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Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism Prevalence of CTEPH after pulmonary embolism Laurent Guérin1; Francis Couturaud2; Florence Parent3; Marie-Pierre Revel4; Florence Gillaizeau5; Benjamin Planquette1; Daniel Pontal1; Marie Guégan2; Gérald Simonneau3; Guy Meyer1,6; Olivier Sanchez1,6 Paris Descartes, Sorbonne Paris Cité; APHP, service de Pneumologie et Soins Intensifs, Hôpital Européen Georges Pompidou, Paris, France; 2Université Européenne de Bretagne, Université de Brest, EA3878, IFR148, et Département de Médecine Interne et de Pneumologie, CHU de La Cavale Blanche, Brest, France; 3Université Paris-Sud ; APHP, service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France; 4Université Paris Descartes, Sorbonne Paris Cité; APHP, service de Radiologie, Hôpital Européen Georges Pompidou, Paris, France; 5Université Paris Descartes, Sorbonne Paris Cité; APHP, Unité de Recherche Clinique, Hôpital Européen Georges Pompidou, Paris, France; 6INSERM UMR970, Paris, France
Summary Chronic thromboembolic pulmonary hypertension (CTEPH) has been estimated to occur in 0.1–0.5% of patients who survive a pulmonary embolism (PE), but more recent prospective studies suggest that its incidence may be much higher. The absence of initial haemodynamic evaluation at the time of PE should explain this discrepancy. We performed a prospective multicentre study including patients with PE in order to assess the prevalence and to describe risk factors of CTEPH. Follow-up every year included an evaluation of dyspnea and echocardiography using a predefined algorithm. In case of suspected CTEPH, the diagnosis was confirmed using right heart catheterisation (RHC). Signs of CTEPH were searched on the multidetector computed tomography (CT) and echocardiography performed at the time of PE. Of the 146 patients analysed, eight patients (5.4%) had suspected CTEPH during a median follow-up of 26 months. CTEPH was confirmed using Correspondence to: Olivier Sanchez, MD, PhD Service de pneumologie et de soins intensifs Hôpital européen Georges Pompidou 20 rue Leblanc, 75015 Paris, France Tel.: +33 1 56 09 34 61, Fax: +33 1 56 09 32 55 E-mail: [email protected]
Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the presence of pulmonary hypertension related to incomplete resolution of unique or recurrent pulmonary embolism (PE) and represents one of the leading cause of pulmonary hypertension (PH) (1). The diagnosis of CTEPH represents a clinical challenge because surgical procedure, such as pulmonary endarterectomy, can potentially cure patients with CTEPH (2). The true incidence of CTEPH after an acute PE is currently unknown (3). According to retrospective series, CTEPH occurs in about 0.1% of patients who survived an acute PE (4). More recently, prevalence of 3.1% at one year and 3.8% at two years were reported in prospective studies (5). This discrepancy may be explained by different © Schattauer 2014
RHC in seven cases (4.8%; 95%CI, 2.3 – 9.6) and ruled-out in one. Patients with CTEPH were older, had more frequently previous venous thromboembolic events and more proximal PE than those without CTEPH. At the time of PE diagnosis, patients with CTEPH had a higher systolic pulmonary artery pressure and at least two signs of CTEPH on the initial CT. After acute PE, the prevalence of CTEPH appears high. However, initial echocardiography and CT data at the time of the index PE suggest that a majority of patients with CTEPH had previously unknown pulmonary hypertension, indicating that a first clinical presentation of CTEPH may mimic acute PE.
Keywords Pulmonary embolism, chronic thromboembolic pulmonary hypertension, epidemiology, echocardiography
Received: August 2, 2013 Accepted after major revision: March 25, 2014 Epub ahead of print: June 5, 2014 http://dx.doi.org/10.1160/TH13-07-0538 Thromb Haemost 2014; 112: 598–605
designs of the studies or various methods used to detect and diagnose CTEPH. It may also suggest that in the studies reporting the higher rates, some of the patients with CTEPH diagnosed during follow-up may have preexistent unidentified CTEPH at the time of the acute PE. The absence of initial haemodynamic evaluation at the time of the acute PE in previous reports does not allow identifying patients who already have CTEPH at the time of the initial PE diagnosis. Therefore, the aims of this study were (1) to assess the prevalence of CTEPH after the acute PE, (2) to describe risk factors of CTEPH and (3) to analyse initial echocardiography and spiral computed tomography results in order to try to identify the proportion of patients who have preexistent unidentified CTEPH at the time of the acute PE. Thrombosis and Haemostasis 112.3/2014
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Methods
Table 1: Medical Research Council dyspnea scale.
Study design
Grade
Degree of breathlessness related to activities
This prospective multicentre study took place at three academic centres in France. Patients were enrolled consecutively between January 2006 and May 2007 and were followed-up until July 2010. The study was approved by ethic committee (Comité de Protection des Personnes Ile de France 2).
1
Not troubled by breathlessness except on strenuous exercise
2
Short of breath when hurrying or walking up a slight hill
3
Walks slower than contemporaries on level ground because of breathlessness, or has to stop for breath when walking at own pace
4
Stops for breath after walking about 100 m or after a few minutes on level ground
Patients with an objectively proven PE based on a positive multidetector computed tomography (CT) showing at least multisubsegmental PE or a high-probability ventilation-perfusion lung scan (V/Q scan) were eligible to participate to this study after written informed consent. The exclusion criteria were: previously known CTEPH or pulmonary hypertension at the time of acute PE diagnosis, and any other medical condition that could have caused non-thromboembolic pulmonary hypertension such as known severe chronic respiratory (total lung capacity < 60% of predicted value (pred), or forced expiratory volume in 1 second (FEV1) < 60% pred, or FEV1 / vital capacity < 60% pred), left cardiac insufficiency (ejection fraction < 30%), hematologic disorders (chronic haemolytic anaemia, myeloproliferative disorders), systemic disorders (sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis), metabolic disorders (glycogen storage disease, Gaucher disease, thyroid disorders), fibrosing mediastinitis, chronic renal failure or any other pulmonary arterial hypertension associated condition (human immunodeficiency virus, connective tissue disease, portal hypertension, congenital heart diseases, schistosomiasis).
