The shadow of the long-term sequelae of submassive pulmonary emboli has stalked the hearts and minds of Emergency Physicians. The use of thrombolytics to prevent these ramification has previously been supported primarily with surrogate data, physiological reasoning and communal anecdotal experience. Thrombolytics for submassive pulmonary emboli have failed to demonstrate an improvement in short-term mortality (1). The argument in favor of a more aggressive approach is based on the physiologic hypothesis that the use of thrombolytics will prevent downstream morbidity in the form of pulmonary hypertension. While some small RCTs have demonstrated potential benefits of systemic thrombolytics, these results are confounded due to surrogate outcomes or small sample sizes (2, 3). With the publication of PEITHO’s 2-year follow up, we finally have some high quality data examining the long-term benefits of thrombolytics for the management of submassive pulmonary embolism.
Published in JACC in 2017 Konstantinides et al examined 709 of the 1,006 patients that were included in the original study (4). We have discussed this trial in prior posts but briefly, the authors randomized patients 18 years or older presenting with a CT confirmed PE with signs of right heart strain demonstrated on CT or echocardiogram and a positive troponin assay to receive either 30-50 mg of IV tenecteplase or placebo. In their original publication the authors claimed a short-term benefit for thrombolytic therapy, but clinically speaking these effects were minimal. Meyer et al found a 3.0% absolute difference in their primary outcome, the rate of 7-day mortality or hemodynamic decompensation. This difference was made up entirely from patients who demonstrated hemodynamic decompensation, in the form of need for IV vasopressors or hypotension. The mortality in each group was 1.2% and 1.8%, respectively. While hemodynamic decompensation appears clinically relevant, it is in reality a surrogate for the more clinically relevant outcome, death. These small benefits were offset by a 1.8% absolute increase in the rate of intracranial hemorrhage and a 9.1% increase in major hemorrhagic complications.
Shortly after the start of enrollment the authors amended their protocol, and enlisted the remaining 70% of the cohort with the plan to perform an analysis 2-years after randomization. The authors examined long-term mortality, signs of dyspnea, rate of New York Heart failure class III and IV, echocardiographic signs of pulmonary hypertension, and rates of clinically diagnosed chronic thromboembolic pulmonary hypertension (CTEPH).
Of the 709 patients who were enrolled, 98% completed the pre-planned long term analysis. The overall mortality rate in the entire cohort was 19.2%, which was impressively higher than the 30-day mortality presented in their original publication. The use of thrombolytics did not reduce the mortality, 20.3% and 18% of the patients in the thrombolytic and placebo groups respectively died in the 2-years following randomization. The majority of the deaths over this period were related to the underlying disease states that lead to the pulmonary embolism in the first place (COPD, cancer, etc.).
More importantly, there was no difference in the rate of chronic respiratory symptoms reported by the patients who received systemic thrombolytics and those who were administered placebo. 36% and 30.1% of the patients in the thrombolytic and placebo groups reported persistent symptoms at 2-years. The majority of these patients experienced mild exertional dyspnea. Only 12% of the patients in the tenectaplase group and 10.9% of the patients in the placebo group were assigned New York class III and IV functional status. 2.1% and 3.2% of the respective groups were diagnosed with CTEPH during the 2-year follow up period. Nor did the authors find any improvement in echocardiographic findings in the patients given tenectaplase, a finding that was used to support the use of thrombolytics in a previous study.
In some ways these results make our clinical decisions at the bedside easier. The spectrum of pathology defined as submassive pulmonary embolism is vast. These patients can range from the well appearing with small elevations in natriuretic peptides or troponin assays, to the clinically ill appearing with multiple signs of impending collapse. The later group of clinically obvious patients are the subset who may still benefit from thrombolytics. Until now we have been burdened by the threat of long-term consequences of withholding thrombolytic therapy. These risks have been abstract, with minimal features to help us predict which patients were destined for negative outcomes. Since the results of Konstantinides et al do not support the use of systemic thrombolytics to prevent the long-term sequelae of submassive pulmonary emboli, no longer should we worry our failure to act will condemn our patients to life-long disability. No longer are we beholden to radiographic findings of right heart strain, or an elevated natriuretic peptide as abstract threats of an intangible diagnosis. Rather, the decision to administer systemic thrombolytics in the Emergency Department is once again a clinical one and should be limited to the small subset of patients that are teetering on hemodynamic collapse.
- 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.
- Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-7
- Kline JA, Nordenholz KE, Courtney DM, 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):459-68.
- Konstantinides et al. Journal of the American College of CardiologyMar 2017, 69 (12) 1536-1544;
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Why do thrombolytics not make a difference? That to me seems the more interesting question. Do they not dissolve clots? Might targeted catheter-based treatment be more effective? How much time between diagnosis and lysis in that study?
I’ve got a previously fit guy on my ward now, who wasn’t lysed despite Echo showing severe RH strain, and I can’t get him off the oxygen. It seems strange that the TPA doesn’t make a difference.
“Submassive PE” is a large and diverse subgroup. The patient on nasal cannula with a slight troponin elevation and mild pulmonary HTN or RV enlargement falls into the same category as the patient in distress on 100% nonrebreather and a massive, dilated RV with D-sign. What they have in common at enrollment is that they have PEs and are not hypotensive. Otherwise, they are phenotypically very different and will likely have different short-term and long-term responses to thrombolytics. Dr. Oren Friedman’s cogent approach to submassive PEs is to sub-categorize them into “high risk submassive” and “low risk submassive” based on… Read more »
I completely agree. I thought I was pretty clear making this point in the post. Thanks for the additional emphasis!
Thanks Rory. I was looking over this follow up trial again recently and feel that there is an important caveat to their (and your) conclusion. They state that they were able to recruit about 70% (709) of the original PEITHO cohort on an institutional basis, presumably reducing the risk of selection bias. 98% “completed” the planned follow up analysis…. even more impressive. However only 358 patients actually had any clinical or echocardiographic assessment; the other half simply had mortality data recorded. What happened to the rest? The authorsa are quiet on this. So, i agree that 24mo mortality appears much… Read more »