Response to letter to the editor: “Clinical controversies in the management of acute pulmonary embolism: evaluation of four important but controversial aspects of acute pulmonary embolism management that are still subject of debate and research”

We appreciate the comments by Casey et al. [1], suggesting that clot burden may be a relevant variable in some pulmonary embolism (PE) patients with initial hemodynamic stability and should continue to be explored as a prognostic marker, while we argued that clot burden as a sole parameter currently has no beneficial role in the risk stratification of hemodynamically stable PE. Right ventricle (RV) dysfunction at presentation of PE is associated with a higher risk of adverse events and mortality, even in hemodynamically stable patients, and a high clot burden is indeed associated with RV dysfunction [2–5]. The question therefore rises whether clot burden can also be used as a sole parameter in predicting clinical adverse events and death, or whether the association between clot burden and clinical outcome is solely based on the causal pathway leading to RV dysfunction eventually resulting in shock. In the latter situation, clot burden would not improve risk stratification algorithms that are based on RV function.

We have summarized the most relevant recent studies on this topic below. A meta-analysis published in 2013 showed no association between clot burden, according to the Qanadli score, and 30-day mortality (odds ratio [OR] 1.22; 95% confidence interval [CI] 0.99–1.51) [6]. Hariharan et al. evaluated the association between clot burden as a sole parameter (measured by Computed tomography (CT)-PASS score) and clinical adverse events (defined as intervention for advanced cardiac life support, intubation or positive pressure ventilation, ventricular tachycardia or ventricular fibrillation, vasopressor therapy, thrombolysis/thrombectomy, or death) in hemodynamically stable patients by performing a multivariate regression analysis adjusting for right-sided heart strain. They also showed no association between a higher clot burden and adverse events (OR 3.34, 95% CI 0.75–14.85). However, as this was a subgroup analysis, loss of power could also be a potential explanation [5]. Vedovati et al. evaluated the predictive role of clot burden (measured by the Qanadli score) and all-cause death or clinical deterioration and showed no association in both the overall study population and hemodynamically stable patients [7]. In contrast, Huang et al. indeed showed a correlation between clot burden (total embolic volume measured by a 3D-based CT method) and impending shock (defined as normotension at arrival and subsequent development of hypotension requiring vasopressor), even in hemodynamically stable patients and when corrected for RV dysfunction (OR 2.28 95%CI 1.27–4.29) [8].

To evaluate the role of clot burden in the risk stratification of PE patients, we should focus on analyses correcting for RV dysfunction that evaluate the additional value of clot burden by measuring relevant parameters such as reclassification index or sensitivity/specificity rather than just a risk or odds ratio. Based on the current literature, increased clot burden as a sole parameter showed no predictive value for mortality. The predictive role of increased clot burden as a parameter in predicting other adverse events is still not fully established as evidence is inconsistent. Notably, available studies used different measurements of clot burden and different definitions of adverse events have been evaluated at unclear timing after acute PE presentation. Also, we expect – but have not thoroughly investigated – that publication bias is applicable, meaning that studies showing no association are less likely to be published and are therefore underrepresented.

Based on the above and taking into account that an accurate measurement of clot burden is time consuming, the best method to measure clot burden is not established and high-quality management studies using clot burden to decide on mode of treatment are unavailable to date, we have argued that clot burden should not be routinely used as a sole parameter to identify hemodynamically stable patients at risk for deterioration in current practice. Moreover, we warn against this practice as it may lead to unjustified application of advanced PE treatment in patients with large clot burden or saddle emboli. We agree that the role of clot burden in acute PE management might be more prominent in the future if studies show that altered management decisions based on the addition of clot burden on top of RV dysfunction result in better health outcomes. However, until such studies have been performed, both the presence and extend of RV dysfunction as well as the hemodynamic and respiratory status of patients should be leading arguments for making management decisions.

Declaration of interest

FA Klok reports grants or contracts from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, Pharm-X, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe Program, all unrelated to this work and paid to his institution. MV Huisman reports grants from The Netherlands Organisation for Health Research and Development (ZonMW) and Dutch Heart Foundation, grants from Boehringer-Ingelheim, grants from Pfizer-BMS, grants from Bayer Health Care all outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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