Author + information
- Received July 11, 2016
- Revision received December 21, 2016
- Accepted December 28, 2016
- Published online March 20, 2017.
- Stavros V. Konstantinides, MD, PhDa,b,∗ (, )
- Eric Vicaut, MD, PhDc,
- Thierry Danays, MDd,
- Cecilia Becattini, MDe,
- Laurent Bertoletti, MD, PhDf,
- Jan Beyer-Westendorf, MDg,
- Helene Bouvaist, MDh,
- Francis Couturaud, MD, PhDi,
- Claudia Dellas, MDj,
- Daniel Duerschmied, MDk,
- Klaus Empen, MDl,
- Emile Ferrari, MDm,
- Nazzareno Galiè, MDn,
- David Jiménez, MD, PhDo,
- Maciej Kostrubiec, MDp,
- Matija Kozak, MDq,
- Christian Kupatt, MDr,
- Irene M. Lang, MDs,
- Mareike Lankeit, MDa,j,
- Nicolas Meneveau, MD, PhDt,
- Massimiliano Palazzini, MDn,
- Piotr Pruszczyk, MDp,
- Matteo Rugolotto, MDu,
- Aldo Salvi, MDv,
- Olivier Sanchez, MDw,x,y,
- Sebastian Schellong, MDz,
- Bozena Sobkowicz, MD, PhDaa and
- Guy Meyer, MDw,x,bb
- aCenter for Thrombosis and Hemostasis, University Medical Center, Mainz, Germany
- bDepartment of Cardiology, Democritus University of Thrace, Alexandroupoli, Greece
- cClinical Research Unit, Fernand-Widal Hospital, Assistance Publique Hôpitaux de Paris, University Paris Diderot, Paris, France
- dBoehringer Ingelheim, Reims, France
- eDepartment of Internal and Cardiovascular Medicine–Stroke Unit, University of Perugia, Perugia, Italy
- fDepartment of Vascular Medicine and Therapy, Saint-Etienne University Hospital Center, Saint-Etienne, France; INSERM (National Institute of Health and Medical Research) U1059, Saint-Etienne, France; INSERM CIC1408, Saint-Etienne, France
- gCenter for Vascular Diseases, Division of Thrombosis Research, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
- hCardiology Service, Michallon Hospital, Grenoble University Hospital Center, Grenoble, France
- iDepartement of Internal Medicine and Pulmonology, Equipe d'Accueil 3878, CIC INSERM 0502, La Cavale Blanche Hospital, University of Western Brittany, Brest, France (INNOVTE, France)
- jCardiology and Pulmonology Clinic, University Medical Center Göttingen, Göttingen, Germany
- kHeart Center, University of Freiburg, Freiberg, Germany
- lErnst Moritz Arndt Greifswald University Hospital, Greifswald, Germany
- mDepartment of Cardiology, University Hospital of Nice, Nice, France
- nDepartment of Experimental, Diagnostic and Specialty Medicine–DIMES, Bologna University Hospital, Bologna, Italy
- oDepartment of Respiratory Diseases, Ramon y Cajal Hospital, IRYCIS, Madrid, Spain
- pDepartment of Internal Medicine and Cardiology, Medical University of Warsaw, Warsaw, Poland
- qUniversity Medical Center, Ljubljana, Slovenia
- rKlinikum Rechts der Isar, TU Munich, and German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
- sDepartment of Cardiology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
- tDepartment of Cardiology, Equipe d'Accueil 3920, Structure Fédérative de Recherche 4234, University Hospital Jean Minjoz, Besançon, France (INNOVTE, France)
- uDepartment of Cardiology, Ca Foncello Hospital, Treviso, Italy
- vAzienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
- wPulmonology and Intensive Care Service, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
- xParis Descartes University, Sorbonne Paris Cité, Paris, France
- yINSERM UMR S 1140, Paris, France (INNOVTE, France)
- zMunicipal Hospital of Dresden-Friedrichstadt, Dresden, Germany
- aaMedical University, Bialystok, Poland
- bbINSERM UMR S 970, Paris, France (INNOVTE, France)
- ↵∗Address for correspondence:
Dr. Stavros V. Konstantinides, Center for Thrombosis and Hemostasis, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Background The long-term effect of thrombolytic treatment of pulmonary embolism (PE) is unknown.
