EBQ:MOPETT Trial

Complete Journal Club Article
Sharifi M et al. "Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial).". The American Journal of Cardiology. 2012. 111(2):273-7.
PubMed PDF

Clinical Question

Does thrombolysis in sub-massive PE result in a reduction of pulmonary artery pressure?

Conclusion

In patients with sub-massive PE, half dose (0.5 mg/kg max 50mg) tPA safely resulted in a immediate and sustained reduction in pulmonary artery pressure

Major Points

The American Heart Association has maintained that for massive pulmonary embolism, thrombolysis with tPA is an effective treatment strategy.[1]. This trial addressed thrombolysis in patients who are hemodynamically stable but had moderate PE evidenced on CTA. Commonly, the group termed, sub-massive PE includes patients with elevated troponin, BNP, or RV dysfunction on echocardiogram.. The standard of treatment for the sub-massive PE group has been unclear and thrombolysis has not been standard care for treatment, with most of these patients receiving heparin to decrease clot propagation while clot is slowly broken down[2] Half does tPA was chosen to reduce the bleeding complication which has occurred in thrombolysis.

In this single study, unblinded study with an physiologic endpoint, there was a large reduction in pulmonary hypertension (16% vs. 57%) as well as in the composite endpoint of recurrent pulmonary embolism. There was no significant mortality benefit. There was no morbidity related to bleeding, causing the authors to coin the term "Safe Dose tPA" for the 0.5mg/kg dosing.

Study Design

  • N=121 patients with submassive PE
  • Single-center, randomized, unblinded non-placebo-controlled study
  • N=121 patients with moderate PE identified by CT criteria
  • Randomization to either low-dose thrombolysis (n=61) or control (n=60)
  • Mean follow-up: 28 months
  • Primary Outcome: Pulmonary hypertension
  • Secondary Composite Outcome: pulmonary hypertension or recurrent PE

Population

  • All recruited from a single US center

Patient Demographics

  • Men: 46%
  • Age: 58yrs
  • PE risks: Unknown 46%, Estrogen use: 10%, Cancer history/active: 18%, prothrombotic: 10%, DVT: 57

Inclusion Criteria

  • Age > 18 yrs
  • Signs and symptoms of a PE and >70% involvement of thrombus in ≥2 lobar or left or right main pulmonary arteries on CTA or high probability ventilation/perfusion scan showing ventilation/ perfusion mismatch in ≥2 lobes
  • >2 new signs and symptoms:
    • Chest pain
    • Tachypnea (respiratory rate at rest >22 breaths/min)
    • Tachycardia (heart rate at rest >90 beats/min)
    • Dyspnea
    • Cough
    • Oxygen desaturation (oxygen partial pressure <95% )
    • Elevated jugular venous pressure >12 cm H2O

Exclusion Criteria

  • Onset of symptoms >10 days
  • >8 hours since the start of parenteral anticoagulation
  • Systemic arterial systolic blood pressure <95 or ≥200/100 mm Hg
  • Eligibility for full-dose thrombolysis
  • Contraindication to unfractionated or low-molecular-weight heparin
  • Severe thrombocytopenia (platelet count <50,000/mm3)
  • Major bleeding within <2 months requiring transfusion
  • Surgery or major trauma within <2 weeks
  • Brain mass
  • Neurologic surgery
  • Intracerebral hemorrhage
  • Subdural hematoma within <1 year
  • End-stage illness with no plan for PE treatment
  • Inability to perform echocardiography because of chest deformities, bandages, or catheters

Interventions

Randomization to:

  1. Half Dose Thrombolysis:
    • tPA 0.5 mg/kg (max 50 mg), given as 10 mg bolus followed by remainder over 2 hours
    • Warfarin started on admission
    • Enoxaparin 1mg/kg subcutaneous twice daily or Heparin at 70U/kg bolus with dosing to keep PTT at 1.5-2x baseline
  2. Control: no tPA
    • Warfarin started on admission
    • Enoxaparin 1mg/kg subcutaneous twice daily or Heparin at 80 U/kg as a bolus followed by 18 U/kg/hour with dosing to keep PTT at 1.5-2x baseline
  • Echocardiogram performed within 2 hours and before treatment with tPA
  • Repeat echocardiogram at 24-48 hours and every 6 months

Outcomes

Primary Outcome

Pulmonary Artery Systolic Pressure
Time tPA Control
admission 50 mm Hg 51 mm Hg
48 hrs 34 mm Hg 41 mm Hg
6 months 31 mm Hg 49 mm Hg
28 months 28 mm Hg 43 mm Hg

Pulmonary Hypertension:

  • Treatment Group: 16%
  • Control Group: 57%
p <0.001

Secondary Outcomes

Recurrent Pulmonary embolism:

  • Treatment Group: 0
  • Control Group: 5% (n=3)
p 0.08

Total Mortality:

  • Treatment Group: 1.6% (n=1)
  • Control Group: 5% (n=3)

Bleeding

  • Treatment Group: 0
  • Control Group: 0

Criticisms & Further Discussion

  • The study was unblinded and only performed at a single center and the primary outcome of pulmonary hypertension reduction may not have a patient centered effect.
  • Even patients with unfractionated heparin and LMWH experience bleeding at a rate ranging between 1-2%. Since patients received both in this trial in addition to a tPA treatment arm, it is suspicious that no bleeding events were reported. [3]
  • No reports of troponin or right ventricular dysfunction rates so direct comparison to the EBQ:PEITHO Trial is not possible.
  • Meta-analysis shows that patients with pulmonary embolism, including those who were hemodynamically stable with right ventricular dysfunction, thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and ICH.[4] Second, in a subset of 1331 pa tients older than 65 years, thrombolysis was associated with a higher rate of major bleeding (12.93% vs 4.10%)[5]

See Also

External Links

Funding

  • Not reported

References

  1. Jaff M. 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 Apr 26;123(16):1788-830
  2. Konstantinides S. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation 1997;96: 882e888
  3. van Dongen C. et al. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2004 Oct 18;(4) PMID: 15495007
  4. Chatterjee S. et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. PMID 24938564
  5. Beckman JA. Thrombolytic therapy for pulmonary embolism. JAMA. 2014;311(23):2385–2386. doi:10.1001/jama.2014.5993.