Management appropriateness and outcomes of patients with acute pulmonary embolism

Patients, setting, and eligibility criteria

For this study, we screened patients who presented to the Emergency Department of Ramón y Cajal Hospital (Madrid, Spain) with symptoms of acute PE from January 01, 2003 until December 31, 2016 (figure 1).

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FIGURE 1

Patient flow diagram. PE: pulmonary embolism.

For confirmation of the diagnosis of PE, we required an intraluminal filling defect on PE-protocol contrast-enhanced helical chest computed tomography (CT) [10]; a high probability ventilation–perfusion scan according to the criteria of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) [11]; or a non-diagnostic ventilation–perfusion lung scan and confirmed lower limb deep vein thrombosis (DVT) on venous compression ultrasound [12]. The only exclusion criterion was treatment with therapeutic doses of anticoagulants initiated ≥24 h prior to eligibility assessment.

Adherence to guidelines

Acute therapy after hospitalisation was evaluated for adherence or non-adherence to the management recommended by guidelines [4–6, 13]. Two investigators independently analysed each patient's chart and classified the management as adherent or non-adherent. Discrepancies in adherence determination were resolved by consensus after asking the opinion of a third investigator. Deviation from guidelines defined non-adherent management and was defined as any of the following: 1) Use of intravenous unfractionated heparin (UFH) in a patient without severe renal failure (i.e. creatinine clearance <30 mL·min⁻¹), without severe obesity (i.e. body weight >120 kg) and without unstable PE (defined as cardiogenic shock, systolic blood pressure (SBP) <90 mmHg, or use of inotropic or vasopressor support) [6]; or use of low-molecular-weight heparin (LMWH) in a patient with severe renal failure, severe obesity, or unstable PE [13]. 2. Use of thrombolytic therapy in a haemodynamically stable patient who did not deteriorate soon after diagnosis [5, 6]; or no use of thrombolytic therapy in a haemodynamically unstable patient without major contraindications owing to bleeding risk [4–6]. 3. Insertion of an inferior vena cava filter in a patient without a contraindication to anticoagulant therapy [4–6]; or no insertion of an inferior vena cava filter in a patient with a contraindication to anticoagulant therapy [4–6].

Study outcome measures

Outcomes were assessed during the first month after the diagnosis of acute PE. We used all-cause mortality as the primary outcome of the study (mortality being assessed using patient or proxy interviews and/or hospital chart review). Pre-specified secondary outcomes included PE-specific mortality, recurrent symptomatic venous thromboembolism (VTE) and major bleeding. Two investigators independently adjudicated the cause of death as 1) definite fatal PE, 2) possible fatal PE, or 3) death from other causes. For deaths confirmed by autopsy or those following a clinically severe PE (either initially or shortly after an objectively confirmed recurrent event), the adjudicators judged death as a definite fatal PE in the absence of any alternative diagnosis. Possible fatal PE consisted of death in a patient who died suddenly or unexpectedly after the diagnosis of PE. In cases of disagreement between the reviewers, a third reviewer established the final cause of death by consensus with the other reviewers.

Recurrent symptomatic VTE was defined as a recurrent PE, or a new or recurrent distal or proximal lower extremity DVT, within 1 month of entry to the study with acute PE. For the recurrent PE diagnosis, we required the presence of a new perfusion defect involving 75% or more of a lung segment on V/Q scintigraphy, or a new intraluminal filling defect or an extension of a previous filling defect on PE-protocol chest CT [10]. For a new or recurrent DVT, we required the appearance of a new noncompressible vein segment, or a 4-mm or more increase in the diameter of a thrombus on complete compression ultrasound (CCUS) [14].

We defined major bleeding episodes as those that required a transfusion of at least 2 units of blood, were retroperitoneal, spinal or intracranial, or were fatal [15].

Statistical analyses

We used the Chi-squared test to compare categorical data between patients who received appropriate or inappropriate management. We used the T-test for parametric comparisons between the two groups and the Mann–Whitney U-test when the data were non-parametric.

To estimate the outcomes of time to death and time to VTE recurrence, Kaplan–Meier probabilities were computed [16] and differences between the groups were assessed with the log-rank test. We used logistic regression to assess if the variable of adherence to guidelines had an independent association with 30-day all-cause mortality after adjusting for other variables that had a p-value of less than 0.05 in the univariate analyses. We used a manual backward stepwise approach to develop the multivariate models. Statistical significance was defined as a two-tailed p-value of <0.05 for all analyses. Analyses were performed using SPSS version 18.0 for the PC (SPSS Inc, Chicago, IL, USA).

We performed several sensitivity analyses and, since some of the criteria that shaped the definition for inappropriate management might be more representative than others, we repeated analyses for the most agreed criteria (i.e. no thrombolysis in an unstable patient; no filter in a patient with contraindication to anticoagulation; and no UFH in a patient with severe renal insufficiency, severe obesity, or unstable PE) alone and in combination. We then examined the association between inappropriate management and outcomes for three separate time periods (2003–2008, 2009–2014 and 2015–2016). Finally, we repeated all analyses for the secondary endpoints.

To ensure that our findings were replicable, we used patient data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE). The study design and patient eligibility criteria for RIETE data have been described elsewhere [17]. The validation cohort for this study consisted of a separate group of 34 380 patients from the RIETE registry with acute symptomatic PE.