Objectives This study investigated the long-term prognosis of patients with intermediate-risk PE and the effect of thrombolytic treatment on the persistence of symptoms or the development of late complications.
Methods The PEITHO (Pulmonary Embolism Thrombolysis) trial was a randomized (1:1) comparison of thrombolysis with tenecteplase versus placebo in normotensive patients with acute PE, right ventricular (RV) dysfunction on imaging, and a positive cardiac troponin test result. Both treatment arms received standard anticoagulation. Long-term follow-up was included in the third protocol amendment; 28 sites randomizing 709 of the 1,006 patients participated.
Results Long-term (median 37.8 months) survival was assessed in 353 of 359 (98.3%) patients in the thrombolysis arm and in 343 of 350 (98.0%) in the placebo arm. Overall mortality rates were 20.3% and 18.0%, respectively (p = 0.43). Between day 30 and long-term follow-up, 65 deaths occurred in the thrombolysis arm and 53 occurred in the placebo arm. At follow-up examination of survivors, persistent dyspnea (mostly mild) or functional limitation was reported by 36.0% versus 30.1% of the patients (p = 0.23). Echocardiography (performed in 144 and 146 patients randomized to thrombolysis and placebo, respectively) did not reveal significant differences in residual pulmonary hypertension or RV dysfunction. Chronic thromboembolic pulmonary hypertension (CTEPH) was confirmed in 4 (2.1%) versus 6 (3.2%) cases (p = 0.79).
Conclusions Approximately 33% of patients report some degree of persistent functional limitation after intermediate-risk PE, but CTEPH is infrequent. Thrombolytic treatment did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea or RV dysfunction in these patients. (Pulmonary Embolism Thrombolysis study [PEITHO]; NCT00639743)
- chronic thromboembolic pulmonary hypertension
- long-term survival
- pulmonary embolism
Randomized controlled trials on anticoagulation and reperfusion treatment helped to develop and optimize risk-adjusted management strategies for the acute phase of pulmonary embolism (PE) (1). In contrast, however, little if any progress has been made in testing whether specific therapeutic interventions may increase long-term survival and prevent late sequelae of PE. In particular, the widespread belief among clinicians that early thrombolytic treatment may, by rapidly and effectively reducing the thrombotic burden, minimize the risk of persistent pulmonary hypertension and possibly (right-sided) heart failure over the long term, has not been prospectively investigated in a controlled randomized setting involving a large patient population.
The international PEITHO (Pulmonary Embolism Thrombolysis) trial compared a single intravenous bolus of the thrombolytic agent tenecteplase plus heparin with placebo plus heparin in 1,006 patients with confirmed PE, right ventricular (RV) dysfunction detected by echocardiography or computed tomographic pulmonary angiography, and a positive troponin I or T test result (2). In the thrombolysis arm of the trial, the primary outcome of all-cause death or hemodynamic decompensation within 7 days occurred less frequently than in the trial arm receiving heparin alone. In parallel, however, a higher incidence of hemorrhagic stroke and major non-intracranial bleeding was observed in patients allocated to tenecteplase than in the placebo arm of the trial (2). Following an amendment of the study protocol, 28 of the PEITHO sites having randomized approximately 70% of the entire study population consented to obtain 2-year survival data and prospectively conduct long-term clinical and echocardiographic follow-up of their patients. The present report, which summarizes these findings, may help to revisit the debate on the possible impact of thrombolysis on the long-term prognosis of patients after acute PE.
