Cardiopulmonary exercise testing during follow-up after acute pulmonary embolism

Ioannis T. Farmakis, Luca Valerio, Stefano Barco, Eva Alsheimer, Ralf Ewert, George Giannakoulas, Lukas Hobohm, Karsten Keller, Anna C. Mavromanoli, Stephan Rosenkranz, Timothy A. Morris, Stavros V. Konstantinides, Matthias Held, Daniel Dumitrescu
European Respiratory Journal 2023 61: 2300059; DOI: 10.1183/13993003.00059-2023

Abstract

Background Cardiopulmonary exercise testing (CPET) may provide prognostically valuable information during follow-up after pulmonary embolism (PE). Our objective was to investigate the association of patterns and degree of exercise limitation, as assessed by CPET, with clinical, echocardiographic and laboratory abnormalities and quality of life (QoL) after PE.

Methods In a prospective cohort study of unselected consecutive all-comers with PE, survivors of the index acute event underwent 3- and 12-month follow-ups, including CPET. We defined cardiopulmonary limitation as ventilatory inefficiency or insufficient cardiocirculatory reserve. Deconditioning was defined as peak O2 uptake (V′O2) <80% with no other abnormality.

Results Overall, 396 patients were included. At 3 months, prevalence of cardiopulmonary limitation and deconditioning was 50.1% (34.7% mild/moderate; 15.4% severe) and 12.1%, respectively; at 12 months, it was 44.8% (29.1% mild/moderate; 15.7% severe) and 14.9%, respectively. Cardiopulmonary limitation and its severity were associated with age (OR per decade 2.05, 95% CI 1.65–2.55), history of chronic lung disease (OR 2.72, 95% CI 1.06–6.97), smoking (OR 5.87, 95% CI 2.44–14.15) and intermediate- or high-risk acute PE (OR 4.36, 95% CI 1.92–9.94). Severe cardiopulmonary limitation at 3 months was associated with the prospectively defined, combined clinical-haemodynamic end-point of “post-PE impairment” (OR 6.40, 95% CI 2.35–18.45) and with poor disease-specific and generic health-related QoL.

Conclusions Abnormal exercise capacity of cardiopulmonary origin is frequent after PE, being associated with clinical and haemodynamic impairment as well as long-term QoL reduction. CPET can be considered for selected patients with persisting symptoms after acute PE to identify candidates for closer follow-up and possible therapeutic interventions.

Abstract

Cardiopulmonary exercise limitation is frequent after PE and associated with persisting clinical, echocardiographic and laboratory abnormalities as well as worse QoL. CPET may serve as a diagnostic modality for patients with persisting symptoms after PE. https://bit.ly/3SRlEGQ

Introduction

Acute pulmonary embolism (PE) affects millions of patients worldwide annually, causing significant morbidity and mortality [1], and imposing a significant burden on healthcare systems [2]. Although global mortality rates have decreased or remained stable over the past two decades [3, 4], survivors of acute PE may suffer from long-term sequelae. “Milder” manifestations may consist of physical deconditioning, while functional limitation may be accompanied by ventilatory inefficiency and gas exchange disturbance in patients diagnosed with chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension [5–7]. However, even in the absence of confirmed CTEPD, objective signs of persisting or progressing right ventricular dysfunction associated with symptoms and/or functional limitation may be found, with a recently reported cumulative incidence of 16% over 2 years [8].

Cardiopulmonary exercise testing (CPET) permits a holistic assessment of cardiopulmonary functional status, and enables the detection of abnormalities in ventilation, gas exchange, the heart and circulation, and musculoskeletal function [9, 10]. The role of CPET in the context of PE and its sequelae has thus far mainly focused on the diagnostic workup of chronic thromboembolic pulmonary hypertension (CTEPH); in case–control studies, CTEPH patients had limited exercise capacity compared with CTEPD without pulmonary hypertension and with sedentary controls [11–13]. Observational studies using CPET have begun to elucidate the origin and prevalence of exercise limitation following acute PE [14–16]; however, it still remains unclear whether, and to what extent, post-PE abnormalities are the result of residual pulmonary vascular occlusion. For example, insufficient regional perfusion could expand ventilatory dead space volume (VD) and compromise ventilatory efficiency, while heightened pulmonary artery obstruction could impede right ventricular function and attenuate the cardiocirculatory response to exercise [15].

