Keep it simple? Half-dose systemic thrombolysis or catheter-directed thrombolysis for pulmonary embolism

There is significant variability in the management of pulmonary embolism (PE) among different physicians and institutions. While systemic thrombolytic therapy may be associated with a reduction in the morbidity and mortality of intermediate and high-risk PE,^1,2 this potential benefit is closely counterbalanced by concerns for major and life-threatening bleeding. Particularly worrisome is the 1.5–2% incidence of intracranial hemorrhage (ICH) associated with systemic thrombolysis that has been demonstrated in both randomized trials and observational analyses.^1,3,4 To address the risks of bleeding with systemic thrombolysis, catheter directed thrombolysis (CDT) was developed as a theoretically safer modality to locally deliver fibrinolytic therapy directly into the pulmonary arteries. The most studied form of CDT has been ultrasound-assisted thrombolysis (USAT) in which CDT is delivered with the use of a specialized US Food & Drug Administration (FDA)-cleared catheter (EKOS Corp., Bothell, WA, USA) that contains an ultrasound transducer, which aims to disrupt clot ultrastructure and enhance thrombolytic penetration into the clot.^5,6

CDT has been used increasingly to reduce the hemodynamic and clinical sequelae of intermediate and high-risk PE. ⁷ However, significant knowledge gaps exist with regard to the comparative safety and efficacy of USAT, standard CDT, and systemic thrombolysis. First, there are no high-quality data to support the superiority of USAT over standard CDT. Prospective studies have provided support for the use of USAT via demonstration of acute reductions in right ventricular (RV) dysfunction and pulmonary artery (PA) pressures in patients with intermediate and high-risk PE. However, to date, no randomized comparison of standard CDT versus USAT has been performed in patients with PE. Multiple modest-sized observational studies have failed to detect differences in the acute clinical and hemodynamic outcomes of PE patients treated with the two approaches.^8–10 The ongoing SUNSET sPE randomized trial (Standard vs. Ultrasound-assisted Catheter Thrombolysis for Submassive Pulmonary Embolism) [clinicaltrials.gov identifier: NCT02758574] aims to shed light on this issue through examination of several surrogate imaging outcomes.

Second, the optimal dose and duration of systemic thrombolytic therapy remains unknown. The elevated risk of bleeding, including ICH, was demonstrated in studies that administered ‘full-dose’ systemic thrombolysis, alteplase 100 mg or tenecteplase 30–50 mg, at a rapid infusion rate. These dosing regimens were largely developed based on prior studies of effective doses in myocardial infarction and stroke. However, this may not be logical because, unlike the heart and brain, the lungs receive 100% of the cardiac output (unless there is a shunt). Therefore, every molecule of thrombolytic administered systemically is expected to reach the lungs. Two prior randomized trials have demonstrated low bleeding rates with good efficacy assessed by surrogate outcomes with the use of half-dose systemic thrombolysis (alteplase 50 mg) when this dosing strategy has been compared to anticoagulation and full-dose thrombolysis, respectively.^11,12 The question remains: how low can the dose of systemic thrombolysis be while still causing acute improvements in PA pressures or resolution of RV dysfunction?

In the current issue of Vascular Medicine, Sharifi and colleagues seek to clarify our understanding of some of these issues through performance of a retrospective, observational analysis of patients with massive or submassive PE undergoing half-dose systemic thrombolysis versus USAT at their institution. ¹³ The authors examined changes in the RV/LV ratio and PA systolic pressures at 36 hours as measured by surface echocardiography among 47 patients treated with USAT and 50 age and sex-matched comparators treated with half-dose thrombolysis. Roughly 85% of studied patients were intermediate risk, with the remainder being high risk. They discovered that changes in both RV/LV ratio and the PA systolic pressure were remarkably similar to the two techniques of thrombolytic administration. Interestingly, the findings in PASP change also mirrored several prior analyses of CDT, with a general trend present throughout the published literature of PASP acutely dropping from approximately 50 to 35 mmHg over 24–48 hours with use of thrombolysis. Finally, the authors also provided the first cost analysis of systemic thrombolysis versus USAT and discovered a roughly $4500 average increase in cost with USAT, primarily driven by the cost of the catheters and intensive care unit (ICU) stays.

Overall, the current study forces us to reconsider a current and expanding practice pattern: delivery of thrombolysis via CDT. Is it possible that we could achieve the perceived benefits of CDT by simply dropping the dose of systemically administered thrombolytic agents in PE? Although we will not know for certain without a prospective study, the question is a logical one and the current study raises the stakes on addressing these issues more systematically. The onus is generally on interventional therapies to prove their worth in terms of clinical outcomes and patient-centric functional measures in order to justify increased complexity of care, potential for intervention-specific complications, and the increased costs associated with procedures. The field of PE intervention is not developing in this fashion, with interventional therapies commonly used in the absence of prospective, comparative safety and effectiveness data supporting their utilization.

In the absence of solid scientific evidence, other incentives can fill the void. Currently, these incentives may favor the use of invasive therapies, but this is unlikely to last forever. As the current study suggests, if the use of invasive PE therapies continues to expand, hospitals will have reason to carefully evaluate their support for these procedures given the possibility of marginal financial losses on these hospitalizations due to associated equipment, catheterization laboratory, and ICU costs. Similarly, payers have often taken a negative view of expensive endovascular procedures that have not demonstrated clear evidence of patient benefit against standard-of-care comparators. Thus, expecting a ‘bail-out’ on hospital costs through enhancement of diagnosis-related group payments is not a good bet in the absence of high-quality research to support this therapeutic approach. As worried as some may now be about the potential for overuse of interventional therapy for PE, it may be even more frustrating in the future to have our hands tied when we would like to employ a therapy for a patient but cannot because the field did not produce the evidence to justify reimbursement a priori.