Patient population, study design, and 30-day follow-up
PEITHO was a multicenter, double-blind, placebo-controlled randomized trial. The study design has been described previously (3). Briefly, patients were eligible for the study if they met all the following criteria: age 18 years or older; objectively confirmed acute PE with first symptoms 15 days or less before randomization; RV dysfunction confirmed by echocardiography or spiral computed tomography of the chest; and myocardial injury confirmed by a positive troponin I or T test result. Eligible patients were centrally randomized using a computerized Internet-based system, and randomization was stratified by center. The protocol required randomization to be performed within 2 h after the investigator became aware of the presence of both RV dysfunction (by receiving the echocardiography or computed tomography report) and myocardial injury (by receiving a positive cardiac troponin test result).
Patients who were assigned to thrombolysis received a single weight-based intravenous bolus (administered over 5 to 10 s) of the thrombolytic agent tenecteplase. Patients assigned to placebo were administered a single intravenous bolus of the same volume and appearance. Unfractionated heparin was started in both arms of the trial as an intravenous bolus followed by infusion at a rate adjusted to achieve and maintain an activated partial thromboplastin time 2.0 to 2.5 times that of control. The use of anticoagulant agents other than unfractionated heparin was not allowed until 48 h after randomization; after that time, treatment with anticoagulant agents was continued according to local practice. The primary efficacy outcome was defined as the clinical composite of all-cause death or hemodynamic decompensation (or collapse) within 7 days of randomization. All patients were followed up for 30 days and were evaluated for death, hemodynamic decompensation (or collapse), bleeding, stroke, recurrent PE, and serious adverse events.
Long-term follow-up and outcomes assessment
The third protocol amendment of the PEITHO trial, which focused on the long-term follow-up of randomized patients, was approved by the central ethics committee in March 2012. The patients’ vital, clinical, and hemodynamic status was recorded 24 months or later after randomization. Clinical and (whenever possible) echocardiographic assessment was performed during an appointment at the participating center. If the assessment was performed earlier, follow-up was repeated at or after month 24. If the patient had died, the date and primary cause of death were recorded by contacting the patient’s physician. In patients whose symptoms and/or echocardiogram indicated pulmonary hypertension, further diagnostic work-up was performed as recommended by guidelines available at the time of the trial (1,4). The diagnostic work-up and management of chronic thromboembolic pulmonary hypertension (CTEPH) were considered standard medical care and were not part of the study protocol.
The statistical analysis of the PEITHO trial has been described previously (2,3). In the present study, the basis of the analysis of the patients’ long-term outcome consisted of events that occurred in the intention-to-treat population, defined as all randomized patients who signed the informed consent form and participated in the follow-up at the 28 sites. Analysis of the long-term mortality rates in the 2 treatment arms, and of the patients’ clinical and echocardiographic parameters at long-term follow-up, was carried out using a 2-sided chi-square test of proportions. In addition, Kaplan-Meier curves representing survival estimates were compared using log-rank statistics. In patients who were alive on the date of the last contact with the study site, the date of this contact was the censoring date. For continuous variables, the Student t test was used for comparison of means. All results are presented in the intention-to-treat population. All tests were performed using SAS software version 9.2 (SAS Institute, Cary, North Carolina).
Baseline characteristics of study patients and 2-year mortality rate
Between November 2007 and July 2012, 1,006 patients were enrolled at 76 sites in 13 countries. The intention-to-treat population consisted of 1,005 patients, 506 randomly assigned to treatment with tenecteplase plus unfractionated heparin and 499 randomly assigned to placebo plus unfractionated heparin. All but 5 patients received the assigned study drug. Overall, 28 PEITHO study sites, which had randomized a total of 709 patients, participated in the long-term follow-up (median 37.8 months; interquartile range: 24.6 to 54.8 months). At these sites, the survival rate and causes of death were assessed in 353 of 359 (98.3%) patients in the tenecteplase arm of the trial and in 343 of 350 (98.0%) in the placebo arm. The demographic data, clinical status at baseline, and medical history of these patients are shown in Table 1. Comparison of baseline parameters between the patients followed over the long term and analyzed in the present study and the subpopulation of “nonfollowed” patients did not reveal significant differences between the 2 treatment arms, with the exception of body weight and a history of previous venous thromboembolism (Table 2).
