MOPETT: “Safe Dose” Thrombolysis in Moderate Pulmonary Embolism (2012)

“In patients with moderate pulmonary embolism, a lower, “safe dose” of tissue plasminogen activator was associated with a significant improvement in pulmonary artery pressures and a reduction in the combined outcome of death or recurrent PE, without an increase in major bleeding.”

  • Adapted from the MOPETT Investigators

1. Publication Details

  • Trial Title: Thrombolysis with Low-Dose Tissue Plasminogen Activator in Moderate Pulmonary Embolism: A Randomized, Controlled Trial
  • Citation: Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; “MOPETT” Investigators. Thrombolysis with low-dose tissue plasminogen activator in moderate pulmonary embolism: a randomized, controlled trial. J Thromb Thrombolysis. 2013;35(3):367-374. DOI: 10.1007/s11239-012-0799-8
  • Published: April 2013, in The Journal of Thrombosis and Thrombolysis
  • Author: Mohsen Sharifi, M.D.
  • Funding: Not explicitly stated.

2. Keywords

  • Pulmonary Embolism, Submassive Pulmonary Embolism, Thrombolysis, Alteplase, t-PA, Right Ventricular Dysfunction, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with moderate (“submassive”) pulmonary embolism (Population), does treatment with a lower, “safe dose” of alteplase (Intervention) compared to standard anticoagulation with heparin alone (Comparison) improve long-term pulmonary hypertension and reduce the composite risk of death or recurrent PE (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The management of intermediate-risk (“submassive”) pulmonary embolism was a major clinical controversy. Full-dose thrombolysis, as studied in the MAPPET-3 trial (2002), was known to improve hemodynamic stability but carried a significant risk of major bleeding.
  • Knowledge Gap: It was unknown if a lower, potentially safer dose of thrombolytic therapy could provide the benefits of clot dissolution (e.g., improved right ventricular function) without the high risk of bleeding associated with the standard 100-mg dose.
  • Proposed Hypothesis: The authors hypothesized that a “safe dose” of alteplase (50 mg) would be superior to heparin alone in improving pulmonary artery pressures and clinical outcomes in patients with moderate pulmonary embolism.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single academic medical center in the United States.
  • Trial Period: Enrollment ran from January 2007 to January 2011.
  • Population:
    • Inclusion Criteria: Adult patients with a new diagnosis of moderate pulmonary embolism, defined by the presence of a large clot burden on CT scan (involving ≥2 lobar or main pulmonary arteries).
    • Exclusion Criteria: Included patients with hemodynamic instability (massive PE) or those with a high risk of bleeding.
  • Intervention: Patients received a “safe dose” of intravenous alteplase (a total of 50 mg: 10 mg bolus followed by 40 mg over 2 hours) in addition to standard heparin therapy.
  • Control: Patients received standard anticoagulation with heparin alone.
  • Management Common to Both Groups: All patients were managed with standard supportive care for pulmonary embolism.
  • Power and Sample Size: The authors calculated that a sample size of 120 patients would be required to have 90% power to detect a significant difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: A composite of the development of pulmonary hypertension or the combined outcome of death and recurrent PE at 28 months.
    • Secondary Outcomes: Included length of hospital stay and bleeding complications.

6. Key Results

  • Enrollment and Baseline: 121 patients were randomized (61 to low-dose alteplase and 60 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The primary composite outcome occurred in a significantly lower proportion of patients in the low-dose alteplase group: 10 of 61 patients (16%) in the alteplase group met the primary endpoint, compared with 34 of 60 patients (57%) in the control group (p<0.001).
  • Secondary Outcomes: The combined outcome of death or recurrent PE was also significantly lower in the alteplase group (1.6% vs. 10%). Patients in the alteplase group had a significantly shorter hospital stay.
  • Adverse Events: There were no major bleeding events (including no intracranial hemorrhages) in either group. The rate of minor bleeding was similar.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who met the composite endpoint between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of <0.001 for the primary outcome is extremely low, indicating that the observed difference is highly statistically significant and very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 57% – 16% = 41%.
      • Clinical Meaning: For every 100 patients with moderate PE treated with low-dose alteplase, about 41 were saved from the composite outcome of death, recurrent PE, or long-term pulmonary hypertension.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.41 = 2.4, which is rounded down to 2.
      • Clinical Meaning: You would only need to treat 2 to 3 patients with low-dose alteplase to prevent one additional adverse long-term outcome.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, controlled design provided a high level of evidence for a novel therapeutic strategy.
  • Patient-Centered Outcomes: The study included important patient-centered outcomes, including a long-term assessment of pulmonary hypertension.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The single-center design is a major limitation, as the results may not be applicable to other centers. The study population was defined by clot burden on CT scan, not by the more common criteria of RV strain on echocardiography or elevated biomarkers.
  • Other: The trial was relatively small. The primary outcome was a composite endpoint driven largely by the physiological measure of pulmonary artery pressure, not by hard clinical outcomes like mortality. The zero rate of major bleeding is highly unusual and may not be reproducible in real-world practice.

10. Conclusion of the Authors

  • The authors concluded that in patients with moderate pulmonary embolism, a lower, “safe dose” of t-PA improves long-term cardiopulmonary outcomes without an apparent increase in bleeding risk.

11. To Summarize

  • Impact on Current Practice: This was a highly influential but also very controversial trial. It provided the first randomized evidence to support the now-common practice of using “half-dose” thrombolysis for submassive PE. However, its significant limitations mean that it should be considered hypothesis-generating rather than definitive.
  • Specific Recommendations:
    • Patient Selection: For adult patients with moderate (“submassive”) pulmonary embolism.
    • Actionable Intervention: The results suggest that a lower-dose thrombolysis strategy may be considered in carefully selected patients with a low bleeding risk.
  • What This Trial Does NOT Mean: This trial does NOT definitively prove that low-dose thrombolysis is safe and effective. Its findings require confirmation in a large, multicenter trial.
  • Implementation Caveats: The decision to use any dose of thrombolysis in a normotensive patient remains a complex one that requires a careful weighing of the potential benefits against the real risks of major bleeding.

12. Context and Related Studies

  • Building on Previous Evidence: The MOPETT trial (2012) was a direct response to the clinical dilemma created by earlier trials like MAPPET-3 (2002), which showed a benefit for full-dose thrombolysis but raised safety concerns.
  • Influence on Subsequent Research: The promising but statistically fragile findings of this trial have spurred a great deal of interest and debate. They have been a major driver for subsequent, larger trials designed to definitively test the efficacy and safety of reduced-dose thrombolysis in this population.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether the remarkable findings of this small, single-center trial are replicable in a large, multicenter setting, and whether the impressive safety profile holds true in a broader population.
  • Future Directions: A large, multicenter randomized controlled trial is needed to definitively confirm or refute the benefit of low-dose thrombolysis in intermediate-risk pulmonary embolism.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a novel strategy to improve the risk-benefit ratio of a high-stakes therapy.
  • Methods: The randomized controlled design was appropriate. However, the single-center, open-label design and the small sample size are major methodological limitations that significantly reduce the strength and generalizability of the findings. The composite primary outcome was driven by a physiological surrogate, not a hard clinical endpoint.
  • Results: The study reported a very large and statistically significant benefit for its primary outcome. An effect size this large (NNT of 2-3) from a small, single-center trial must be interpreted with extreme caution, as such results are often not replicated in larger, multicenter studies.
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their data, but the applicability of the findings is limited by the study’s significant methodological weaknesses. This trial is a classic example of a seminal, hypothesis-generating study that has been highly influential in changing practice, but whose findings require confirmation before being accepted as definitive.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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