Evaluation at the time of the acute PE Within 24 hours of their acute PE diagnosis, all patients had a complete clinical evaluation, an echocardiography in order to measure their end-diastolic right-to-left ventricle diameter ratio (RV/LV), and systolic pulmonary artery pressure (sPAP). On admission, a blood sample was collected in order to measure their levels of brain natriuretic peptide (BNP) with an electrochemiluminescence immunoassay (BNP-Triage Biosite assay; lower limit of detection: 10 ng/l) on a DxI analyser (Beckman Coulter Inc., Brea, CA, USA).
Prospective follow-up after PE diagnosis After PE diagnosis, patients were prospectively followed-up each year during a maximum of two years. The duration of curative anticoagulant therapy was left to the discretion of the clinician in charge. At each visit, patients had an evaluation of dyspnea (Medical Research Council [MRC] scale, ▶ Table 1) and an echocardiography using a predefined algorithm as previously described (▶ Figure 1) (6, 7). Colour-flow Doppler echocardiogrphy was used to obtain the best possible alignment between the tricuspid regurgitation and the Doppler ultrasound beam and to measure Thrombosis and Haemostasis 112.3/2014
peak velocity of the tricuspid regurgitation (VTR). If tricuspid regurgitation was absent or VTR not measurable, peak velocity of pulmonary regurgitation (VPR) was considered. CTEPH was suspected in patients with persistent dyspnea (MRC ≥ 2) and if VTR was ≥ 2.8 m/second (s) or if proto-diastolic VPR was ≥ 2.0 m/s and end-diastolic VPR was ≥ 1.2 m/s as previously described in other screening programs of PH (▶ Figure 1) (6, 7). In case of suspected CTEPH, the diagnosis was confirmed in patients with pre-capillary PH defined as mean PAP ≥ 25 mmHg and pulmonary capillary wedge pressure ≤ 15 mmHg on right heart catheterisation (RHC), and at least one segmental perfusion defect on V/Q scan (8). The time between the index PE diagnosis and right heart catheterisation was calculated.
Signs of CTEPH on initial spiral computed tomography In patients for whom acute PE was diagnosed on the basis of a multidetector CT, a senior radiologist, blinded to the presence or absence of confirmed CTEPH during follow-up and to initial echocardiographic data, retrospectively examined the initial CT performed for diagnosing the PE and searched for signs of CTEPH in the CT, such as organised mural thrombi lining the pulmonary vascular walls, arterial webs or bands, mosaic parenchymal perfusion patterns, or dilated bronchial arteries (≥1.5 mm) (9–11).
Statistical methods Prevalence is calculated as the ratio of confirmed CTEPH at RHC during follow-up and the number of patients analysed (per protocol analysis). The 95% confidence interval (CI) was calculated assuming a Poisson distribution. Categorical variables are presented as numbers and percentages, and continuous variables are presented as means ± SD or medians [25% percentile – 75% percentile]. Univariate analysis, based on Chi2-tests or Fisher’s exact test or Student’s t-tests, was performed to assess the association between the characteristics of the patients at PE onset and the presence of CTEPH during followup. Statistical significance was considered at the 0.05 level. We used SAS software version 9.2 (SAS Inc. Cary, NC, USA) for all statistical analysis.
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Patients
Figure 1: Diagnostic algorithm based on evaluation of dyspnea (Medical Research Council (MRC) scale, transthoracic Doppler echocardiography and right heart catheterisation. VTR: peak velocity of the tricuspid regurgitation, VPR : peak velocity of pulmonary regurgitation, CTEPH: chronic thromboembolic pulmonary hypertension, RHC: right heart catheterization, mPAP: mean pulmonary artery pressure, PcwP: pulmonary capillary wedge pressure.
Results
Prevalence of CTEPH
Patients
During follow-up, 8 (5.4%) patients had persistent dyspnea and abnormal echocardiographic findings and were considered as suspected for CTEPH. The diagnosis of CTEPH was confirmed on RHC and abnormal V/Q scan in seven patients and ruled out in one patient. Thus, the overall prevalence, in a per-protocol analysis, of CTEPH among the study population was 4.8% (95% CI, 2.3 – 9.6).
During the study period, 261 patients with an acute objectively proven PE were eligible for this study. Among them, 103 patients were not included for the following reasons: 42 patients died within the first year after PE diagnosis (cancer n=22, PE n=7, sepsis n=3, major bleeding n=1, other n=9), 45 patients refused to consent, eight patients were lost to follow-up, and eight patients had known severe respiratory or cardiac failure. Among the 158 remaining patients enrolled, 12 were excluded based on uninterpretable echocardiography data in five, and seven did not undergo the requested protocol investigations. Thus, the final study population consisted of 146 patients (▶ Figure 2). The median follow-up was 26 (7–45) months. The clinical characteristics of the study population are summarised in ▶ Table 2. All patients received curative anticoagulants during a median duration of 11.7 months (6–24) and five (3%) received thrombolysis. © Schattauer 2014
Characteristics of patients with confirmed CTEPH Individual clinical and haemodynamic characteristics of patients with CTEPH are summarised in ▶ Table 3 and ▶ Table 4. None of these patients had other associated condition for pulmonary hypertension. At the time of their acute PE, patients with confirmed CTEPH had severe elevation of pulmonary pressure (mean systolic PAP (sPAP) = 75 ± 20 mmHg) and right ventricular dilatation (mean RV/LV 0.97 ± 0.3) on initial echocardiography. The Thrombosis and Haemostasis 112.3/2014
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Figure 2: Flow-chart of the study.
diagnosis of CTEPH was confirmed by right heart catheterisation after a mean duration of 13.7 ± 9 months after the PE diagnosis and showed severe pre-capillary pulmonary hypertension in most cases (▶ Table 3). All patients with CTEPH were evaluated for pulmonary endarterectomy (PTE PEA) at the French referral centre for pulmonary hypertension. Two patients were considered operable (#2 and #5) but only one (5, ▶ Table 3) agreed and underwent PEA. Four patients received bosentan for distal severe inoperable CTEPH and the two remaining patients were treated with vitamin K antagonist (VKA) alone (▶ Table 3). Univariate analysis showed that patients with CTEPH were significantly older, had more previous thromboembolic events, had significantly higher sPAP, more proximal PE and significantly higher levels of BNP at the time of the index PE. Thrombosis and Haemostasis 112.3/2014
Signs of pre-existing CTEPH in the CT at the time of the index PE Among the 146 patients analysed (7 with CTEPH and 139 without CTEPH), 118 patients had a multidetector CT for their acute PE diagnosis, 106 were available and were independently interpreted by a senior radiologist. The presence of at least two signs of CTEPH in the multidetector CT was observed in all patients with confirmed CTEPH, compared with 19/99 patients without CTEPH (▶ Table 5).