Table 3 displays the rates of overall and cause-specific early (within 30 days of randomization) death, as well as the late mortality rates (i.e., deaths occurring between 30 days and long-term follow-up in the 2 treatment arms). The corresponding Kaplan-Meier curves representing the long-term survival estimates are shown in the Central Illustration. The overall mortality rate in the entire study population was 19.2%; no significant differences were observed between patients who underwent thrombolysis with tenecteplase and patients randomized to heparin anticoagulation alone (p = 0.43). Most late deaths occurring between day 30 and long-term follow-up resulted from cancer, acute or chronic respiratory failure, or other illness (mostly acute infections or chronic systemic inflammatory diseases). The cause of death could not be identified in 32 and 35 cases in the tenecteplase and placebo arms of the trial, respectively (Table 3).
Long-term clinical and echocardiographic follow-up
Clinical and echocardiographic follow-up examination of PE was performed in survivors. The clinical status could be obtained in 175 and 183 patients in the tenecteplase and placebo arms of the trial, respectively. Sixty-three (36.0%) of the patients in the tenecteplase arm and 55 (30.1%) in the placebo arm reported persistent clinical symptoms after PE (p = 0.23). In most of these cases (55 of 63 and 50 of 55 patients, respectively), the leading symptom was mild exertional dyspnea; only 21 patients (12.0%) randomized to tenecteplase and 20 (10.9%) randomized to placebo were in New York Heart Association functional class III or IV. Peripheral edema was recorded in 9 (5.1%) and 4 patients (2.2%), respectively. Other symptoms or clinical signs indicating heart failure (syncope or pre-syncope on exertion, chest pain at rest or on exertion, prominent RV impulse, accentuation or splitting of the second heart sound, auscultation of a third [S3] or fourth [S4] heart sound, jugular venous distention, hepatomegaly, or ascites) were distinctly rare and were documented in <2% of the patients in each treatment arm.
Echocardiography was performed as part of the long-term follow-up in 144 and 146 patients in the thrombolysis and control arms, respectively. The findings, which are summarized in Table 4, did not reveal significant differences between the 2 treatment arms regarding the presence of residual pulmonary hypertension or RV dysfunction. Among patients with data obtained on at least 4 of the echocardiographic parameters shown in Table 4, 1 or more indicators of pulmonary hypertension and/or RV dysfunction were recorded in 63 (44.1%) of the patients randomized to tenecteplase and in 52 (36.6%) of those who received placebo (p = 0.20). However, echocardiographically estimated systolic pulmonary artery pressures were mildly elevated in the majority of cases (median 30.0 mm Hg; interquartile range: 25.0 to 35.0 mm Hg) (Table 4). Post hoc application of the echocardiographic criteria proposed in the 2015 European Society of Cardiology/European Respiratory Society Guidelines for the diagnosis and treatment of pulmonary hypertension (5) classified the probability of (chronic) pulmonary hypertension as low in 60% of the patients randomized to tenecteplase and 68% of the patients who received placebo (p = 0.26) and as intermediate in 25% and 28% of the patients, respectively, in the 2 groups.
A definitive diagnosis of CTEPH was made in 4 of 190 (2.1%) patients randomized to tenecteplase and in 6 of 186 (3.2%) allocated to placebo (p = 0.79). All these patients were alive and had not (yet) undergone surgical treatment at the time of follow-up.
In PEITHO, a large randomized thrombolysis trial of acute PE, treatment with tenecteplase significantly reduced the incidence of the combined primary outcome “death or hemodynamic collapse at 7 days,” but it was also associated with a 2% rate of hemorrhagic stroke and a 6.3% rate of major extracranial bleeding (2). The present analysis of the trial patients who underwent long-term follow-up revealed no impact of thrombolysis on the overall long-term mortality rate, which was relatively low (20.3% and 18.0%, respectively) in both treatment arms. Persisting symptoms were reported by 33% of the study patients, but the degree of functional limitation and the elevation of echocardiographically estimated systolic pulmonary artery pressure were mild in most cases, regardless of whether the patients had initially been treated with thrombolysis or anticoagulation alone. In agreement with these findings, most patients (85% and 96% in the tenecteplase and placebo arms, respectively) had a low or intermediate ultrasound-based probability of chronic pulmonary hypertension. The diagnosis of CTEPH was confirmed in 2.1% and 3.2% of the patients randomized to tenecteplase and placebo, respectively.
