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Submassive pulmonary emboli (PE) are those that are severe enough to produce right ventricular dysfunction on echocardiogram or elevated biomarkers (mainly troponin), but not hemodynamic instability (i.e., systemic blood pressure and cardiac output are preserved). The management of the patient with submassive PE is a matter of controversy with several recent trials looking at safety, dosing, and route of administration of tPA. The American College of Chest Physicians (ACCP) 2012 consensus guidelines recommended systemic tPA in submassive PE patients only if there is a high risk of developing into massive PE (a grade 2C suggestion based on low quality evidence/expert consensus). ACCP also recommended full dose systemic tPA (defined as alteplase 100 mg over 2 hours) via a peripheral route.
The American Heart Association (AHA) also says systemic tPA "may be considered" in submassive PE with signs of right ventricular dysfunction or other signs of an impending adverse outcome in its 2011 guidelines (a grade 2C suggestion). Editor's note: PulmCCM is not affiliated with ACCP or AHA.
While the recently published PEITHO study was conducted in Europe, the TOPCOAT trial was simultaneously conducted in the US looking at safety and efficacy of thrombolytics in submassive PE. Like the PEITHO study, the study drug was tenecteplase which is not yet approved for PE in the US.
What They Did
This was a double blinded randomized control trial at 8 academic centers across the US. Inclusion criteria included age>17 years, PE diagnosed on CT-angiogram, and evidence of right ventricular strain (on echocardiogram or by elevated biomarkers).
Major exclusion criteria included hemodynamic instability, end stage conditions and contraindication for thrombolysis. Like the PEITHO study, non-terminal cancer patients were included.
643 patients were screened, and 83 patients were included and randomized 1:1 to tenecteplase or placebo. All patients received low molecular weight heparin at the time of diagnosis before randomization and after the treatment arm. The decision for long term anticoagulation was left to the primary team.
Mortality and bleeding complications at day 5 (vs. 7 days in PEITHO) were observed. At 90 days (vs 30 days in PEITHO) other outcomes including poor functional capacity (evaluated by right ventricular dysfunction on echo, dyspnea symptoms, and exercise tolerance), and health related quality of life were compared in both groups, in a composite outcome.
What They Found
There was no improvement in mortality or increased bleeding risk with tenecteplase when compared to placebo at 5 days. 85% patients in the tenecteplase group and 63% patients in placebo group became asymptomatic (p value 0.017) at follow-up, based on subjective evidence (dyspnea and quality of life scores), echocardiogram and walk distance.
There was one death in each group: a death from cardiac arrest due to PE in the placebo group, and a death from intracranial hemorrhage in the tenecteplase group -- both occurring in the first 5 days. Two additional patients receiving placebo required vasopressors or intubation (while none receiving tenecteplase did).
The trial was unfortunately stopped early due to administrative issues (a principal investigator changing jobs), authors report. They describe running multiple tests for bias and finding none.
What It Means
Although important as the first US randomized double blinded trial, TOPCOAT is a much smaller study compared to PEITHO (12 times larger with 1,000 patients). There was no mortality benefit as seen in the PEITHO study, but the sample size was too small to make definite conclusions about mortality or bleeding risk. The follow up was little longer (90 days vs 30 days in PEITHO), but the smaller sample size, the composite outcome and the equipoise in short-term safety all make it difficult to recommend systemic tPA in submassive PE unless patients are in impending hemodynamic collapse. Tenecteplase probably improved outcomes overall, but at the cost of one iatrogenic death from intracranial hemorrhage.
Clinical Takeaway: Like PEITHO, TOPCOAT shows thrombolytics might be beneficial for submassive pulmonary embolism, but does not tip the balance of clinical decision making toward using thrombolytics as standard care for submassive PE. This remains an area of clinical controversy.
Treatment of Submassive Pulmonary Embolism with Tenecteplase or Placebo: Cardiopulmonary Outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. (TOPCOAT trial) J Thromb Haemost. 2014 Apr;12(4):459-68