Original article 649

Prevalence of undiagnosed chronic thromboembolic pulmonary hypertension after pulmonary embolism Livio Giuliania, Cristina Piccininob, Maria A. D’Arminic, Sabrina Manganiellob, Lorena Ferrarottib, Piero E. Balbod, Alessandro Lupib and Paolo N. Marinob Chronic thromboembolic pulmonary hypertension is associated with adverse prognosis. Early diagnosis is important to better identify patients who would benefit from a well established therapeutic strategy. The purpose of our study was to evaluate long-term incidence of undiagnosed chronic thromboembolic pulmonary hypertension after acute pulmonary embolism and the utility of a long-term follow-up including an echocardiographic-based screening programme to early detect this disease. We evaluated retrospectively 282 patients discharged from the ‘Maggiore della Carita`’ Hospital, Universita` del Piemonte Orientale, Novara, Italy, with diagnosis of acute pulmonary embolism between November 2006 and October 2009. One hundred and eleven patients underwent a clinical late echocardiographic screening programme after the acute event. Patients with suspected pulmonary hypertension based on echocardiographic evidence of systolic pulmonary artery pressure of at least 40 mmHg underwent complete work-up for chronic thromboembolic pulmonary hypertension assessment, including ventilation-perfusion lung scintigraphy and right heart catheterization. One hundred and eleven patients were included in the study. Pulmonary hypertension was suspected in 15 patients; five patients had chronic thromboembolic pulmonary hypertension confirmed by ventilation-perfusion lung scintigraphy, right heart catheterization and pulmonary angiography. Two patients with clinical class functionally advanced underwent surgical pulmonary endarterectomy

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening but potentially surgically correctable cause of pulmonary hypertension. It is characterized by chronic organized thrombi that obstruct the pulmonary vessels and lead to high morbidity and mortality [1]; increased pulmonary vascular resistance (PVR) subsequently leads to progressive pulmonary hypertension and right heart failure. In the nonoccluded areas, a pulmonary arteriopathy indistinguishable from that of pulmonary arterial hypertension (PAH) can develop and contribute to disease progression [2]. It is important to recognize that proper CTEPH identification can make a huge difference in clinical terms, as there are therapies now available that lead to improvement of quality of life and have a haemodynamically striking impact as well. Pulmonary endarterectomy (PEA), however, is the treatment of choice. After PEA, improvement is dramatic and 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

and two asymptomatic patients underwent medical treatment. The prevalence of undiagnosed chronic thromboembolic pulmonary hypertension was 4.5%. Chronic thromboembolic pulmonary hypertension is a serious disease with a poor prognosis if not treated early. Surgical treatment is decisive. After surgery, the majority of patients have a substantial improvement in their functional status and in haemodynamic variables. Many patients are asymptomatic. Implementation of screening programmes may be helpful for an early diagnosis and early proper therapy. Blood Coagul Fibrinolysis 25:649–653 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Blood Coagulation and Fibrinolysis 2014, 25:649–653 Keywords: chronic thromboembolic pulmonary hypertension, echocardiogram, perfusion lung scan, pulmonary arterial hypertension, pulmonary thromboendarterectomy, screening program a Department of Cardiology, ASL TO4 Azienda Sanitaria Locale Cirie`, Chivasso e Ivrea, bDepartment of Cardiology, ‘Maggiore della Carita`’ Hospital, Universita` del Piemonte Orientale, Novara, cDepartment of Cardiochirurgy, ‘Fondazione IRCSS Policlinico S. Matteo’, Pavia and dDepartment of Pneumology, ‘Maggiore della Carita`’ Hospital, Universita` del Piemonte Orientale, Novara, Italy

Correspondence to Sabrina Manganiello, MD, Cardiology Division, Department of Cardiology, ‘Maggiore della Carita`’ Hospital, Corso Mazzini 18, 28100 Novara, Italy Tel: +39 0321 3733731; fax: +39 0321 3733407; e-mail: [email protected] Received 7 August 2013 Revised 26 December 2013 Accepted 26 December 2013

immediate: PVR and pulmonary artery pressure (PAP) decrease to nearly normal levels and cardiac output (CO) increases markedly. Because the surgical and perioperative morbidity and mortality are influenced substantially by the degree of right ventricular dysfunction and because of the presence of secondary small vessel vasculopathy, surgical intervention is best considered earlier in the disease process [3]. The incidence of CTEPH in survivors of acute pulmonary embolism is still unclear, ranging from 0.5 up to a 3.8% as reported by more recent studies [4]. As recommend by international guidelines, patients with acute pulmonary embolism showing signs of pulmonary hypertension or right ventricular dysfunction at any time during their hospital stay should receive a follow-up echocardiography after discharge (usually after 3–6 months) to determine whether or not pulmonary hypertension has resolved [5], but it is rarely performed in clinical practice, DOI:10.1097/MBC.0000000000000084

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650 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 7

so potentially curable patients with late CTEPH will be missed. Moreover, we often get to the diagnosis of CTEPH at much later stages, at a time when there is already a severe vascular injury and advanced right-sided heart failure [6]. The aim of the present study was to assess the prevalence of undiagnosed CTEPH in a population of symptomatic and asymptomatic patients after an acute episode of pulmonary embolism.