Since 2005, several controlled randomized trials (6) contributed to substantial improvement in the management of acute PE, mainly by optimizing diagnostic algorithms as well as anticoagulation and reperfusion strategies. In parallel, data obtained from registries (7) and population studies (8–10) consistently documented a decrease in case-fatality rates in the acute phase of PE, even though some doubts remain that overdiagnosis of the disease could exert a confounding effect on these favorable trends (10,11). The 30-day mortality rates in the PEITHO trial (2), which focused on a population with elevated risk of an adverse outcome (termed “intermediate-high-risk” PE), are in agreement with these observations. PEITHO thus provides solid evidence to support the recommendations of current guidelines, which emphasize that prompt initiation of anticoagulation treatment may, along with hemodynamic monitoring and the option of rescue reperfusion if signs of hemodynamic decompensation appear, result in high early survival rates even in patients with “severe” PE (1,12). In contrast, the existing data on the long-term outcome of patients with PE, and particularly on the possible impact of early therapeutic interventions on the risk of late death, are much less conclusive. In 1992, investigators reported that as many as 24% of patients with PE were dead at 1-year follow-up, and most deaths were the result of cancer or serious cardiopulmonary comorbidity (13). In another cohort study, published in 2004, a lower cumulative all-cause mortality rate of 13% at 1 year was reported (14). Importantly, none of the randomized thrombolysis trials (15) was powered to permit reliable assessment of late clinical outcomes. In the present study, the long-term all-cause mortality rate was 19.2%, and no significant differences were observed between patients who were randomized to thrombolysis with tenecteplase and patients who initially received heparin anticoagulation alone. As in the previous reports, most deaths occurring after the first 30 days resulted from comorbidity or underlying disease, and there was no evidence that they might have resulted from progressive right-sided heart failure following the index event or from recurrent PE thereafter. Consequently, it is not surprising that early thrombolysis did not appear capable of preventing these late deaths.
It is conceivable that early thrombolysis may exert favorable prolonged effects other than reducing overall mortality rates. In fact, some degree of persistent pulmonary hypertension or RV dysfunction has been reported in as many as 40% of survivors followed over 6 months to 1 year after acute PE (16). However, the number of patients followed in cohort studies was rather small, standardization of the echocardiographic parameters remains a largely unresolved issue, and, most importantly, a correlation of ultrasound findings with the severity of patients’ symptoms or the degree of functional limitation at follow-up could not be demonstrated (17). In the present study, echocardiographic follow-up, which was performed in 290 randomized patients, yielded 1 or more indicators of pulmonary hypertension and/or RV dysfunction in a high proportion (44%) of the patient population. However, persistent clinical symptoms, which were reported by 33% of the patients evaluated, were mostly mild, with 11.5% of the patients in New York Heart Association functional class III or IV. Moreover, there was no indication that early thrombolysis had a positive impact on the presence or severity of symptoms, the patients’ functional status, or the echocardiographic parameters over the long term. These results do not appear to support the hypothesis generated by 2 small randomized trials, namely that thrombolysis might improve, compared with anticoagulation alone, functional capacity (as part of a combined clinical outcome) at 3 months (18) or the persistence (or development) of pulmonary hypertension at 28 months (19). However, in the former study, the absolute numbers of late events were low in both treatment arms, and the small difference in favor of thrombolysis over the long term appeared to be mainly driven by the rates of “low perception of wellness” determined on the basis of the 36-Item Short Form (SF-36) survey (18). In the latter study, which used nonstandardized criteria to define “moderate” acute PE and allocate patients to reduced-dose alteplase treatment versus heparin alone, mean estimated systolic pulmonary artery pressure at 28-month follow-up was 43 ± 6 mm Hg in the control (anticoagulation-only) arm, and as many as 57% of the patients in that group were reported to have an estimated systolic pressure higher than 40 mm Hg (19). Late morbidity of such severity appears surprising in view of the findings of the present study, in which mean systolic pulmonary pressures were approximately 31 mm Hg in either treatment arm, even though we focused on patients with elevated-risk (intermediate- to high-risk) acute PE.