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Variable
Value
Age, years (mean ± SD)
61 ± 19
Sex M/F, n (%)
60 (41) / 86 (59)
Previous VTE, n (%)
35 (24)
Surgery or trauma < 1 month, n (%)
35 (24)
Cancer, n (%)
17 (12)
Associated DVT, n (%)
52 (36)
HR, bpm (mean ± SD)
88 ±19
RR, bpm (mean ± SD)
23 ± 6
sBP, mm Hg (mean ± SD)
137 ± 23
Cardiogenic shock, n (%)
8 (5)
Diagnosis on multidetector CT, n (%) Troncular PE Lobar PE Segmental PE Multiple sub-segmental PE
118 (81) 38 (32) 35 (30) 40 (34) 5 (4)
Diagnosis on V/Q lung scan, n (%)
28 (19)
RV/LV (mean ± SD) RV/LV > 1, n (%)
0.7 ± 0.3 22 (15)
sPAP, mmHg (mean ± SD) sPAP> 60 mm Hg, n (%)
43 ± 15 20 (14)
BNP, ng/l (mean ± SD)
168 ± 292
VTE: venous thromboembolic disease; DVT: deep venous thrombosis; HR: heart rate; RR: respiratory rate; sBP: systolic blood pressure; PE: pulmonary embolism; RV/LV: right to left end-diastolic diameter ratio; sPAP: systolic pulmonary pressure.
Discussion We found that the prevalence of symptomatic CTEPH was 4.8% (95%CI, 2.3–9.6) among patients who were followed-up for a median time of 26 months after the index PE. Age, previous VTE, proximal PE, high levels of sPAP and BNP at the time of the index PE were identified as risk factors for CTEPH. Lastly, we showed that a majority of patients with CTEPH had already several signs of pre-existing CTEPH in the multidetector CT at the time of the acute PE episode. Initial estimates suggested that 0.1 to 0.5% of patients surviving an episode of acute PE would develop CTEPH (4). More recently, several prospective observational studies have reported that the prevalence of CTEPH varies between 0.4 to 8.8% (5, 12–18) (Suppl. Table 1, available online at www.thrombosis-online.com). This wide variation of prevalence can be explained by differences in inclusion criteria and methods used for screening CTEPH. Studies which performed a single echocardiography reported a lower prevalence of CTEPH (12, 14, 17, 18). Lastly, studies which didn’t confirm CTEPH by RHC (13, 15) found a higher prevalence than those which confirmed the diagnosis by invasive procedures (5, 12, 14, 17, 18). We included patients with a first episode of PE or with previous VTE, but without any other condition that could have caused non thromboembolic pulmonary hypertension. These patients were submitted to a predefined screening algorithm that included dyspnea, echocardiography and RHC. This algorithm was derived from the one used in studies evaluating the prevalence of PH in various populations at risk (6, 7, 19). We used a threshold of 2.8 m/s rather than 2.5 m/s for VTR because it has been suggested that this threshold was associated with a reduction of the false positive rate of echocardiography (7, 19). Indeed, in our study, only one patient had VTR > 2.8 m/s without confirmed
Table 3: Individual characteristics of patients with confirmed CTEPH.
Patient Initial PE
During follow-up
Age (years)
sPAP RV/LV MRC VTR sPAP RV/LV Time to RHC RAP mPAP CO PVR (mmHg) (m/s) (mmHg) (months) (mmHg) (mmHg) (l/min) (UI)
Treatment
1
71
45
0.9
2
3.8
73
1.1
27
11
54
4.9
8.8
VKA + bosentan
2
74
70
1.1
3
5.4
132
1.3
7.2
10
58
3.2
16.1
VKA + bosentan
3
81
81
1.3
5
4.7
100
1.4
7.4
7
52
3.1
11.6
VKA + bosentan
4
77
84
1.1
2
3.5
58
NA
10
7
30
6.2
2.9
VKA
5
70
43
0.5
2
4.2
75
0.7
22.7
4
36
5.7
4.6
VKA + PEA
6
75
62
0.5
2
2.8
56
0.72
3
3
30
3.7
6.1
VKA
7
72
102
0.8
2
4
81
1.1
6.6
4
53
4.5
10.7
VKA + bosentan
Mean
75
75
0.97
13.7
7
45
4.5
7.5
± SD
4
20
0.3
9
3
12
1.2
3.5
RAP =right atrial pressure, CO= cardiac output, PVR = pulmonary vascular resistance, NA= not available, VKA: vitamin K antagonist, PEA: pulmonary thromboendarterectomy.
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Table 2: Clinical, computed tomography and echocardiography findings of 146 patients at the time of the initial PE diagnosis.
603 Table 4: CTEPH+ vs CTEPH-: Analysis of risk factors.
Variable
CTEPH + (N= 7)
CTEPH – (N= 139)
P-value
Age, years (mean ± SD)
74 ± 4
60.5 ± 19
1 n, (%)
0.9 ± 0.3 3 (43)
0.7 ± 0.3 20 (14)
0.2 0.009
sPAP, mm Hg (mean ± SD) sPAP > 60 mm Hg, n (%)
70 ± 21 5 (71)
41 ± 13 15 (10)
0.0009 60 mmHg. These data are unusual in the context of an acute PE. Indeed, it has been shown that despite proximal PE with angiographically estimated vascular obstruction that exceeded 50%, the mean pulmonary arterial pressure did not exceed 40 mmHg in any of patients without prior cardiopulmonary disease or PE (21, 22). It thus appears that the upper limit of pulmonary arterial pressure which the normal human right ventricle can
to the quality of injections in bronchial arteries, this sign was interpretable in only 4 out the 7 CT.
