EBQ:TOPCOAT Trial

Complete Journal Club Article

Kline J. et al.. "Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial.". J Thromb Haemost. 2014. 12(4):459-468.
PubMed PDF

Clinical Question

Does thrombolysis of submissive PE with tenecteplase increases the probability of a favorable composite outcome of death, circulatory shock, intubation, major bleeding in 5 days, recurrent PE, functional capacity or a Physical component summary at 90 day followup.

Conclusion

• Treatment of patients with submassive pulmonary embolism with tenecteplase was associated with increased probability of a favorable composite outcome.

Major Points

• The adjunctive use of fibrinolysis to treat acute submas- sive pulmonary embolism (PE) remains controversial. The American Heart Association has maintained that for massive pulmonary embolism, thrombolysis with tPA is an effective treatment strategy.. 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

• The MOPETT Trial and the PEITHO Trial have suggested there is a possible mortality benefit however the risks of treatment are weighted against the bleeding risks.

• In patients with submassive PE, the use of tenecteplase resulted in a reduction in adverse outcomes based on a complicated composite outcome. However, the only independent variable that reached statistical significance was related to a self assessment of overall health at 90 days. This was simply the patients' response to being asked 'how would you rate your overall health?' (mean was 2.4 vs. 3.3 out of 10). The study was small, under powered and incomplete due to early termination, which limits any conclusions that can be made.

Study Design

• Multicenter, double-blinded, intention to treat, placebo-controlled, randomized controlled efficacy trial
• 8 academic centers in the United States

Population

Patient Demographics

Placebo vs Tenecteplase

• Male: 67% vs 50%
• Previous Surgery (in 6 weeks): 9% vs 3%
• Trauma (in 6 weeks) 5% vs 8%
• Systolic Heart Failure: 5% vs 3%
• Prior PE or DVT: 21% vs 15%
• COPD: 7% vs 0%
• Age > 75: 9% vs 10%

Inclusion Criteria

• Age > 17 years
• PE diagnosed on computed tomographic pulmonary angiography performed within 24 h
• Normal arterial systolic blood pressure with evidence of right ventricular strain
  • Hypokinesis on echocardiography
  • Elevated troponin I or T using local thresholds (values exceeding the 99 percentile with coefficient of variability < 10%) OR
  • Brain natriuretic peptide (BNP) measurement > 90 pg mL^-1 or NT proBNP > 900 pg mL^-1 (not more than 6 h prior to CT angiography and not more than 30 h before enrollment).

Exclusion Criteria

• Exclusions included systolic hypotension (< 90 mmHg), inability to walk, contraindications to fibrinolysis, and end-stage conditions

Interventions

All patients were treated with fulldose low-molecular-weight heparin (LMWH), 1 mg/kg enoxaparin, or weight-based dalteparin, 200 units/kg, administered subcutaneously prior to injection of study drug or placebo

Treatment Group

• Tiered dose tenecteplase in accordance with the TNKase (Genentech guidelines)

Placebo Group

• Only received LMWH

Outcomes

• Trial terminated early due to lead author relocating to a new institution as well as

• At followup, 13 (30%; 95% CI, 17–46) patients treated with placebo developed a study-defined adverse outcome, compared with five (12.5%; 95% CI, 4–27) patients treated with tenecteplase.
• Adverse Outcomes: 16/43 patients (37%; 95% CI, 23–53) treated with placebo and 6/40 patients (15%; 95% CI, 6–30) treated with tenecteplase had an adverse outcome (95% confidence interval for the difference of 22%, 3.2–40
• Table 4 in the paper lists the multiple composite outcomes

Criticisms & Further Discussion

• Although the author concluded that tenectaplase was associated with increased probability of a favorable outcome, the trial contained a very difficult to interpret composite outcome
• The trial was also prematurely terminated
• The placebo cohort had increased comorbidities most likely due to incomplete trial enrollment

See Also

• Pulmonary Embolism (PE)
• PEITHO Trial
• TOPCOAT Trial
• MOPETT Trial
• Intermediate risk PE Metaanalysis

External Links

Wessexics - The Bottom Line PulmCC - TOPCOAT

Funding

• J. A. Kline owns stock in CP Diagnostics LLC, is a consutant for Daiichi Sankyo Inc, Donawa Lifesciences Consulting and Stago Diagnostica, and has received funding from the Agency for Healthcare Reform, National Institutes for Health.
• This study was funded by an investigator initiated grant from Genentech, Inc.
• A. E. Jones has received 2014 International Society on Thrombosis and Haemostasis funding from the National Institutes of Health. D. B. Diercks serves as a consultant for Daiichi Sankyo, Beckmann Coulter, Mylan, and has received research support from Radiometer, Alere, DOD and the National Institutes of Health.
• C. Kabrhel is a consultant for Stago Diagnostica

Sources

Authors

Daniel Ostermayer