First, long-term follow-up was performed by only 28 of the 76 PEITHO sites, which had included, in total, 709 patients or approximately two-thirds of the entire randomized population. However, selection bias is unlikely because randomization was, by protocol, stratified by center and, within centers, performed in blocks to ensure balanced distribution of the treatment groups; moreover, comparison between the patients who were followed over the long term and analyzed in the present study and patients who did not participate in the follow-up did not, with the exception of body weight and a history of previous venous thromboembolism, reveal significant differences with regard to baseline characteristics. Second, the causes of late death (beyond the first 30 days) were not centrally adjudicated and remained unidentified in some cases. Third, clinical and echocardiographic examinations could not be performed in all survivors. The echocardiographic findings analyzed in the present study therefore cannot be considered definitive evidence of how often pulmonary hypertension or RV dysfunction persists (or develops) after acute PE and cannot ascertain the possible impact of thrombolysis on the long-term hemodynamic course of these patients.
Finally, and despite the relatively large number of randomized patients and patients in follow-up, the PEITHO trial cannot resolve the debate on the true incidence of CTEPH after acute PE and on whether thrombolysis might help to prevent this late complication. Over a median follow-up exceeding 3 years, CTEPH was diagnosed in 2.7% of the study patients. This rate appears slightly lower than that observed in some of the earlier cohort studies (14,20), but extrapolation of previous data and of our data to the general population is limited by the possibility that an unknown proportion of patients may have had pre-existing pulmonary hypertension at baseline (20). The diagnostic algorithm for suspected CTEPH was not part of the PEITHO trial protocol, and confirmed cases were not externally adjudicated.
In a large, prospective randomized controlled trial of patients with intermediate- to high-risk PE, thrombolytic treatment with tenecteplase did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea, functional limitation, or persisting RV dysfunction, which were mostly mild in both treatment arms. These results suggest that future trials investigating advanced reperfusion regimens and modalities for acute PE should primarily focus on early efficacy and, particularly, safety outcomes while also prospectively including an adequately long period of prospective follow-up that will permit the assessment of the patients’ clinical and hemodynamic course as well as their functional status and quality of life.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Systemic thrombolysis in the acute phase of PE in normotensive patients with RV dysfunction (intermediate-risk PE) did not affect mortality rates over more than 3 years of follow-up, nor did it reduce residual dyspnea, functional limitation, or echocardiographic signs of RV pressure overload. Thus, an expectant strategy of anticoagulation, early monitoring, and rescue reperfusion in cases of hemodynamic decompensation is the preferable initial approach to patients with intermediate-risk PE.
TRANSLATIONAL OUTLOOK: Future trials of alternative reperfusion strategies for acute PE should focus on early efficacy and safety and include sufficient follow-up with standardized assessment of clinical, hemodynamic, and functional outcomes.
The authors are particularly grateful to the members of the PEITHO Steering Committee, Drs. Samuel Z. Goldhaber, Nils Kucher, and Giancarlo Agnelli, for their important contributions to the design, performance, and successful completion of the PEITHO trial. The authors also thank Philippe Gallula, Luigi Visani, Marco Villa, Laurence Guery, Veronique Jouis, Murielle Courrèges-Viaud, Florence Ghrenassia, and Gudrun Heinrichs for their support.