In the present study, we prospectively studied a large population of patients who were discharged from hospital after an index acute PE episode; they belonged to a multicentre cohort of consecutive unselected patients (“all-comers”) with acute PE [8]. We sought to determine 1) the association between exercise intolerance after PE with patterns of ventilatory inefficiency or insufficient cardiocirculatory reserve; and 2) the relation between CPET-defined abnormalities with baseline parameters and comorbidities at the time of acute PE as well as with outcome parameters, notably a prespecified combination of persisting clinical, functional and haemodynamic abnormalities, and quality of life (QoL).

Methods

Study population

This prospective cohort study was conducted at four large-volume German sites. All of them participated in the FOllow-up after aCUte pulmonary emboliSm (FOCUS) study that consecutively enrolled unselected adult patients with confirmed diagnosis of acute symptomatic PE [8]. Patients with incidental PE and patients with previously diagnosed CTEPH were excluded. The primary objective of FOCUS was to determine the incidence of CTEPH and clinically relevant “post-PE impairment” over a 24-month systematic follow-up.

The centres participating in the present study had prospectively agreed to integrate CPET in their follow-up visit protocols. CPET was performed at the predefined visits 3 and 12 months after the index event. The CPET-generated parameters were exported from the devices of each centre, interpreted by one experienced investigator (D.D.) who was blinded to the patients’ baseline characteristics and findings at follow-up, and subsequently integrated into the FOCUS complete dataset captured in the electronic case report form [17]. The study was approved by the ethics committees of the participating sites and written informed consent was obtained from all patients before enrolment.

CPET protocol, parameter selection and functional status classification

A prespecified cycle ergometer protocol was implemented at each one of the four participating sites; it included a resting phase, an unloaded phase, an incremental exercise phase and a recovery phase. The incremental phase was performed with a ramp protocol until the patient stopped the exercise or an adverse event on exercise occurred (supplementary table S1). The exercise goal included a respiratory exchange ratio (RER) at peak exercise >1.05. Among the parameters recorded or calculated during CPET, we focused on those recently proposed as being best associated with (ab)normal exercise response and patterns of exercise limitation [18, 19]. We defined the following patterns of exercise limitation, adapting thresholds recommended in expert consensus statements [18, 19]: 1) cardiopulmonary limitation, meeting at least one of the following criteria: a) ventilatory inefficiency, defined as either minute ventilation to CO2 production (V′E/V′CO2) slope ≥30 or V′E/V′CO2 nadir ≥30, or b) insufficient cardiocirculatory reserve, defined as peak O2 pulse <80% of the predicted value when RER >1.05); 2) exercise intolerance without a pattern of cardiopulmonary limitation (deconditioning), defined as peak O2 uptake (V′O2) <80% of the predicted value and meeting none of the criteria of ventilatory inefficiency or insufficient cardiocirculatory reserve; 3) normal CPET, defined as peak V′O2 ≥80% of the predicted value and meeting none of the criteria of ventilatory inefficiency or insufficient cardiocirculatory reserve; and 4) submaximal effort, defined as early termination of the test and meeting none of the criteria of ventilatory inefficiency or insufficient cardiocirculatory reserve.

We defined severe ventilatory inefficiency as V′E/V′CO2 slope or V′E/V′CO2 nadir ≥36 and mild/moderate inefficiency as V′E/V′CO2 slope or V′E/V′CO2 nadir ≥30 but <36. Severe insufficient cardiocirculatory reserve was defined as peak O2 pulse <70% of the predicted value with RER >1.05; mild/moderate insufficiency was present when peak O2 pulse was ≥70% but <80% of the predicted value, combined with RER >1.05.

