MAPPET-3: Thrombolysis in Intermediate-Risk Pulmonary Embolism (2002)

“In patients with acute pulmonary embolism without arterial hypotension and shock, thrombolysis can prevent the escalation of treatment and is associated with a good outcome.”

  • The MAPPET-3 Investigators

1. Publication Details

  • Trial Title: Management Strategies and Prognosis of Pulmonary Embolism-3 Trial (MAPPET-3)
  • Citation: Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347(15):1143-1150. DOI: 10.1056/NEJMoa021274
  • Published: October 10, 2002, in The New England Journal of Medicine
  • Author: Stavros Konstantinides, M.D.
  • Funding: Boehringer Mannheim.

2. Keywords

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

3. The Clinical Question

  • In normotensive adult patients with acute, intermediate-risk (“submassive”) pulmonary embolism (Population), does treatment with heparin plus alteplase (Intervention) compared to heparin plus placebo (Comparison) reduce the composite risk of death or clinical deterioration requiring treatment escalation (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Thrombolysis was the standard of care for patients with high-risk (“massive”) pulmonary embolism who presented with shock. However, the management of patients who were hemodynamically stable but had evidence of right ventricular (RV) strain (so-called “submassive” or intermediate-risk PE) was a major clinical controversy.
  • Knowledge Gap: It was unknown if the benefits of thrombolysis in dissolving the clot and improving RV function in these intermediate-risk patients outweighed the significant risks of major bleeding, particularly intracranial hemorrhage.
  • Proposed Hypothesis: The authors hypothesized that thrombolysis with alteplase plus heparin would be superior to heparin alone in preventing death or clinical deterioration in patients with submassive pulmonary embolism.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: Multiple medical centers in Germany.
  • Trial Period: Enrollment ran from March 1997 to March 2001.
  • Population:
    • Inclusion Criteria: Adult patients with confirmed acute pulmonary embolism who were hemodynamically stable (systolic BP > 90 mm Hg) but had evidence of right ventricular dysfunction (on echocardiography) or pulmonary hypertension (on pulmonary artery catheter).
    • Exclusion Criteria: Included patients with active bleeding or other contraindications to thrombolysis.
  • Intervention: Patients received intravenous alteplase (100 mg over 2 hours) in addition to standard heparin therapy.
  • Control: Patients received a matching intravenous placebo in addition to standard heparin therapy.
  • Management Common to Both Groups: All patients received a standard intravenous heparin infusion.
  • Power and Sample Size: The authors calculated that a sample size of 256 patients would be required to have 80% power to detect a 15% absolute risk reduction in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: A composite of in-hospital death or clinical deterioration requiring treatment escalation (defined as catecholamine infusion for shock, secondary thrombolysis, or mechanical ventilation).
    • Secondary Outcomes: Included the individual components of the primary outcome and the incidence of major bleeding.

6. Key Results

  • Enrollment and Baseline: 256 patients were randomized (118 to alteplase and 138 to placebo). 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 alteplase group: 13 of 118 patients (11.0%) in the alteplase group met the primary endpoint, compared with 34 of 138 patients (24.6%) in the placebo group (p=0.006).
  • Secondary Outcomes: The difference was driven primarily by a reduction in the need for treatment escalation. There was no significant difference in in-hospital mortality between the groups (3.4% in the alteplase group vs. 2.2% in the placebo group).
  • Adverse Events: There was no significant difference in the rates of major or minor bleeding between the two groups. No fatal bleeding or intracranial hemorrhage occurred in either group.

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 0.006 for the primary outcome is well below the 0.05 threshold, 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 = 24.6% – 11.0% = 13.6%.
      • Clinical Meaning: For every 100 patients with submassive PE treated with alteplase, about 14 were saved from death or clinical deterioration.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.136 = 7.4, which is rounded down to 7.
      • Clinical Meaning: You would need to treat only 7 patients with submassive PE with alteplase to prevent one additional case of death or clinical deterioration.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of multiple centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome and found a significant effect.
  • Patient-Centered Outcomes: The primary outcome was a composite of death and major clinical deterioration, which are highly relevant endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The study was conducted in a relatively young population (mean age ~60), and the results may not be fully generalizable to older patients who are at higher risk of bleeding.
  • Other: The trial was not powered to detect a difference in mortality, which is the most important patient-centered outcome. The lack of any fatal bleeding events in the trial was unusual and may not reflect real-world practice.

10. Conclusion of the Authors

  • The authors concluded that in normotensive patients with acute submassive pulmonary embolism, thrombolytic therapy with alteplase can prevent the need for treatment escalation and is associated with a good outcome.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided the first strong, randomized evidence to support the use of thrombolysis in the controversial “submassive” PE population. It was highly influential in shaping guidelines and practice for this condition.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute pulmonary embolism who are hemodynamically stable but have evidence of right ventricular strain.
    • Actionable Intervention: Consider treatment with thrombolysis (alteplase).
    • Expected Benefit: This intervention can be expected to prevent one case of death or clinical deterioration for every 7 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that all patients with submassive PE should receive thrombolysis. The decision remains a complex one that requires balancing the potential benefit against the significant risk of major bleeding.
  • Implementation Caveats: The key is careful patient selection. This therapy should be reserved for patients with clear evidence of RV strain and a low bleeding risk.

12. Context and Related Studies

  • Building on Previous Evidence: The MAPPET-3 trial (2002) was designed to provide a definitive answer to the question of thrombolysis in submassive PE, which was a major area of clinical uncertainty.
  • Influence on Subsequent Research: The positive findings of this trial, particularly the lack of a clear mortality benefit, led directly to the design of the much larger PEITHO trial (2014). PEITHO confirmed the benefit of thrombolysis on preventing hemodynamic collapse but also showed a significantly higher risk of major bleeding and stroke, further highlighting the difficult risk-benefit trade-off of this therapy.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not definitively answer whether thrombolysis improves survival in this population. It also did not address the role of lower, “safer” doses of thrombolytics.
  • Future Directions: The results of this trial and the subsequent PEITHO trial have spurred a great deal of research into safer reperfusion strategies for submassive PE, including half-dose thrombolysis and catheter-directed therapies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and high-stakes clinical dilemma.
  • Methods: The multicenter, double-blind RCT design was of high quality. The primary composite outcome was appropriate.
  • Results: The study reported a statistically significant and clinically meaningful benefit for its primary outcome (NNT of 7). However, this was driven by a reduction in clinical deterioration, not mortality. The surprisingly low rate of bleeding complications is a key point for critical discussion.
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their data. The trial provided strong, hypothesis-generating evidence for the use of thrombolysis in this population. However, its findings must be interpreted in the context of the later, larger PEITHO trial, which provided a more complete picture of both the benefits and the significant risks of this therapy.

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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