"Post-Pulmonary Embolism Syndrome" after a First Episode of PE: Results of the E.L.O.P.E. Study

Background: Most pulmonary embolism (PE) research has focused on acute and short-term outcomes such as mortality and PE recurrence. Whether long-term morbidity such as exercise limitation, impaired quality of life (QOL) and persistent dyspnea occurs after PE is largely unstudied. To address this knowledge gap, we performed the ELOPE study, a prospective, observational, multicenter cohort study of long-term outcomes after acute PE (www.clinicaltrials.gov NCT01174628).

Objectives: The objectives of the ELOPE (Evaluation of Long-term Outcomes after PE) Study were: (1) to describe and quantify degree of exercise limitation, QOL impairment and persistent dyspnea at 1 year after PE; and (2) to identify predictors of poor functional status at 1 year.

Methods: Patients ≥18 years old with a 1^st episode of acute PE diagnosed within the previous 10 days screened at 5 Canadian recruiting centers were potentially eligible to participate. Exclusion criteria were subsegmental-only PE, preexisting severe cardiopulmonary comorbidity, previous proximal DVT, contraindication to CT pulmonary angiography (CTPA), life expectancy <1 year, unable to read questionnaire in English and French or to attend follow-up visits, and unable or unwilling to consent.

After the Baseline (B) visit, patients attended follow-up (FU) visits at 1, 3, 6 and 12 months to measure QOL (SF-36, PEmbQoL), dyspnea (UCSD SOBQ), and 6-minute walk test (6MWT) [all FU visits]; undergo CTPA [B, 12], echocardiogram [B, 12], Q scan [6, 12], cardiopulmonary exercise testing (CPET) [1, 12] and pulmonary function tests [1, 12]; and measure biomarkers (BNP, ddimer, troponin) [B, 6].

The primary study outcome was maximal aerobic capacity defined by peak oxygen uptake (VO2) as a percent of predicted maximal VO2 (VO2max) on 1-year CPET, with <80% predicted VO2max considered abnormal, as per American Thoracic Society guidelines.

For the present analysis, we summarized demographic and clinical characteristics of study subjects, the proportion of patients with VO2max <80% predicted on 1 year CPET (primary outcome), and compared mean QOL and dyspnea scores in patients with vs. without the primary outcome. Multivariate logistic regression analyses were done to identify demographic, clinical and functional predictors of abnormal VO2max at 1 year, with adjustment for relevant confounding variables.

Results: 984 patients were screened for participation; of these, 150 were eligible and 100 (67%) consented to participate. Mean (SD) age was 50 (15) years, 57% were male, 80% were outpatients and 33% had concomitant DVT. PE was provoked in 21% and unprovoked in 79%; none were cancer-related.

At 1 year, 40/86 (46.5%) of patients had <80% predicted VO2max on CPET; these patients had worse 1-year SF-36 MCS (mental) (p=0.002) and PCS (physical) (p=0.009) scores, PEmbQoL scores (p=0.002) and SOBQ scores (p=0.003), compared to patients with >80% predicted VO2max at 1 year.

Independent baseline predictors of abnormal VO2max at 1 year included: male sex (relative risk (RR)= 3.2 [95% CI 1.3-8.1]; p=0.015), age (RR 0.98 [95% CI 0.96-0.99] per 1 year age increase; p=0.002), BMI (RR 1.1 [95% CI 1.01-1.2] per 1 kg/m² BMI increase; p=0.023), and smoker (RR 1.8 [95% CI 1.1-2.9]; p=0.023). In addition, VO2max <80% predicted at 1 month and 6MWT distance at 1 month were significantly associated with risk of abnormal VO2max at 1 year (RR 3.8 [95% CI 1.9-7.2; p<0.0005] and RR 0.82 [95% CI 0.7-0.9; p=0.001] per 30m increased walking distance, respectively). Inpatient status at enrolment, previous lung disease, unprovoked vs. provoked PE, concurrent DVT, and number of days with symptoms before PE diagnosis did not influence VO2max at 1 year.

Conclusions: PE is a common and serious cardiovascular illness, yet clinically relevant information on characteristics and determinants of long-term outcome after PE have been lacking. Results of the ELOPE Study indicate that almost half of PE patients can be considered to have a "post-PE syndrome" characterized by exercise limitation at 1 year, which influences their QOL and degree of dyspnea. Predictors of this post-PE syndrome include male sex, younger age, higher BMI and smoking. CPET testing or 6MWT testing at 1 month may help to identify patients with a higher risk of post-PE syndrome at 1 year.

Funding: Canadian Institutes of Health Research (MOP-93627)