Definitions of late PE sequelae

The diagnosis of CTEPH was adjudicated by an independent committee based on a dedicated adjudication charter and according to guideline recommendations in effect during the conduct of the study [20]. The outcome “post-PE impairment” was defined as progression in severity or persistence in the highest severity category, of 1) at least one echocardiographic (haemodynamic) abnormality of the right ventricle or pulmonary circulation plus 2) at least one clinical, functional or laboratory abnormality at two consecutive post-PE follow-up visits [8].

QoL measures

QoL was assessed at 3 and 12 months with the use of disease-specific and generic health-related QoL questionnaires. Disease-specific QoL was assessed with the German validated version of the Pulmonary Embolism Quality of Life Questionnaire (PEmb-QoL) instrument, which generates a global percentage score (0–100%) with higher values indicating worse QoL [21]. Generic health-related QoL was assessed with the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire, which generates an overall index ranging from 0 (lowest QoL) to 1 (highest QoL) [22].

Statistical analysis

Categorical variables are presented as frequency and percentage, while continuous variables are presented as median with interquartile range (IQR). We performed a descriptive analysis of the CPET parameters by characterising the course of exercise limitation patterns, as defined earlier, at the two visits and illustrating it with an alluvial plot. Subsequently, we investigated the effect of baseline variables and that of time (3-month versus 12-month visit) on 1) the pattern of exercise limitation (cardiopulmonary limitation, deconditioning and submaximal effort, with normal findings as reference) using mixed effects multivariable multinomial logistic regression; and 2) the presence and severity of cardiopulmonary limitation using mixed effects multivariable ordinal logistic regression. The mixed effects design allowed the intercept to vary by subject to account for the association of measurements performed on the same subject. We also used mixed effects multivariable linear regression models to investigate the effect of time on the different CPET parameters, again allowing the intercept to vary by subject.

Multivariable logistic regression was used to investigate the association of the presence and severity of cardiopulmonary limitation at the 3-month visit with the presence of post-PE impairment as a dependent variable. Since this outcome could be evaluated already at the 3-month visit, and in view of the fact that two CPET-derived parameters (peak V′O2 and peak systolic blood pressure) could be used as a criterion for its diagnosis, we performed a sensitivity analysis excluding the patients with evaluable post-PE impairment at the 3-month visit. Finally, we used mixed effects multivariable linear regression to investigate the association of the presence and severity of cardiopulmonary limitation at 3 months with the global PEmb-QoL score and EQ-5D-5L index at 3 and 12 months, again allowing the intercept to vary by subject.

All regression models were adjusted for the following covariates assessed at baseline (time of PE diagnosis): age (per decade), sex, body mass index (continuous), history of heart failure or coronary heart disease, history of chronic lung disease, active cancer, smoking, acute PE risk class (intermediate- or high-risk PE versus low-risk PE, based on current guidelines) [1] and time of follow-up. Two-tailed p-values <0.05 were considered significant. R version 4.1.3 (www.r-project.org) was used for data analysis.

Results

Study population

Of 580 patients enrolled at the participating sites, 396 (68.3%) had at least one CPET examination during follow-up and were included in the analysis (supplementary figure S1). Patients undergoing CPET at follow-up were younger (median (IQR) age 60 (48–71) versus 70 (58–77) years) and less likely to suffer from heart failure, coronary artery disease, chronic lung disease or cancer (24% versus 44%) than those who did not (supplementary table S2). Baseline characteristics of the patients who underwent CPET are provided in table 1.