Materials and methods Between November 2006 and October 2009, 59 622 patients were consecutively admitted to ‘Maggiore della Carita`’ Hospital, Universita` del Piemonte Orientale, Novara, Italy. The study enrolled 282 patients with a diagnosis of acute pulmonary embolism who were hospitalized in the departments of our hospital. Acute pulmonary embolism was recognized in all patients by clinical signs (dyspnoea, syncope and/or chest pain), D-dimer test and contrast-enhanced helical multidetector computed tomographic (CT) scanning or perfusion lung scanning. Each patient underwent standardized assessment and was treated at diagnosis with low molecular weight heparin, followed by oral vitamin K-antagonist for at least 6 months. Patients were followed-up for a mean of 6 months by echocardiography. For the present study all patients with objectively confirmed acute pulmonary embolism diagnosis during hospitalization were potentially eligible for long-term followup. Exclusion criteria included patients who were geographically inaccessible for follow-up, had other disease that could have caused nonthromboembolic pulmonary hypertension or declined to participate in the study and patients who had a previous splenectomy. Patients who were undergoing surgery or situations at risk of venous thromboembolism (pacemakers or central venous catheters implantation, major surgery, prolonged periods of immobilization from any cause) were excluded from the study to avoid selection bias. These conditions were also sought during the period of follow-up. In the literature, the major incidence of CTEPH is reported at 2 years [4], and this is why we decided to analyse the situation of those patients on an average 22 months after the acute episode of pulmonary embolism. Medical records were retrospectively reviewed and data from eligible patients were entered in to a database. These data included main demographic information (age, sex, BMI), medical history, baseline clinical characteristics, treatment, clinical course and duration of anticoagulation after pulmonary embolism (Table 1). Importantly, the entry of date data into this registry does not require any alterations of treatment or hospital care and is not contingent on the use of particular treatment

Baseline clinical characteristics of the 111 patients with pulmonary embolism

Table 1

Patients Age (years)  SD Male sex, n (%) BMI (kg/m2)a WHO functional class, n (%)

I II III IV Supportive therapy, n (%) Oxygen Diuretics Duration of anticoagulation after PE (months)a a

n ¼ 111 65  13.4 46 (41) 29.0  5.72 49 (44) 48 (43) 14 (13) 0 (0) 7 (6) 39 (35) 20.3  14.7

Mean ( SD).

regimen. The Institutional Review Board approved the study protocol and informed consent was obtained for all participants. We had screened 111 patients who met inclusion criteria for the study. All of them underwent a screening programme: the status of all patients was determined, the interim clinical history focused on cardiorespiratory symptoms, development of other heart or lung disease and treatment. Long-term treatment with oral anticoagulant was arbitrarily considered as adequate. For patients who died during the follow-up, cause of death was investigated; the surviving patients were invited for evaluation, which consisted of physical examination, ECG and transthoracic echocardiography (TTE). The severity of symptomatic impairment was classified according to the WHO functional class (WHO-FC) of heart failure. We considered eligible patients either asymptomatic (WHO-FC I) or symptomatic (WHO-FC II–IV). Pulmonary hypertension was suspected in the presence of a systolic PAP (sPAP) of at least 40 mmHg [7]. The sPAP and the right atrial pressure (RAP) were determined using standard protocols [8,9]. Those patients who had signs of pulmonary hypertension at echocardiography were investigated firstly with standardized V/Q lung scintigraphy and finally with right heart catheterization, according to current guidelines [5]. Patients who did not show echocardiographc pulmonary hypertension did not undergo other investigations. Patients who had a negative V/Q lung scintigraphy and pulmonary hypertension not confirmed by right heart catheterization were addressed to referred for echocardiographic follow-up, still in progress. CTEPH was considered if sPAP was at least 40 mmHg and V/Q lung scanning showed multiple areas of mismatch. If these findings were positive, presence of other disease potentially responsible for pulmonary hypertension was excluded by consulting hospital records and careful medical history taking. All these patients underwent further diagnostic workup with right heart

