Low-Dose Alteplase May Be a Potential Treatment in Some but Not All Submassive Pulmonary Embolism: the Importance of an Abstract Conclusion

We read with interest “Low-dose alteplase for the treatment of submassive pulmonary embolism: a case series.” In brief, Layman and colleagues presented 5 patients given reduced-dose thrombolysis for submassive pulmonary embolism (PE). All survived and experienced symptomatic improvement. Three had echocardiographic benefit and none had bleeding. The abstract concluded the cases series illustrated the potential for low-dose alteplase to be a safe and efficacious treatment for submassive PE. Although we applaud the authors for writing about a difficult clinical situation, we also believe for a few reasons the abstract conclusion warrants further discussion. First, submassive PE is associated with lower mortality risk, and 30-day mortality rates have been noted to be <5%. Current guidelines suggest systemic thrombolytics in submassive PE with new-onset hemodynamic instability or high-risk clinical characteristics, such as worsening respiratory status, severe right ventricle (RV) dysfunction, or major myocardial necrosis. Deep vein thrombosis (DVT) is an additional high-risk characteristic not mentioned in the guidelines. All 5 patients in the reported case series had high-risk characteristics, such as DVT or severe RV dysfunction with or without myocardial necrosis. The abstract conclusion implies low-dose alteplase as a potential treatment in all submassive PE and not just high-risk patients or patients with evolving hemodynamic instability. Readers unfamiliar with submassive PE treatment could infer low-dose alteplase as a potential treatment for submassive PE without high-risk characteristics or hemodynamic instability. This inference is not representative of the case series patients, is outside current guideline recommendations, and has unclear safety and efficacy. Second, the abstract concluded low-dose alteplase potentially efficacious based on symptomatic and echocardiographic improvement. Although important, it is unclear if these outcomes are attributable to thrombolytics or if they have long-term morbidity or mortality benefit. Konstantinides et al published long-term follow-up on 709 patients with submassive PE and high-risk characteristics who were treated with thrombolysis or placebo. Median follow-up was 37.8 months. Systemic thrombolysis did not improve long-term mortality, chronic pulmonary hypertension, functional limitation, or residual dyspnea. Additional evidence has not shown short-term mortality benefit with systemic thrombolysis. Given these data, the observed short-term morbidity benefit is unlikely to improve long-term morbidity or mortality and we feel one cannot conclude low-dose alteplase potentially efficacious based on short-term observations of symptomatic and echocardiographic benefit alone. Interestingly, no patients experienced clinical deterioration in this case series, despite high complication risk. Systemic thrombolysis decreases hemodynamic decompensation and treatment escalation, though the effect size appears as small as 4%. Given the limited sample and small expected effect size, it is difficult to ascertain whether absence of clinical deterioration was due to treatment effect, chance, or sampling bias. Third, the authors observed no bleeding events and concluded low-dose alteplase potentially safe. Major bleeding is the primary complication of systemic thrombolysis. Reduceddose thrombolysis may decrease risk but evidence is inconsistent. Rothschild et al presented a case series of 45 patients administered low-dose alteplase for submassive PE with high-risk characteristics and 22% had moderate or major bleeding. Although higher than previous reports, this result is interesting as this case series is the largest real-life report of low-dose alteplase utilization for submassive PE. Given the known bleeding event rate, a case series including only 5 patients cannot demonstrate reasonable and generalizable conclusions regarding true risk. Layman and colleagues’ observation of no bleeding events could, in our opinion, simply be due