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Guérin et al. Prevalence of CTEPH after PE
maintain acutely is approximately 40 mmHg (22). This significant rise of pulmonary pressure may thus reflect an adaptation of the right ventricle to a chronic obstruction of the pulmonary vascular bed and could explain the significant higher level of BNP at the time of the index PE in patients with CTEPH. In order to test this hypothesis, we returned to the initial multidetector CT in patients with a PE confirmed by this test. Interestingly, we found that all patients with confirmed CTEPH during follow-up had at least two CT signs of CTEPH at the time of the index PE. All multidetector CT were re-interpreted centrally by a senior radiologist who was blinded to the presence or absence of confirmed CTEPH in order to exclude any bias. To the best of our knowledge, our study is the first one that could evaluate the evolution of both pulmonary haemodynamic and imaging data at the time of the index PE and during follow-up. Our study identified several risk factors of CTEPH. Many of them had already been highlighted in previous studies, including previous VTE, older age and the level of importance of pulmonary vascular obstruction during the initial episode of PE (5). Recently, an international prospective registry of CTEPH reported the presence of a confirmed previous PE in 75% of patients, which was reported as massive in 41% (2, 23). Interestingly, pulmonary vascular obstruction at PE onset had been found as an independent risk factor associated with the presence of a perfusion defect after PE (24). Thus, complete reversal of the pulmonary vascular bed by the fibrinolytic system could be made more difficult in cases of proximal obstruction which would promote the development of CTEPH. This hypothesis has been raised by Morris et al., who showed that fibrin from patients with CTEPH was more resistant to plasmin-mediated fibrinolysis than fibrin from healthy control subjects (25). CTEPH represents the only cause of pulmonary hypertension that can be cured by pulmonary endarterectomy. Therefore, early
What is known about this topic?
• • •
The prevalence of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE) varies widely from 0.5% to 8.8%. This discrepancy may be explained not only by different designs and methods of the studies but it may also suggest that some of the patients with CTEPH may have preexistent unidentified CTEPH at the time of the acute PE. However, the absence of initial hemodynamic evaluation at the time of the acute PE does not allow identifying patients who already have CTEPH at the time of the initial PE diagnosis.
What does this paper add?
• •
Symptomatic CTEPH represents a relatively common complication after an acute PE. Initial echocardiography and multidetector CT performed at the time of the index PE suggest that a majority of patients with CTEPH had previously unknown pulmonary hypertension.
© Schattauer 2014
diagnosis of this disease is crucial for timely referral to a centre specialised in the management of CTEPH. Routine screening of CTEPH in all patients after PE is difficult in current clinical practice. However, our study suggests that patients, especially those with previous VTE, who have a proximal PE, an abnormal rise of sPAP > 60 mmHg, and a high level of BNP should be followed-up carefully after their index PE. A systematic reevaluation of sPAP by echocardiography and perfusion defect on V/Q scan especially in patients who remain dyspneic after 3-6 months of curative anticoagulation would be useful in order to detect CTEPH at an early stage. Several years ago, Ribeiro et al. showed that a sPAP > 50 mmHg at the time of diagnosis of the acute PE was associated with persistent pulmonary hypertension after one year (26). However, in our study, among the 20 patients with sPAP > 60 mm Hg at the time of the index PE, five of them developed CTEPH. In the remaining 15 patients, we observed a normalisation of sPAP during follow-up. The reasons why some patients with similar elevation of their sPAP at the time of PE will normalise their pulmonary pressure while others will develop CTEPH remain poorly understood. We included in this screening algorithm patients without significant cardiogenic or respiratory failure, therefore it is unlikely that another disease was responsible for the abnormal rise in pulmonary pressure at the time of the initial PE. Interestingly, among the 15 patients who normalised their sPAP during follow-up, 10 showed a persistent perfusion defect on their V/Q lung scan and one had persistent dyspnea. Whether these patients may develop CTEPH over a longer follow-up period remains unknown. Our study has several limitations. Firstly, because of the small number of patients with CTEPH, we were not able to perform a multivariate analysis and we did not identify independent risk factors for CTEPH. Secondly, the limited duration of the follow-up period (2 years) after the index PE may be the cause of an underestimation of the prevalence of symptomatic CTEPH. However, as previously suggested by Pengo et al., no cases of CTEPH occurred after two years among patients who had more than two years of follow-up data (5). Thirdly, this multicentre study took place in referral centres for PE and pulmonary hypertension in France, therefore we cannot exclude a selection bias in the study population which may have caused an overestimation of the prevalence of CTEPH. However, we found a prevalence of CTEPH which appears to be consistent with results previously reported in other prospective studies. Lastly, the prevalence reported represents the prevalence of CTEPH in a population who survived a PE and with interpretable data. However, if we include the patients who died (n=42) before evaluation and those who were excluded (n=12), the prevalence would be, in an “intention to diagnose” analysis, 3.5% (95% CI, 1.7 – 7.0) which is quite similar to those reported in the per protocol analysis. In conclusion, symptomatic CTEPH represents a relatively common complication after an acute PE. Older age, previous VTE, proximal PE, sPAP > 60 mm Hg and higher BNP levels at the time of the index PE are associated with the diagnosis of CTEPH during follow-up. Initial echocardiography and multidetector CT data at the time of the index PE suggest that a majority of patients with CTEPH had previously unknown pulmonary hypertension at the Thrombosis and Haemostasis 112.3/2014
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605 time of PE and that the first identified clinical presentation of CTEPH may mimic acute PE. Conflicts of interest
L. Guerin, F. Couturaud, F. Parent, M-P. Revel, F. Gillaizeau, B. Planquette, D. Pontal, M. Guégan and G. Meyer have no conflict of interest. G. Simonneau has served as a consultant, served on scientific advisory boards and has been investigator in trials involving Actelion, Bayer, Eli Lilly, GSK, Novartis and Pfizer. O. Sanchez has received reimbursement of travel expenses for attending symposia, speaker fees and research funds from Actelion, GSK, Pfizer, Bayer, Boehringer Ingelheim, has been investigator in trials involving Bayer, Daiichi Sankyo, and has participated in advisory board of Bayer.