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Undiagnosed thromboembolic pulmonary hypertension Giuliani et al. 651

catheterization: direct measurement of mean pulmonary arterial hypertension (mPAP) was performed to confirm or refute the diagnosis of pulmonary hypertension and pulmonary capillary wedge pressure (PCWP) was determined to sort out patients who suffered from pulmonary hypertension due to severe left heart disease. The final diagnosis of pulmonary hypertension was based on the presence of mPAP more than 25 mmHg, PCWP of 15 mmHg or less and PVR more than 2 Wood units. When CTEPH was diagnosed, patients underwent angiography to demonstrate extensive chronic thromboembolism. Statistics

Continuous data are expressed as mean þ standard deviation (SD) and categorical data as percentages. All calculations were performed with the use of Matlab software (MathWorks, Natick, Massachusetts, USA). Differences between the categorical variables were analysed using Fisher’s exact tests for normally distributed continuous variables. A P value of less than 0.05 was considered to indicate statistical significance and reported P values are two-sided.

Results We identified 282 patients eligible for the study. Fiftythree patients died before being enrolled into the study: 18 had died as a result of cardiovascular diseases, three of sepsis; seven had died of metastatic cancer; one patient was involved in a traumatic incident and one patient died from complication of hepatic cirrhosis. In 23 patients, the cause of death could not be retrieved in detail. Nonsurvivors made up 18.8% of the total number of patients with pulmonary embolism. Another 118 patients were excluded because they lived too far from the study centre (n ¼ 38), had other disease that could have caused nonthromboembolic pulmonary hypertension (n ¼ 25) or declined to take part in the study (n ¼ 55). Demographics and clinical characteristics of the remaining 111 patients (46 men and 65 women) are depicted in Table 1; 49 were asymptomatic (WHO-FC I) and 62 symptomatic (48 WHO-FC II, 14 WHO-FC III, 0 WHO-FC IV). All patients had received at least 6 months Table 2 Patients 1. 2. 3. 4. 5.

of oral anticoagulant treatment (mean 20.3  14.7 months). None of patients enrolled was treated with venacaval filter after pulmonary embolism. In 15 out of 111 patients (13.5%), echocardiography showed clear evidence of significant pulmonary hypertension. Patients were examined on average 24.3  37.2 months after acute pulmonary embolism. They underwent V/Q lung isotope scanning that in five out of 13 patients revealed V/Q mismatch. In all these patients, right heart catheterization confirmed the pulmonary hypertension diagnosis. In these five patients, diagnosis of CTEPH was subsequently established: clinical, echocardiographic and haemodynamic characteristics are listed in Table 2. Two out of these five patients underwent successful PEA in our referral centre (IRCCS Fondazione Policlinico San Matteo, University of Pavia, Italy), wherein patients were selected for PEA on the basis of combined clinical, anatomical and haemodynamic characteristics according to a standardized protocol [10]; postsurgery right heart catheterization showed a significant trend towards a decrease of mean PAP (in the first one 55 vs. 17 mmHg and in the second one 44 vs. 17 mmHg) and PVR (21.5 vs. 3.1 and 7.8 vs. 2.3, respectively), associated with an increase of confidence interval (CI, 1.23 vs. 2.3 and 3.2 vs. 3.3 ml/m2, respectively), consistent with patients substantial reduction of dyspnoea and improvement in functional class. One out of five patients was considered unsuitable for surgery for advanced neoplastic disease and, according to more recent studies [11], received disease-modifying therapy with Bosentan, a dual endothelin receptor antagonist (Tracleer; Actelion Pharmaceuticals Ltd, Switzerland) at a starting dose of 62.5 mg twice a day for 4 weeks, up-titred to a target dose of 125 mg twice a day. The remaining two patients were completely asymptomatic and were referred for a strict clinical and echocardiographic follow-up. Ten out of 15 patients with echocardiographic signs of pulmonary hypertension, but not V/Q mismatch at lung scintigraphy and with normal PAP at right heart catheterization, were addressed to echocardiographic/clinical follow-up and their condition remained stable over 1 year of observation time. They were all in NYHA class I (Fig. 1).

Echocardiographic and haemodynamic parameters of patients with chronic thromboembolic pulmonary hypertension WHO-FC (I/IV)

EF (%)

sPAP (mmHg)

TAPSE (mm)

TR (þ/þþþþ)

PCWP (mmHg)

mPAP (mmHg)

CO (l/min)

CI (l/min/m2)

PVR (Wood units)

III II II I I

58 67 55 60 65

100 65 70 65 50

23 21 19 20 22

þþþ þ þþ þ þ

12 5 8 12 10

55 44 55 30 28

2.0 5.0 2.14 4.2 4.5

1.23 3.2 1.64 2.37 2.35

21.5 7.8 21.9 4.3 4

CI, cardiac index; CO, cardiac output; EF, ejection fraction; mPAP, mean pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; sPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; WHO-FC, WHO-functional class.

