 mmHg for ≥15 min with findings of end organ hypoperfusion, or need for catecholamines to maintain organ perfusion and SBP >90 mmHg, including dopamine infused at >5 mcg/kg/min.
Time until outcome: 1.54 vs. 1.79 days

Secondary Outcomes

All-cause mortality
At 7 days: 1.2% vs. 1.8% (OR 0.65; 95% CI 0.23-1.85; P=0.42)
At 30 days: 2.4% vs. 3.2% (OR 0.73; 95% CI 0.34-1.57; P=0.42)
Hemodynamic decompensation at 7 days
1.6% vs. 5.0% (OR 0.30; 95% CI 0.14-0.68; P=0.002; NNT 29)
Recurrent PE at 7 days
0.2% vs. 1.0% (OR 0.20; 95% CI 0.02-1.68; P=0.12; NNT 125)
Fatal: 0% vs. 0.6%
Non-fatal: 0.2% vs. 0.4%
Serious adverse events at 30 days
Other adverse events are detailed below as they were not considered secondary outcomes.
10.8% vs. 11.8% (OR 0.91; 95% CI 0.62-1.34; P=0.63)

Additional Outcomes

Ongoing hospitalization at day 30
11.7% vs. 10.0%
Rehospitalization at 30 days
4.4% vs. 3.0%
In hospital events and requirements
Mechanical ventilation: 1.6% vs. 3.0%
Surgical embolectomy: 0.2% vs. 0.4%
Catheter thrombus fragmentation: 0.2% vs. 0.0%
Vena cava interruption: 1.0% vs. 0.2%
Thrombolytic treatment outside of study medications: 0.8% vs. 4.6%

Subgroup Analysis

For the primary outcome. Data for the prespecified analysis of country of origin not presented by the authors. Multiple post-hoc subgroup analyses are presented in the supplementary appendix.

Age
≤ 75 years: 1.7% vs. 5.1% (OR 0.33; 95% CI 0.313-0.85)
>75 years: 4.3% vs. 6.7% (OR 0.63; 95% CI 0.24-1.66)
P-value for interaction 0.36
Sex
Male: 2.9% vs. 6.1% (OR 0.46; 95% CI 0.0.18-1.16)
Female: 2.3% vs. 5.2% (OR 0.42; 95% CI 0.16-1.12)
P-value for interaction 0.90

Adverse Events

Bleeding at 7 days
Major extracranial: 6.3% vs. 1.2% (OR 5.55; 95% CI 2.3-13.39; P<0.001; NNH 20)
Categorized as moderate (requiring blood transfusion but not thought to be life-threatening or needing emergency volume, ionotropes, or interventions) or severe (hemodynamic compromise requiring emergency interventions, bleeding thought to be life-threatening, or resulting in death). Individual moderate and severe bleeding rates were not presented by the authors, however. Major and minor bleeding per the ISTH criteria.[5]
Minor bleeding: 32.6% vs. 8.6%
Major bleeding: 11.5% vs. 2.4%
Stroke at 7 days
2.4% vs. 0.2% (OR 12.10; 95% CI 1.57-93.39; P=0.003; NNH 45)
Ischemic: 0.4% vs. 0%
Hemorrhagic: 2.0% vs. 0.2%

Criticisms

  • Not powered to detect differences in mortality
  • Unclear clinical significance of the hemodynamic decompensation outcome

Funding

  • Program Hospitalier de Recherche Clinique (France)
  • Federal Ministry of Education and Research (Germany)
  • Boehringer Ingelheim

Further Reading

  1. Jaff MR, et al. "Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: A scientific statement from the American Heart Association." Circulation. 2011;123(16):1788-1830.
  2. Konstantinides S, et al. "Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism." The New England Journal of Medicine. 2002; 347(15):1143-1150.
  3. Sharifi M et al. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am. J. Cardiol. 2013. 111:273-7.
  4. Supplementary appendix, table S1.
  5. Schulman S, et al. "Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients." Journal of Thrombosis and Haemostasis. 2005;3(4):692-694.