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Guérin et al. Prevalence of CTEPH after PE
New Technologies, Diagnostic Tools and Drugs
Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism Prevalence of CTEPH after pulmonary embolism Laurent Guérin1; Francis Couturaud2; Florence Parent3; Marie-Pierre Revel4; Florence Gillaizeau5; Benjamin Planquette1; Daniel Pontal1; Marie Guégan2; Gérald Simonneau3; Guy Meyer1,6; Olivier Sanchez1,6 Paris Descartes, Sorbonne Paris Cité; APHP, service de Pneumologie et Soins Intensifs, Hôpital Européen Georges Pompidou, Paris, France; 2Université Européenne de Bretagne, Université de Brest, EA3878, IFR148, et Département de Médecine Interne et de Pneumologie, CHU de La Cavale Blanche, Brest, France; 3Université Paris-Sud ; APHP, service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France; 4Université Paris Descartes, Sorbonne Paris Cité; APHP, service de Radiologie, Hôpital Européen Georges Pompidou, Paris, France; 5Université Paris Descartes, Sorbonne Paris Cité; APHP, Unité de Recherche Clinique, Hôpital Européen Georges Pompidou, Paris, France; 6INSERM UMR970, Paris, France
Summary Chronic thromboembolic pulmonary hypertension (CTEPH) has been estimated to occur in 0.1–0.5% of patients who survive a pulmonary embolism (PE), but more recent prospective studies suggest that its incidence may be much higher. The absence of initial haemodynamic evaluation at the time of PE should explain this discrepancy. We performed a prospective multicentre study including patients with PE in order to assess the prevalence and to describe risk factors of CTEPH. Follow-up every year included an evaluation of dyspnea and echocardiography using a predefined algorithm. In case of suspected CTEPH, the diagnosis was confirmed using right heart catheterisation (RHC). Signs of CTEPH were searched on the multidetector computed tomography (CT) and echocardiography performed at the time of PE. Of the 146 patients analysed, eight patients (5.4%) had suspected CTEPH during a median follow-up of 26 months. CTEPH was confirmed using Correspondence to: Olivier Sanchez, MD, PhD Service de pneumologie et de soins intensifs Hôpital européen Georges Pompidou 20 rue Leblanc, 75015 Paris, France Tel.: +33 1 56 09 34 61, Fax: +33 1 56 09 32 55 E-mail: [email protected]
Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the presence of pulmonary hypertension related to incomplete resolution of unique or recurrent pulmonary embolism (PE) and represents one of the leading cause of pulmonary hypertension (PH) (1). The diagnosis of CTEPH represents a clinical challenge because surgical procedure, such as pulmonary endarterectomy, can potentially cure patients with CTEPH (2). The true incidence of CTEPH after an acute PE is currently unknown (3). According to retrospective series, CTEPH occurs in about 0.1% of patients who survived an acute PE (4). More recently, prevalence of 3.1% at one year and 3.8% at two years were reported in prospective studies (5). This discrepancy may be explained by different © Schattauer 2014
RHC in seven cases (4.8%; 95%CI, 2.3 – 9.6) and ruled-out in one. Patients with CTEPH were older, had more frequently previous venous thromboembolic events and more proximal PE than those without CTEPH. At the time of PE diagnosis, patients with CTEPH had a higher systolic pulmonary artery pressure and at least two signs of CTEPH on the initial CT. After acute PE, the prevalence of CTEPH appears high. However, initial echocardiography and CT data at the time of the index PE suggest that a majority of patients with CTEPH had previously unknown pulmonary hypertension, indicating that a first clinical presentation of CTEPH may mimic acute PE.
Keywords Pulmonary embolism, chronic thromboembolic pulmonary hypertension, epidemiology, echocardiography
Received: August 2, 2013 Accepted after major revision: March 25, 2014 Epub ahead of print: June 5, 2014 http://dx.doi.org/10.1160/TH13-07-0538 Thromb Haemost 2014; 112: 598–605
designs of the studies or various methods used to detect and diagnose CTEPH. It may also suggest that in the studies reporting the higher rates, some of the patients with CTEPH diagnosed during follow-up may have preexistent unidentified CTEPH at the time of the acute PE. The absence of initial haemodynamic evaluation at the time of the acute PE in previous reports does not allow identifying patients who already have CTEPH at the time of the initial PE diagnosis. Therefore, the aims of this study were (1) to assess the prevalence of CTEPH after the acute PE, (2) to describe risk factors of CTEPH and (3) to analyse initial echocardiography and spiral computed tomography results in order to try to identify the proportion of patients who have preexistent unidentified CTEPH at the time of the acute PE. Thrombosis and Haemostasis 112.3/2014
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Methods
Table 1: Medical Research Council dyspnea scale.
Study design
Grade
Degree of breathlessness related to activities
This prospective multicentre study took place at three academic centres in France. Patients were enrolled consecutively between January 2006 and May 2007 and were followed-up until July 2010. The study was approved by ethic committee (Comité de Protection des Personnes Ile de France 2).
1
Not troubled by breathlessness except on strenuous exercise
2
Short of breath when hurrying or walking up a slight hill
3
Walks slower than contemporaries on level ground because of breathlessness, or has to stop for breath when walking at own pace
4
Stops for breath after walking about 100 m or after a few minutes on level ground
Patients with an objectively proven PE based on a positive multidetector computed tomography (CT) showing at least multisubsegmental PE or a high-probability ventilation-perfusion lung scan (V/Q scan) were eligible to participate to this study after written informed consent. The exclusion criteria were: previously known CTEPH or pulmonary hypertension at the time of acute PE diagnosis, and any other medical condition that could have caused non-thromboembolic pulmonary hypertension such as known severe chronic respiratory (total lung capacity < 60% of predicted value (pred), or forced expiratory volume in 1 second (FEV1) < 60% pred, or FEV1 / vital capacity < 60% pred), left cardiac insufficiency (ejection fraction < 30%), hematologic disorders (chronic haemolytic anaemia, myeloproliferative disorders), systemic disorders (sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis), metabolic disorders (glycogen storage disease, Gaucher disease, thyroid disorders), fibrosing mediastinitis, chronic renal failure or any other pulmonary arterial hypertension associated condition (human immunodeficiency virus, connective tissue disease, portal hypertension, congenital heart diseases, schistosomiasis).