View this table:
TABLE 1

Baseline characteristics of study patients (n=396)

Course of CPET parameters and exercise limitation patterns during follow-up

Of the included patients, 363 had CPET at 3 months and 268 at 12 months (table 2). Patterns of exercise limitation at each one of the follow-up visits are shown in supplementary figure S2. At 3 months, 182/363 patients (50.1%) had at least one abnormal parameter among V′E/V′CO2 slope, V′E/V′CO2 nadir and peak O2 pulse, indicating cardiopulmonary limitation (figure 1). Of these, 69.2% showed only ventilatory inefficiency, 13.2% had only insufficient cardiocirculatory reserve and 17.6% had both. Severe cardiopulmonary limitation was observed in 56/363 patients (15.4%) at 3 months (figure 1). Among these, severe ventilatory inefficiency was present in 31/56 (55.4%) patients, severely insufficient cardiocirculatory reserve in 12/56 (21.4%) patients and both in 13/56 (23.2%) patients. At 12 months, cardiopulmonary limitation of any severity was present in 120/268 patients (44.8%) (figure 1). Of patients with CPET at both time-points, cardiopulmonary limitation resolved among 27/109 (24.8%) patients, while 21/126 (16.7%) patients developed new cardiopulmonary limitation after the first test at 3 months. Cardiopulmonary limitation was severe in 42/268 (15.7%) patients (figure 1). Subgroup analyses are shown in supplementary figure S3. Analysis of comorbidities and other baseline characteristics yielded, with the exception of smoking and chronic pulmonary disease, no significant differences between patients who underwent CPET only at 3 months and those in whom it was repeated at 12-month follow-up.

View this table:
TABLE 2

Cardiopulmonary exercise testing parameters 3 and 12 months after acute pulmonary embolism

FIGURE 1
FIGURE 1

Alluvial plot depicting the levels of cardiopulmonary limitation over 1-year follow-up in patients with pulmonary embolism.

Age, history of chronic lung disease, smoking and intermediate- or high-risk (versus low-risk) index PE were all independently associated with the presence and severity of cardiopulmonary limitation (table 3). The severity of limitation did not change considerably throughout the duration of follow-up after PE and none of the CPET parameters appeared to improve or deteriorate when examined individually as continuous variables (supplementary table S3).

View this table:
TABLE 3

Mixed effects ordinal logistic regression showing the association between baseline variables and follow-up visit with the presence and severity of cardiopulmonary limitation

As shown in supplementary figure S4, 100/253 (39.5%) patients without significant chronic comorbidities (active cancer, history of heart failure or coronary artery disease, or history of chronic lung disease and age ≥80 years) showed cardiopulmonary limitation on CPET at 3 months, while 71/194 (36.6%) patients did so at 12 months. Among those patients without comorbidities, an intermediate- or high-risk index PE event remained significantly associated with the presence or increasing severity of cardiopulmonary limitation (OR 4.99, 95% CI 1.86–13.39).

Of note, deconditioning at follow-up was not associated with the baseline variables apart from chronic lung disease (supplementary table S4).

CPET parameters and late PE sequelae

Throughout the study period, 9/396 patients (2.3%) were diagnosed with CTEPH. Median (IQR) time to diagnosis was 134 (111–182) days. Eight of the nine patients underwent CPET at 3 months after the initial PE. Of the six patients in whom V′E/V′CO2 slope and V′E/V′CO2 nadir were recorded, all manifested severe ventilatory inefficiency, while insufficient cardiocirculatory reserve was present in four out of eight patients (supplementary table S5).

Out of 393 patients with evaluable criteria for post-PE impairment, 48 (12.2%) were diagnosed with this late outcome. Individual CPET values in these patients are presented in supplementary table S6. A normal CPET was present only in 7.0% and 7.1% of patients with post-PE impairment at 3 and 12 months, respectively, while deconditioning was present in 14.0% and 10.7%, respectively. Cardiopulmonary limitation was highly prevalent in patients with this outcome, being detected in 79.1% (39.5% with severe) and 78.6% (64.3% with severe) at 3 and 12 months, respectively (figure 2). Ventilatory inefficiency was much more common among patients with post-PE impairment (88.2%) than insufficient cardiocirculatory reserve (38.3%) (supplementary table S7). In patients with post-PE impairment, V′O2 at anaerobic threshold, apex end-tidal CO2 tension (PETCO2), V′E/V′CO2 slope and V′E/V′CO2 nadir worsened over time (supplementary table S3). After adjusting for baseline variables, patients with severe cardiopulmonary exercise limitation at 3 months were more likely to be diagnosed with post-PE impairment compared with those without limitation (OR 6.40, 95% CI 2.35–18.45).