This work was supported by grants from the Federal Ministry of Education and Research (BMBF; 01KG0802, 01EO1003, and 01EO1503) of Germany; grants from the Programme Hospitalier de Recherche Clinique (PHRC; AOM 03063, AOM 08231, and AOM 10171) of France; and by a grant from the market authorization holder of tenecteplase, Boehringer Ingelheim, to the trial sponsor, Assistance Publique Hôpitaux de Paris. Dr. Konstantinides has received consultant fees and lecture honoraria from Bayer HealthCare, Boehringer Ingelheim, Daiichi-Sankyo, Pfizer, and Bristol-Myers Squibb (BMS); has received payment for travel accommodation and meeting expenses from Bayer HealthCare; and has received institutional grants from Boehringer Ingelheim, Bayer HealthCare, and Daiichi-Sankyo. Dr. Vicaut has received honoria for advisory board membership and lectures from AstraZeneca, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Johnson & Johnson, Merck Sharpe & Dohme, and Pfizer; has received consulting fees from Pfizer, Bristol-Myers Squibb, Eli Lilly, Celgene, Novartis, and Abbott; and has received institutional grants from Boehringer Ingelheim. Dr. Danays is an employee of Boehringer Ingelheim. Dr. Becattini has received lecture honoraria from Bayer HealthCare, Pfizer, Bristol-Myers Squibb, and Boehringer Ingelheim. Dr. Bouvaist has received payment for travel accommodation and meeting expenses and lecture honoraria from Bayer HealthCare, AstraZeneca, Medtronic, GlaxoSmithKline, and Actelion; and has received institutional grants from Biosensor. Dr. Couturaud has received research grant support from Pfizer; has been a co-investigator in clinical trials with Bayer, Bristol-Myers Squibb, Boehringher Ingelheim, AstraZeneca, GlaxoSmithKline, Leo Pharma, Pfizer, Roche, Novartis, Merck Sharpe & Dohme, Daiichi-Sankyo, Gilead; has received fees for scientific board memberships or symposia from Bristol-Myers Squibb, Boehringer Ingelheim, Bayer HealthCare, Merck Sharpe & Dohme, and AstraZeneca; and has received travel support from Bristol-Myers Squibb, AstraZeneca, Bayer HealthCare, Daiichi-Sankyo, Leo Pharma, Roche, and Actelion. Dr. Kupatt has received lecture honoraria from Boehringer Ingelheim. Dr. Lang has received consultant fees and lecture honoraria from AOP Orphan Pharmaceuticals, Actelion, Bayer-Schering, AstraZeneca, Servier, Cordis, Medtronic, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics; and was an investigator in trials involving products of these companies. Dr. Lankeit has received consultant fees and lecture honoraria from Bayer HealthCare, Daiichi-Sankyo, Pfizer, Bristol-Myers Squibb, and Actelion. Dr. Meneveau has received payment for travel accommodation or meeting expenses from Bayer HealthCare, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo; is a member of the scientific advisory board for Bayer HealthCare, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo; has received consultant fees and lecture honoraria paid to his institution from Bayer HealthCare, Pfizer, Bristol-Myers Squibb, AstraZeneca, St. Jude Medical, and Daiichi-Sankyo; and has received institutional grants from Boehringer Ingelheim, Bayer HealthCare, and Daiichi-Sankyo. Dr. Meyer has received reimbursement for travel accommodation or meeting expenses from Bayer HealthCare and Daiichi-Sankyo; is a member of the scientific advisory board of Leo Pharma; has received consultant fees and lecture honoraria paid to his institution from Bayer HealthCare, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo; and has received institutional grants from Boehringer Ingelheim. Dr. Pruszczyk has received payment for travel accommodation or meeting expenses, consultant fees, and lecture honoraria from Bayer HealthCare, Pfizer, and Boehringer Ingelheim. Dr. Sanchez has received payment for travel accommodation or meeting expenses from Bayer HealthCare, GlaxoSmithKline, Actelion, Boehringer Ingelheim, and Chiesi; is a member of the scientific advisory board for Actelion, Bayer HealthCare, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, and Chiesi; has received consultant fees and lecture honoraria paid to his institution from Actelion, Bayer HealthCare, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, and Chiesi; and has received institutional grants from Bayer HealthCare, Actelion, Daiichi-Sankyo, and Portola. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- chronic thromboembolic pulmonary hypertension
- pulmonary embolism
- right ventricular
- Received July 11, 2016.
- Revision received December 21, 2016.
- Accepted December 28, 2016.
- 2017 American College of Cardiology Foundation
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