Evaluation at the time of the acute PE Within 24 hours of their acute PE diagnosis, all patients had a complete clinical evaluation, an echocardiography in order to measure their end-diastolic right-to-left ventricle diameter ratio (RV/LV), and systolic pulmonary artery pressure (sPAP). On admission, a blood sample was collected in order to measure their levels of brain natriuretic peptide (BNP) with an electrochemiluminescence immunoassay (BNP-Triage Biosite assay; lower limit of detection: 10 ng/l) on a DxI analyser (Beckman Coulter Inc., Brea, CA, USA).
Prospective follow-up after PE diagnosis After PE diagnosis, patients were prospectively followed-up each year during a maximum of two years. The duration of curative anticoagulant therapy was left to the discretion of the clinician in charge. At each visit, patients had an evaluation of dyspnea (Medical Research Council [MRC] scale, ▶ Table 1) and an echocardiography using a predefined algorithm as previously described (▶ Figure 1) (6, 7). Colour-flow Doppler echocardiogrphy was used to obtain the best possible alignment between the tricuspid regurgitation and the Doppler ultrasound beam and to measure Thrombosis and Haemostasis 112.3/2014
peak velocity of the tricuspid regurgitation (VTR). If tricuspid regurgitation was absent or VTR not measurable, peak velocity of pulmonary regurgitation (VPR) was considered. CTEPH was suspected in patients with persistent dyspnea (MRC ≥ 2) and if VTR was ≥ 2.8 m/second (s) or if proto-diastolic VPR was ≥ 2.0 m/s and end-diastolic VPR was ≥ 1.2 m/s as previously described in other screening programs of PH (▶ Figure 1) (6, 7). In case of suspected CTEPH, the diagnosis was confirmed in patients with pre-capillary PH defined as mean PAP ≥ 25 mmHg and pulmonary capillary wedge pressure ≤ 15 mmHg on right heart catheterisation (RHC), and at least one segmental perfusion defect on V/Q scan (8). The time between the index PE diagnosis and right heart catheterisation was calculated.
Signs of CTEPH on initial spiral computed tomography In patients for whom acute PE was diagnosed on the basis of a multidetector CT, a senior radiologist, blinded to the presence or absence of confirmed CTEPH during follow-up and to initial echocardiographic data, retrospectively examined the initial CT performed for diagnosing the PE and searched for signs of CTEPH in the CT, such as organised mural thrombi lining the pulmonary vascular walls, arterial webs or bands, mosaic parenchymal perfusion patterns, or dilated bronchial arteries (≥1.5 mm) (9–11).
Statistical methods Prevalence is calculated as the ratio of confirmed CTEPH at RHC during follow-up and the number of patients analysed (per protocol analysis). The 95% confidence interval (CI) was calculated assuming a Poisson distribution. Categorical variables are presented as numbers and percentages, and continuous variables are presented as means ± SD or medians [25% percentile – 75% percentile]. Univariate analysis, based on Chi2-tests or Fisher’s exact test or Student’s t-tests, was performed to assess the association between the characteristics of the patients at PE onset and the presence of CTEPH during followup. Statistical significance was considered at the 0.05 level. We used SAS software version 9.2 (SAS Inc. Cary, NC, USA) for all statistical analysis.
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Patients
Figure 1: Diagnostic algorithm based on evaluation of dyspnea (Medical Research Council (MRC) scale, transthoracic Doppler echocardiography and right heart catheterisation. VTR: peak velocity of the tricuspid regurgitation, VPR : peak velocity of pulmonary regurgitation, CTEPH: chronic thromboembolic pulmonary hypertension, RHC: right heart catheterization, mPAP: mean pulmonary artery pressure, PcwP: pulmonary capillary wedge pressure.
Results
Prevalence of CTEPH
Patients
During follow-up, 8 (5.4%) patients had persistent dyspnea and abnormal echocardiographic findings and were considered as suspected for CTEPH. The diagnosis of CTEPH was confirmed on RHC and abnormal V/Q scan in seven patients and ruled out in one patient. Thus, the overall prevalence, in a per-protocol analysis, of CTEPH among the study population was 4.8% (95% CI, 2.3 – 9.6).
During the study period, 261 patients with an acute objectively proven PE were eligible for this study. Among them, 103 patients were not included for the following reasons: 42 patients died within the first year after PE diagnosis (cancer n=22, PE n=7, sepsis n=3, major bleeding n=1, other n=9), 45 patients refused to consent, eight patients were lost to follow-up, and eight patients had known severe respiratory or cardiac failure. Among the 158 remaining patients enrolled, 12 were excluded based on uninterpretable echocardiography data in five, and seven did not undergo the requested protocol investigations. Thus, the final study population consisted of 146 patients (▶ Figure 2). The median follow-up was 26 (7–45) months. The clinical characteristics of the study population are summarised in ▶ Table 2. All patients received curative anticoagulants during a median duration of 11.7 months (6–24) and five (3%) received thrombolysis. © Schattauer 2014
Characteristics of patients with confirmed CTEPH Individual clinical and haemodynamic characteristics of patients with CTEPH are summarised in ▶ Table 3 and ▶ Table 4. None of these patients had other associated condition for pulmonary hypertension. At the time of their acute PE, patients with confirmed CTEPH had severe elevation of pulmonary pressure (mean systolic PAP (sPAP) = 75 ± 20 mmHg) and right ventricular dilatation (mean RV/LV 0.97 ± 0.3) on initial echocardiography. The Thrombosis and Haemostasis 112.3/2014
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Guérin et al. Prevalence of CTEPH after PE
Figure 2: Flow-chart of the study.
diagnosis of CTEPH was confirmed by right heart catheterisation after a mean duration of 13.7 ± 9 months after the PE diagnosis and showed severe pre-capillary pulmonary hypertension in most cases (▶ Table 3). All patients with CTEPH were evaluated for pulmonary endarterectomy (PTE PEA) at the French referral centre for pulmonary hypertension. Two patients were considered operable (#2 and #5) but only one (5, ▶ Table 3) agreed and underwent PEA. Four patients received bosentan for distal severe inoperable CTEPH and the two remaining patients were treated with vitamin K antagonist (VKA) alone (▶ Table 3). Univariate analysis showed that patients with CTEPH were significantly older, had more previous thromboembolic events, had significantly higher sPAP, more proximal PE and significantly higher levels of BNP at the time of the index PE. Thrombosis and Haemostasis 112.3/2014
Signs of pre-existing CTEPH in the CT at the time of the index PE Among the 146 patients analysed (7 with CTEPH and 139 without CTEPH), 118 patients had a multidetector CT for their acute PE diagnosis, 106 were available and were independently interpreted by a senior radiologist. The presence of at least two signs of CTEPH in the multidetector CT was observed in all patients with confirmed CTEPH, compared with 19/99 patients without CTEPH (▶ Table 5).