FIGURE 2
FIGURE 2

Doughnut plots depicting the levels of cardiopulmonary limitation in patients with and without post-pulmonary embolism (PE) impairment at a) 3 months and b) 12 months.

Association of severity of cardiopulmonary exercise limitation at 3 months with long-term QoL

Of the 363 patients with a CPET examination at 3 months, 93.1% and 79.9% had a recorded PEmb-QoL questionnaire and 94.8% and 84.6% had a recorded EQ-5D-5L questionnaire at 3 and 12 months, respectively. Figure 3 presents the distribution of PEmb-QoL dimensions across the levels of cardiopulmonary exercise limitation. After baseline adjustment, severe cardiopulmonary limitation at 3-month follow-up was associated (compared with no cardiopulmonary limitation) both with a worse global PEmb-QoL score (β 14.8, 95% CI 8.4–21.2) and a worse EQ-5D-5L index (β −0.08, 95% CI −0.14– −0.02), while mild/moderate cardiopulmonary limitation was not (β for PEmb-QoL 4.7, 95% CI −0.2–9.5; β for EQ-5D-5L index −0.03, 95% CI −0.08–0.01).

FIGURE 3
FIGURE 3

Box-and-whisker plots depicting the distribution of Pulmonary Embolism Quality of Life Questionnaire (PEmb-QoL) dimensions at a) 3 months and b) 12 months across the three levels of cardiopulmonary limitation (at 3 months). PEmb-QoL score: best=0%, worst=100%. ADL: activities of daily living.

Discussion

In this prospective cohort of unselected patients with acute PE, a cardiopulmonary exercise limitation pattern was observed in 50% of the patients at 3-month follow-up; of these, approximately 90% had evidence of ventilatory inefficiency and 30% had evidence of insufficient cardiocirculatory reserve. Cardiopulmonary limitation was severe in 15% of the patients, without evidence of amelioration throughout the 1-year follow-up period. Importantly, severe limitation at 3 months strongly predicted subsequent “post-PE impairment” as defined by a combination of clinical, functional and echocardiographic criteria, and it was associated with worse long-term disease-specific and generic health-related QoL.

The findings of our study may help to shed light into an as-yet understudied field of research. It has in fact been proposed that deconditioning may by far be the most prevalent explanation of persisting functional limitation [23]. This notion was mainly supported by a study in which 47% of apparently healthy patients with a first episode of acute symptomatic PE showed peak V′O2 <80% at 12 months [14]. The authors concluded that the most likely cause for the exercise limitation was muscle deconditioning rather than any circulatory or ventilatory defect. By encompassing a broader, unselected population (also including survivors of intermediate- and high-risk PE) in the FOCUS study, and by utilising CPET parameters more likely to reflect physiological defects related to residual pulmonary vascular obstruction [9, 15], we observed that a significant proportion of all PE patients (∼50%) had at least one marker of ventilatory or cardiocirculatory defect and that ∼65% of patients with post-PE impairment had severe cardiopulmonary limitation at 12 months. Our results are thus in agreement with a recent study, in which 65% of 40 patients complaining of post-PE dyspnoea showed an elevated physiological dead space proportion (VD/tidal volume (VT)) at anaerobic threshold and/or a decreased stroke volume reserve, indicating cardiopulmonary limitation rather than sole deconditioning [15].

As expected, increasing age and important comorbidities were significantly associated with cardiopulmonary limitation in our study. Nevertheless, after excluding patients exhibiting these baseline characteristics, as high as 40% of PE patients without major chronic comorbidities showed a pattern indicating a cardiopulmonary origin of exercise limitation. Of note, intermediate- or high-risk PE as defined in European guidelines [1] was associated with more severe cardiopulmonary limitation and specifically with ventilatory inefficiency during follow-up. In a previous small study of 20 survivors of submassive and massive PE, exercise limitation was common and was attributed to physical deconditioning [16]. Although in the present study we used relatively high CPET threshold values to define cardiopulmonary exercise limitation [19], functional impairment could indeed be attributed to intrinsic cardiopulmonary defects.

