Management of high-risk acute pulmonary embolism: an emulated target trial analysis

Abstract

Background: High-risk acute pulmonary embolism (PE) is a life-threatening condition necessitating hemodynamic stabilization and rapid restoration of pulmonary perfusion. In this context, evidence regarding the benefit of advanced circulatory support and pulmonary recanalization strategies is still limited.

Methods: In this observational study, we assessed data of 1060 patients treated for high-risk acute PE with 991 being included in a target trial emulation to investigate all-cause in-hospital mortality estimates with different advanced treatment strategies. The four treatment groups consisted of patients undergoing (I) veno-arterial extracorporeal membrane oxygenation (VA-ECMO) alone (n = 126), (II) intrahospital systemic thrombolysis (SYS) (n = 643), (III) surgical thrombectomy (ST) (n = 49), and (IV) percutaneous catheter-directed treatment (PCDT) (n = 173). VA-ECMO was allowed as bridging to pulmonary recanalization in groups II, III, and IV. Marginal causal contrasts were estimated using the g-formula with logistic regression models as the primary approach. Sensitivity analyses included targeted maximum likelihood estimation (TMLE) with machine learning, inverse probability of treatment weighting (IPTW), as well as variations of estimands, handling of missing values, and a complete target trial emulation excluding the VA-ECMO alone group.

Results: In the overall target trial population, the median age was 62.0 years, and 53.3% of patients were male. The estimated probability of in-hospital mortality from the primary target trial intention-to-treat analysis for VA-ECMO alone was 57% (95% confidence interval [CI] 47%; 67%), compared to 48% (95% CI 44%; 53%) for intrahospital SYS, 34% (95%CI 18%; 50%) for ST, and 43% (95% CI 35%; 51%) for PCDT. The mortality risk ratios were largely in favor of any advanced recanalization strategy over VA-ECMO alone. The robustness of these findings was supported by all sensitivity analyses. In the crude outcome analysis, patients surviving to discharge had a high probability of favorable neurologic outcome in all treatment groups.

Conclusion: Advanced recanalization by means of SYS, ST, and several promising catheter-directed systems may have a positive impact on short-term survival of patients presenting with high-risk PE compared to the use of VA-ECMO alone as a bridge to recovery.

Keywords: High-risk pulmonary embolism; Mechanical circulatory support; Percutaneous catheter-directed treatment; Surgical thrombectomy; Systemic thrombolysis.

Fig. 1

Overview of treatment approaches. Each column includes all patients, who first received the respective treatment approach (VA-ECMO, intrahospital SYS, ST, or PCDT). Number of patients receiving only one treatment approach shown in yellow boxes. Second- and third-line treatment approaches shown in green, and orange, respectively. Group I in the intention-to-treat analysis corresponds to the “VA-ECMO alone” group (dark yellow box). Group II includes patients who received intrahospital SYS, regardless of prior stabilization with VA-ECMO (checkered boxes). Group III consists of patients undergoing ST, regardless of prior VA-ECMO stabilization (boxes with straight lines). Group IV includes patients treated with PCDT, regardless of prior VA-ECMO stabilization (boxes with oblique lines). PCDT percutaneous catheter-directed treatment, ST surgical thrombectomy, SYS systemic thrombolysis, VA-ECMO veno-arterial extracorporeal membrane oxygenation

Fig. 2

In-hospital mortality prediction plots adjusted for all non-modifiable risk factors according to treatment strategy. Adjusted prediction plots providing the expected probability of in-hospital death for a given treatment strategy adjusted for non-modifiable risk factors with point estimates as points and 66.66% and 95% confidence intervals given through thick and thin bars, respectively. A intention-to-treat analysis, B adjusted per-protocol analysis and C as-treated analysis