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Variable
Value
Age, years (mean ± SD)
61 ± 19
Sex M/F, n (%)
60 (41) / 86 (59)
Previous VTE, n (%)
35 (24)
Surgery or trauma < 1 month, n (%)
35 (24)
Cancer, n (%)
17 (12)
Associated DVT, n (%)
52 (36)
HR, bpm (mean ± SD)
88 ±19
RR, bpm (mean ± SD)
23 ± 6
sBP, mm Hg (mean ± SD)
137 ± 23
Cardiogenic shock, n (%)
8 (5)
Diagnosis on multidetector CT, n (%) Troncular PE Lobar PE Segmental PE Multiple sub-segmental PE
118 (81) 38 (32) 35 (30) 40 (34) 5 (4)
Diagnosis on V/Q lung scan, n (%)
28 (19)
RV/LV (mean ± SD) RV/LV > 1, n (%)
0.7 ± 0.3 22 (15)
sPAP, mmHg (mean ± SD) sPAP> 60 mm Hg, n (%)
43 ± 15 20 (14)
BNP, ng/l (mean ± SD)
168 ± 292
VTE: venous thromboembolic disease; DVT: deep venous thrombosis; HR: heart rate; RR: respiratory rate; sBP: systolic blood pressure; PE: pulmonary embolism; RV/LV: right to left end-diastolic diameter ratio; sPAP: systolic pulmonary pressure.
Discussion We found that the prevalence of symptomatic CTEPH was 4.8% (95%CI, 2.3–9.6) among patients who were followed-up for a median time of 26 months after the index PE. Age, previous VTE, proximal PE, high levels of sPAP and BNP at the time of the index PE were identified as risk factors for CTEPH. Lastly, we showed that a majority of patients with CTEPH had already several signs of pre-existing CTEPH in the multidetector CT at the time of the acute PE episode. Initial estimates suggested that 0.1 to 0.5% of patients surviving an episode of acute PE would develop CTEPH (4). More recently, several prospective observational studies have reported that the prevalence of CTEPH varies between 0.4 to 8.8% (5, 12–18) (Suppl. Table 1, available online at www.thrombosis-online.com). This wide variation of prevalence can be explained by differences in inclusion criteria and methods used for screening CTEPH. Studies which performed a single echocardiography reported a lower prevalence of CTEPH (12, 14, 17, 18). Lastly, studies which didn’t confirm CTEPH by RHC (13, 15) found a higher prevalence than those which confirmed the diagnosis by invasive procedures (5, 12, 14, 17, 18). We included patients with a first episode of PE or with previous VTE, but without any other condition that could have caused non thromboembolic pulmonary hypertension. These patients were submitted to a predefined screening algorithm that included dyspnea, echocardiography and RHC. This algorithm was derived from the one used in studies evaluating the prevalence of PH in various populations at risk (6, 7, 19). We used a threshold of 2.8 m/s rather than 2.5 m/s for VTR because it has been suggested that this threshold was associated with a reduction of the false positive rate of echocardiography (7, 19). Indeed, in our study, only one patient had VTR > 2.8 m/s without confirmed
Table 3: Individual characteristics of patients with confirmed CTEPH.
Patient Initial PE
During follow-up
Age (years)
sPAP RV/LV MRC VTR sPAP RV/LV Time to RHC RAP mPAP CO PVR (mmHg) (m/s) (mmHg) (months) (mmHg) (mmHg) (l/min) (UI)
Treatment
1
71
45
0.9
2
3.8
73
1.1
27
11
54
4.9
8.8
VKA + bosentan
2
74
70
1.1
3
5.4
132
1.3
7.2
10
58
3.2
16.1
VKA + bosentan
3
81
81
1.3
5
4.7
100
1.4
7.4
7
52
3.1
11.6
VKA + bosentan
4
77
84
1.1
2
3.5
58
NA
10
7
30
6.2
2.9
VKA
5
70
43
0.5
2
4.2
75
0.7
22.7
4
36
5.7
4.6
VKA + PEA
6
75
62
0.5
2
2.8
56
0.72
3
3
30
3.7
6.1
VKA
7
72
102
0.8
2
4
81
1.1
6.6
4
53
4.5
10.7
VKA + bosentan
Mean
75
75
0.97
13.7
7
45
4.5
7.5
± SD
4
20
0.3
9
3
12
1.2
3.5
RAP =right atrial pressure, CO= cardiac output, PVR = pulmonary vascular resistance, NA= not available, VKA: vitamin K antagonist, PEA: pulmonary thromboendarterectomy.
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Table 2: Clinical, computed tomography and echocardiography findings of 146 patients at the time of the initial PE diagnosis.
603 Table 4: CTEPH+ vs CTEPH-: Analysis of risk factors.
Variable
CTEPH + (N= 7)
CTEPH – (N= 139)
P-value
Age, years (mean ± SD)
74 ± 4
60.5 ± 19
1 n, (%)
0.9 ± 0.3 3 (43)
0.7 ± 0.3 20 (14)
0.2 0.009
sPAP, mm Hg (mean ± SD) sPAP > 60 mm Hg, n (%)
70 ± 21 5 (71)
41 ± 13 15 (10)
0.0009 60 mmHg. These data are unusual in the context of an acute PE. Indeed, it has been shown that despite proximal PE with angiographically estimated vascular obstruction that exceeded 50%, the mean pulmonary arterial pressure did not exceed 40 mmHg in any of patients without prior cardiopulmonary disease or PE (21, 22). It thus appears that the upper limit of pulmonary arterial pressure which the normal human right ventricle can
to the quality of injections in bronchial arteries, this sign was interpretable in only 4 out the 7 CT.