The vast majority of patients with post-PE impairment based on prospectively defined criteria [8] exhibited cardiopulmonary limitation at 3 and 12 months; there was in fact a strong association between severe limitation at 3 months and the subsequent diagnosis of post-PE impairment. Of note, ventilatory inefficiency was not as severe in patients with post-PE impairment as it was in patients with confirmed CTEPH. In this context it has been reported that, in patients with CTEPD without pulmonary hypertension, pulmonary vascular inefficiency as depicted by the V′E/V′CO2 slope is present but less severe than in CTEPH [7, 24, 25]. Viewed together with these previous data, our findings suggest that post-PE impairment may share common pathophysiological abnormalities with CTEPD. Follow-up imaging after PE is not standard of care and was not routinely available in the present study; consequently, we can neither confirm nor contradict previous data that suggested a lack of association of residual thrombus in the pulmonary vasculature with exercise limitation in patients 12 months post-PE [26]. Our prior work, however, disclosed that ventilatory dead space proportion (VD/VT) during exercise, which we estimate by V′E/V′CO2, highly correlated with the number of lung segments containing unmatched perfusion defects after PE [15].

Our results are in line with current recommendations for post-PE patient follow-up [1]; they appear to support the diagnostic role and the potential prognostic value of CPET 3 months after acute PE. Although CPET is currently not routinely recommended in the follow-up of all patients after PE [1], our results suggest that it may be helpful in patients who complain of persisting symptoms and functional limitation, especially if echocardiography yields inconclusive findings regarding the presence of pulmonary hypertension. In these cases, CPET could help to identify the origin of functional limitation, discriminate it from deconditioning and potentially guide further targeted examinations, such as stress echocardiography, ventilation/perfusion lung scan and (if indicated) right heart catheterisation, possibly along with prescription of a cardiopulmonary rehabilitation programme if appropriate [6, 27]. Whether there is a role for measures shown to prevent or ameliorate physiological defects disclosed by CPET in CTEPH [28, 29] in patients after PE, even in the absence of pulmonary hypertension, remains to be investigated.

The multicentre prospective design with a large population of consecutive all-comers with acute PE and a systematic, comprehensive long-term follow-up, including CPET evaluation, are the major strengths of this study. However, a number of limitations need to be kept in mind in order to put our results into the right perspective. First, not all patients from the four participating centres underwent CPET, which may particularly affect the extrapolation of our findings to frail patients, notably those at advanced age and with comorbidities. Second, there was no matched control group of patients without PE in this observational study and there could also be no “baseline” CPET data of the included patients before the index PE event. We further acknowledge the V′E/V′CO2 is an imperfect reflection of the VD/VT [30], which is the most direct physiological reflection of residual pulmonary vascular occlusion [15, 27]. For example, elevated V′E/V′CO2 could be found not only in pulmonary vascular pathologies, but also in patients with panic disorder [31]. The alveolar–arterial CO2 tension gradient (PA–aCO2) might be a valuable parameter to discriminate between the two; however, measurement requires either an arterial catheter or transcutaneous PCO2 measurement, which was only infrequently performed in our cohort. In addition, apart from a history of chronic pulmonary disease which was captured in the electronic case report form, data on lung function or computed tomography reads were generally lacking; of patients with available data, only a small percentage (<10%) had a breathing reserve <15%, suggesting little participation of the breathing reserve in their exercise limitation. Finally, we cannot exclude slight deviations from the harmonised CPET protocol among the participating centres.

Conclusions

As many as half of patients show abnormal exercise capacity of cardiopulmonary origin after PE. Severe cardiopulmonary limitation is evident in up to 15% of the patients, and is significantly associated with the presence of post-PE impairment and worse long-term QoL. CPET may serve as a powerful diagnostic modality for patients with persisting symptoms or functional limitations after PE in order to identify a population eligible for closer follow-up and potential therapeutic considerations.

