There has been exciting research into submassive PE (a.k.a., intermediate-risk PE) recently with the release of MOPETT, PEITHO, TOPCOAT, and ULTIMA.   In a prior blog post I discussed these studies in detail and suggested that our approach to PE is based on tradition rather than evidence.   In summary, heparin is viewed as the mainstay of therapy despite a lack of evidence that it causes acute improvement.   Alteplase is proven to cause immediate improvement in submassive PE.   However, alteplase is avoided due to fear of bleeding, despite little evidence that it increases the risk of intracranial hemorrhage or major bleeding compared to heparin (tables below).   New studies suggest that half-dose alteplase may be safer with equivalent efficacy.

Although prior studies have suggested a mortality benefit of thrombolysis in submassive PE, mortality rates are so low that it is nearly impossible for a single study to prove mortality benefit.   It is plausible that thrombolysis should reduce mortality.   Thrombolysis has been proven to cause immediate improvements in pulmonary hypertension, which is the mechanism of death due to PE.   While many of us may have secretly believed that thrombolysis reduces mortality, the new meta-analysis in JAMA provides evidence for this.

This paper is a meta-analysis of prospective randomized trials of thrombolysis in 2,115 patients with submassive or massive PE.   Thrombolysis reduced all-cause mortality by 44% with a NNT of 59 (p=0.01), an effect also seen among the subgroup with submassive PE.   Thrombolysis did increase major bleeding from 3% to 9%, but this effect was largely restricted to patients >65 years old (among patients <65 years old, major bleeding increased by 0.6% which was not statistically significant).   Despite increased bleeding among patients >65 years old, this subgroup still experienced a 1.6% reduction in mortality with thrombolysis (p = 0.07).

The main limitation of this study is that it lumps all doses and types of thrombolytics together.   This will obscure differences between different drugs and different dosages.   For example, the intracranial hemorrhage rate with full-dose tenecteplase was very high (12/574).   In contrast, all of the half-dose alteplase studies combined had an intracranial hemorrhage rate of 0/293 (table below).   This difference in intracranial hemorrhage rate is statistically significant, suggesting that it may not be valid to combine all studies when evaluating the risk of adverse events.   Likewise, it is possible that the mortality reduction could be greater than 44% when using half-dose alteplase (if this dosing has similar efficacy with reduced bleeding complications).

Until recently submassive PE has left physicians in a very uncomfortable position.  There was increasing evidence that thrombolysis improves long-term outcomes and reduces the risk of hemodynamic collapse and death.   However, the mortality benefit of thrombolysis remained unproven, and this exposed physicians to professional liability if there was a hemorrhagic complication.   In some cases, a single catastrophic hemorrhage may have scared an entire institution away from thrombolysis.  

Evidence that thrombolysis reduces mortality in submassive PE may clarify this situation.   The absolute mortality benefit of thrombolysis for submassive PE (1.5%) is greaterthan the mortality benefit of thrombolysis for inferior ST-elevation myocardial infarction (0.9%), which is standard therapy at facilities without percutaneous coronary intervention (Bates 1997).   Thrombolysis of submassive PE is far superior to thrombolysis for ischemic stroke, which has no mortality benefit and carries a 5% risk of intracranial hemorrhage (Cochrane Rev 2009).

Overall this mortality benefit suggests that younger patients should be offered thrombolytic therapy in the context of shared decision-making with informed consent.   Half-dose alteplase has been shown to be effective and safe in several studies (table above), so this may be a reasonable approach as we await additional evidence.   It should be emphasized that there is no risk-free approach to submassive PE, and some bad outcomes will occur regardless of what treatment pathway is taken.  

With emerging evidence including Chatterjee et al, it is increasingly clear that thrombolysis improves mortality and morbidity for many patients with submassive PE.   However, important questions remain including how to approach older patients (although patients >65 years old experience an increased risk of bleeding, they retained a strong trend towards reduced mortality).   The precise definition of submassive PE remains unclear, especially in patients who may have chronic right ventricular dilation due to pulmonary hypertension.

This study may pave the way for a randomized controlled trial of heparin versus thrombolysis for submassive PE (figure above).   To date, most large studies of thrombolysis have compared heparin to heparin plus thrombolysis.   This design is based on the assumption that heparin must be provided urgently to all patients.   Typically any excess bleeding is blamed on the thrombolytic (rather than the synergistic combination of heparin plus thrombolysis).   In this fashion, the dogma that all patients require heparin leads to circular logic which maintains this assumption (figure below).   Given increasing evidence of benefit with thrombolysis, it is time to question whether thrombolytics (rather than heparin) should be the initial therapy for patients with submassive and massive PE.