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Guérin et al. Prevalence of CTEPH after PE
maintain acutely is approximately 40 mmHg (22). This significant rise of pulmonary pressure may thus reflect an adaptation of the right ventricle to a chronic obstruction of the pulmonary vascular bed and could explain the significant higher level of BNP at the time of the index PE in patients with CTEPH. In order to test this hypothesis, we returned to the initial multidetector CT in patients with a PE confirmed by this test. Interestingly, we found that all patients with confirmed CTEPH during follow-up had at least two CT signs of CTEPH at the time of the index PE. All multidetector CT were re-interpreted centrally by a senior radiologist who was blinded to the presence or absence of confirmed CTEPH in order to exclude any bias. To the best of our knowledge, our study is the first one that could evaluate the evolution of both pulmonary haemodynamic and imaging data at the time of the index PE and during follow-up. Our study identified several risk factors of CTEPH. Many of them had already been highlighted in previous studies, including previous VTE, older age and the level of importance of pulmonary vascular obstruction during the initial episode of PE (5). Recently, an international prospective registry of CTEPH reported the presence of a confirmed previous PE in 75% of patients, which was reported as massive in 41% (2, 23). Interestingly, pulmonary vascular obstruction at PE onset had been found as an independent risk factor associated with the presence of a perfusion defect after PE (24). Thus, complete reversal of the pulmonary vascular bed by the fibrinolytic system could be made more difficult in cases of proximal obstruction which would promote the development of CTEPH. This hypothesis has been raised by Morris et al., who showed that fibrin from patients with CTEPH was more resistant to plasmin-mediated fibrinolysis than fibrin from healthy control subjects (25). CTEPH represents the only cause of pulmonary hypertension that can be cured by pulmonary endarterectomy. Therefore, early
What is known about this topic?
• • •
The prevalence of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE) varies widely from 0.5% to 8.8%. This discrepancy may be explained not only by different designs and methods of the studies but it may also suggest that some of the patients with CTEPH may have preexistent unidentified CTEPH at the time of the acute PE. However, the absence of initial hemodynamic evaluation at the time of the acute PE does not allow identifying patients who already have CTEPH at the time of the initial PE diagnosis.
What does this paper add?
• •
Symptomatic CTEPH represents a relatively common complication after an acute PE. Initial echocardiography and multidetector CT performed at the time of the index PE suggest that a majority of patients with CTEPH had previously unknown pulmonary hypertension.
© Schattauer 2014
diagnosis of this disease is crucial for timely referral to a centre specialised in the management of CTEPH. Routine screening of CTEPH in all patients after PE is difficult in current clinical practice. However, our study suggests that patients, especially those with previous VTE, who have a proximal PE, an abnormal rise of sPAP > 60 mmHg, and a high level of BNP should be followed-up carefully after their index PE. A systematic reevaluation of sPAP by echocardiography and perfusion defect on V/Q scan especially in patients who remain dyspneic after 3-6 months of curative anticoagulation would be useful in order to detect CTEPH at an early stage. Several years ago, Ribeiro et al. showed that a sPAP > 50 mmHg at the time of diagnosis of the acute PE was associated with persistent pulmonary hypertension after one year (26). However, in our study, among the 20 patients with sPAP > 60 mm Hg at the time of the index PE, five of them developed CTEPH. In the remaining 15 patients, we observed a normalisation of sPAP during follow-up. The reasons why some patients with similar elevation of their sPAP at the time of PE will normalise their pulmonary pressure while others will develop CTEPH remain poorly understood. We included in this screening algorithm patients without significant cardiogenic or respiratory failure, therefore it is unlikely that another disease was responsible for the abnormal rise in pulmonary pressure at the time of the initial PE. Interestingly, among the 15 patients who normalised their sPAP during follow-up, 10 showed a persistent perfusion defect on their V/Q lung scan and one had persistent dyspnea. Whether these patients may develop CTEPH over a longer follow-up period remains unknown. Our study has several limitations. Firstly, because of the small number of patients with CTEPH, we were not able to perform a multivariate analysis and we did not identify independent risk factors for CTEPH. Secondly, the limited duration of the follow-up period (2 years) after the index PE may be the cause of an underestimation of the prevalence of symptomatic CTEPH. However, as previously suggested by Pengo et al., no cases of CTEPH occurred after two years among patients who had more than two years of follow-up data (5). Thirdly, this multicentre study took place in referral centres for PE and pulmonary hypertension in France, therefore we cannot exclude a selection bias in the study population which may have caused an overestimation of the prevalence of CTEPH. However, we found a prevalence of CTEPH which appears to be consistent with results previously reported in other prospective studies. Lastly, the prevalence reported represents the prevalence of CTEPH in a population who survived a PE and with interpretable data. However, if we include the patients who died (n=42) before evaluation and those who were excluded (n=12), the prevalence would be, in an “intention to diagnose” analysis, 3.5% (95% CI, 1.7 – 7.0) which is quite similar to those reported in the per protocol analysis. In conclusion, symptomatic CTEPH represents a relatively common complication after an acute PE. Older age, previous VTE, proximal PE, sPAP > 60 mm Hg and higher BNP levels at the time of the index PE are associated with the diagnosis of CTEPH during follow-up. Initial echocardiography and multidetector CT data at the time of the index PE suggest that a majority of patients with CTEPH had previously unknown pulmonary hypertension at the Thrombosis and Haemostasis 112.3/2014
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605 time of PE and that the first identified clinical presentation of CTEPH may mimic acute PE. Conflicts of interest
L. Guerin, F. Couturaud, F. Parent, M-P. Revel, F. Gillaizeau, B. Planquette, D. Pontal, M. Guégan and G. Meyer have no conflict of interest. G. Simonneau has served as a consultant, served on scientific advisory boards and has been investigator in trials involving Actelion, Bayer, Eli Lilly, GSK, Novartis and Pfizer. O. Sanchez has received reimbursement of travel expenses for attending symposia, speaker fees and research funds from Actelion, GSK, Pfizer, Bayer, Boehringer Ingelheim, has been investigator in trials involving Bayer, Daiichi Sankyo, and has participated in advisory board of Bayer.
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Guérin et al. Prevalence of CTEPH after PE