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Footnotes

  • This work was registered with the German Clinical Trials Register (DRKS) with identifier DRKS00005939. Proposals for data access will be considered in accordance with the data access policy of the study sponsor (University Medical Center of the Johannes Gutenberg University, Mainz, Germany).

  • Author contributions: I.T. Farmakis contributed to the design of the study, statistical analysis, interpretation of the results, writing of the manuscript and final approval of the article. L. Valerio contributed to statistical analysis, interpretation of the results, critical revision of the manuscript and final approval of the article. S. Barco, E. Alsheimer, R. Ewert, G. Giannakoulas, L. Hobohm, K. Keller, A.C. Mavromanoli and S. Rosenkranz contributed to the interpretation of the results, critical revision of the manuscript and final approval of the article. T.A. Morris, S.V. Konstantinides, M. Held and D. Dumitrescu contributed to the concept and design of the study, interpretation of the results, writing of the manuscript, and final approval of the article.

  • Conflicts of interest: S. Barco reports grants or contracts from Bayer, INARI, Boston Scientific, Medtronic, Bard, Sanofi and Concept Medical, consulting fees from INARI, payment or honoraria from INARI, Boston Scientific and Concept Medical, and support for attending meetings and/or travel from Bayer and Daiichi Sankyo. R. Ewert reports lecture fees from Boehringer Ingelheim, OMT, Novartis, Janssen-Cilag, United Therapeutics, AstraZeneca and Berlin-Chemie, research funding from Boehringer Ingelheim, OMT and Janssen-Cilag, and consulting fees from BetaPharm, OMT and Lungpacer Medical. G. Giannakoulas reports personal lecture/advisory fees from Bayer HealthCare, Pfizer and LeoPharma. L. Hobohm reports consulting fees and lecture honoraria from MSD and Janssen. S. Rosenkranz reports grants or contracts from Actelion, AstraZeneca, Bayer, Janssen and Novartis, consulting fees from Abbott, Acceleron, Actelion, Bayer, Janssen, MSD, Novartis, Pfizer, United Therapeutics and Vifor, and payment or honoraria from Actelion, Bayer, BMS, Ferrer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, United Therapeutics and Vifor. T.A. Morris reports research funding from INARI. S.V. Konstantinides reports grants or contracts from Bayer AG, consulting fees from Bayer AG, Daiichi Sankyo and Boston Scientific, and payment or honoraria from Bayer AG, INARI Medical, MSD, Pfizer and BMS. M. Held reports honoraria for lectures and advisory board activities from AstraZeneca, Bayer HealthCare, Berlin-Chemie, Boehringer Ingelheim, BMS, Daichi Sankyo, Janssen, MSD, OMT, Pfizer and Santis. D. Dumitrescu reports honoraria for lectures or consulting fees from Actelion, Bayer, Boehringer Ingelheim Pharma, GlaxoSmithKline, Janssen, MSD, Novartis, OMT, Pfizer, Servier and Vifor. The remaining authors disclose no potential conflicts of interest.

  • Support statement: This cohort study used data from the FOllow-up after aCUte pulmonary emboliSm (FOCUS) study. FOCUS is an independent, investigator-initiated study with an academic sponsor (University Medical Center of the Johannes Gutenberg University, Mainz, Germany). The work of S.V. Konstantinides and S. Barco was supported by the German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503). In addition, the sponsor received a grant from Bayer AG. The funding bodies had no influence on the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received January 10, 2023.
  • Accepted March 3, 2023.
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Cardiopulmonary exercise testing during follow-up after acute pulmonary embolism
Ioannis T. Farmakis, Luca Valerio, Stefano Barco, Eva Alsheimer, Ralf Ewert, George Giannakoulas, Lukas Hobohm, Karsten Keller, Anna C. Mavromanoli, Stephan Rosenkranz, Timothy A. Morris, Stavros V. Konstantinides, Matthias Held, Daniel Dumitrescu
European Respiratory Journal Jun 2023, 61 (6) 2300059; DOI: 10.1183/13993003.00059-2023
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