PEITHO: Thrombolysis in Intermediate-Risk Pulmonary Embolism (2014)

“In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.”

  • The PEITHO Investigators

1. Publication Details

  • Trial Title: Thrombolysis with Tenecteplase in Patients with Acute, Intermediate-Risk Pulmonary Embolism
  • Citation: Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. DOI: 10.1056/NEJMoa1302097
  • Published: April 10, 2014, in The New England Journal of Medicine
  • Author: Guy Meyer, M.D.
  • Funding: The French Ministry of Health; Boehringer Ingelheim.

2. Keywords

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

3. The Clinical Question

  • In adult patients with acute, intermediate-risk (“submassive”) pulmonary embolism (Population), does treatment with the fibrinolytic agent tenecteplase (Intervention) compared to placebo (Comparison) reduce the composite risk of death or hemodynamic decompensation within 7 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The management of patients with intermediate-risk pulmonary embolism (i.e., those who are hemodynamically stable but have evidence of right ventricular [RV] strain) was a major clinical controversy. The MAPPET-3 trial (2002) had shown that full-dose thrombolysis could prevent clinical deterioration, but it was underpowered for mortality and raised concerns about bleeding.
  • Knowledge Gap: A larger, more definitive randomized controlled trial was needed to clarify the true risk-benefit balance of thrombolysis in this population, particularly with respect to the risk of major bleeding and intracranial hemorrhage.
  • Proposed Hypothesis: The authors hypothesized that thrombolysis with tenecteplase plus heparin would be superior to heparin alone in preventing death or hemodynamic decompensation in patients with intermediate-risk pulmonary embolism.

5. Study Design and Methods

  • Design: A multicenter, international, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 76 sites in 13 countries.
  • Trial Period: Enrollment ran from November 2007 to July 2012.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with confirmed acute pulmonary embolism who were hemodynamically stable but had evidence of both right ventricular dysfunction (on echocardiography or CT) and myocardial injury (positive troponin test).
    • Exclusion Criteria: Included patients with a high risk of bleeding, recent surgery, or uncontrolled hypertension.
  • Intervention: Patients received a single intravenous bolus of tenecteplase (a fibrinolytic agent) 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 1000 patients would provide 80% power to detect a 4.5% 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 all-cause mortality or hemodynamic decompensation within 7 days of randomization.
    • Secondary Outcomes: Included all-cause mortality at 30 days, recurrent PE, and the incidence of major bleeding, including intracranial hemorrhage.

6. Key Results

  • Enrollment and Baseline: 1006 patients were randomized (506 to tenecteplase and 500 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 tenecteplase group: 13 of 506 patients (2.6%) in the tenecteplase group met the primary endpoint, compared with 28 of 499 patients (5.6%) in the placebo group (p=0.02).
  • Secondary Outcomes: The difference was driven entirely by a reduction in hemodynamic decompensation. There was no significant difference in 30-day mortality between the groups (1.2% in the tenecteplase group vs. 1.8% in the placebo group).
  • Adverse Events: The incidence of major bleeding was significantly higher in the tenecteplase group (6.3% vs. 1.2%; p<0.001). Most critically, the rate of hemorrhagic stroke was also significantly higher in the tenecteplase group (2.0% vs. 0.2%; p=0.003).

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: Odds Ratio (OR) for the primary outcome: 0.44 (95% CI, 0.23 to 0.87; P-value: 0.02).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Primary Outcome in Intervention Group) / (Odds of Primary Outcome in Control Group).
      • Calculation: The paper reports the result as 0.44.
      • Clinical Meaning: The OR of 0.44 means that the odds of dying or having a hemodynamic collapse were 56% lower in the tenecteplase group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.23 to 0.87.
      • Clinical Meaning: Since this entire range is below the line of no effect (1.0), it confirms that the result is statistically significant.
    • P-value: The p-value of 0.02 is below the 0.05 threshold, indicating the result is statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (for the primary outcome):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 5.6% – 2.6% = 3.0%.
      • Clinical Meaning: For every 100 patients treated with tenecteplase, about 3 were saved from death or hemodynamic collapse.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.03 = 33.
      • Clinical Meaning: You would need to treat 33 patients with tenecteplase to prevent one additional case of death or hemodynamic collapse.
  • Subgroup Analyses: The benefit was consistent across subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of 76 diverse sites in 13 countries increases the applicability of the findings.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • 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 population was relatively young (mean age ~60), and the risk-benefit balance may be different in older patients.
  • Other: The trial did not show a mortality benefit. The benefit in preventing hemodynamic collapse came at the cost of a significant increase in major bleeding and stroke.

10. Conclusion of the Authors

  • The authors concluded that in patients with intermediate-risk pulmonary embolism, thrombolytic therapy with tenecteplase prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided a clear and sobering picture of the risk-benefit trade-off of thrombolysis in submassive PE. It demonstrated that while the therapy is effective at preventing collapse, this benefit comes at the cost of a significant risk of life-threatening bleeding.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute pulmonary embolism who are hemodynamically stable but have evidence of both RV strain and myocardial injury.
    • Actionable Intervention: The decision to use thrombolysis must be highly individualized. It should be considered primarily for patients at high risk of decompensation and a very low risk of bleeding.
  • What This Trial Does NOT Mean: This trial does NOT mean that thrombolysis should never be used in submassive PE. It only clarifies the magnitude of the risks involved.
  • Implementation Caveats: The key takeaway is the critical importance of shared decision-making with patients and families, explicitly discussing the trade-off between preventing shock and causing a major bleed or stroke.

12. Context and Related Studies

  • Building on Previous Evidence: The PEITHO trial (2014) was the large, definitive successor to the earlier, smaller MAPPET-3 trial (2002).
  • Influence on Subsequent Research: The significant bleeding risk demonstrated in this trial has been a major driver for research into safer reperfusion strategies for submassive PE, including half-dose thrombolysis and catheter-directed therapies.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is how to identify the specific patients for whom the benefit of preventing hemodynamic collapse outweighs the risk of major bleeding.
  • Future Directions: Future research is focused on safer reperfusion strategies, such as lower-dose thrombolytics and catheter-based interventions, to try and achieve the benefits of clot dissolution with a lower risk of hemorrhage.

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 large, multicenter, double-blind RCT design was of high quality. The primary composite outcome was appropriate.
  • Results: The study reported a statistically significant benefit for its primary outcome (NNT of 33). However, this was counterbalanced by a statistically significant and clinically profound increase in harm from major bleeding and stroke. The lack of a mortality benefit is a critical finding.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial is a classic example of a study that clarifies a major risk-benefit trade-off. Its findings are highly applicable and have been instrumental in shaping a more cautious and selective approach to the use of thrombolysis in intermediate-risk PE.

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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