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652 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 7

Fig. 1

111 patients underwent clinical evaluation and echocardiography

Echocardiographic

Yes

No

Did V/Q lung scintigraphy and right heart catheterization confirme diagnosis (15)

Yes

PEA

No

Pharmacologic treatment (1)

(2)

Echo follow-up (2) + (10)

Exclusion of other potential causes of PH

Screening programme flowchart.

Global prevalence of undiagnosed CTEPH in our study population was 4.5%: 1.8% in asymptomatic patients and 2.7% in symptomatic patients. Patients with confirmed diagnosis of CTEPH proved to have received anticoagulant therapy for a shorter time than patients without CTEPH, but the difference did not reach statistical significance (2.1  1.9 vs. 4  0.7 years; mean  SD; P ¼ 0.06). Number of patients with sPAP values of at least 40 mmHg was not statistically different in asymptomatic and symptomatic patients (P > 0.05); the same was true for patients with confirmed diagnosis of CTEPH (P > 0.05).

Discussion Pulmonary hypertension is responsible for substantial morbidity and mortality worldwide. CTEPH is the only form of pulmonary hypertension that is potentially curable with surgery; thus, its recognition is crucial [10–12]. In our study, prevalence of CTEPH was 4.5%. The incidence of CTEPH we observed challenges the data from other studies reporting higher incidence of CTEPH

ranging from 0.8 to 3.8%. These previous studies included selected patients cohorts, for example, excluding asymptomatic patients [4,17]. In our study, prevalence of patients who fulfilled criteria for pulmonary hypertension echocardiographic diagnosis (sPAP >40 mmHg) was not statistically different in asymptomatic or symptomatic patients (P > 0.05), but this finding needs to be validated in larger studies. More detailed investigations are required to confirm our data, but it seems that even asymptomatic patients need to be followed-up after acute pulmonary embolism. In these patients, PEA is the treatment of choice [3]. At present, there is substantial agreement on favourable outcomes early after PEA with regard to survival, functional status, quality of life, haemodynamics, right ventricular function and gas exchange [13–15]. In our experience, two out of five patients with CTEPH underwent PEA that provided pulmonary hypertension regression and striking clinical improvement; the anticoagulant therapy was the only treatment at hospital discharge. In any case, an early identification of patients with clinically silent CTEPH may be critically important as

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Undiagnosed thromboembolic pulmonary hypertension Giuliani et al. 653

well. Moreover, recent studies indicate that early treatment of PAH may benefit even patients in WHO-FC II [16].

for an early diagnosis and a more efficacy therapy in either symptomatic or asymptomatic patients.

Echocardiography is a noninvasive and cost-effective modality that can be used to systematically search for CTEPH in patients diagnosed with acute pulmonary embolism [16]. Interestingly, although international guidelines strongly recommended echocardiography in the short-term follow-up after acute pulmonary embolism [5], they do not address the need for a long-term followup in order to detect CTEPH. Because the main incidence of CTEPH is observed at 24 months [4], it might be argued that by applying current guidelines, curable patients who develop CTEPH will be lost at follow-up, with potentially serious consequences. In our study, population echocardiography has not been planned in more than 60% of cases.

Acknowledgements

Moreover, our patients were traditionally treated with anticoagulants at least for 6 months after an acute episode of pulmonary embolism. We cannot exclude an imperfect control of the international normalized ratio (INR) in some of them, as it has been previously recognized that in patients with CTEPH, treated with vitamin K antagonists, the INR is below the therapeutic range approximately 20% of the time [4]. Nevertheless, patients who received a shorter time anticoagulant therapy after pulmonary embolism had higher prevalence of diagnosed CTEPH. This finding suggests a possible relation between CTEPH and duration of anticoagulant treatment after acute pulmonary embolism, but due to the relatively low incidence rate and the small sample size the observation, requires a wider population to be confirmed. Even so, this hypothesis warrants attention. Limitations of this study included, first, a great number of excluded patients casting doubts on the real prevalence of CTEPH after pulmonary embolism. Second, the lack of accurate data about management of long-term anticoagulant therapy can lead to potential misinterpretation of our observations.

Conflicts of interest

There are no conflicts of interest.

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Conclusion

CTEPH is a late complication of pulmonary embolism. Although not strictly recommended by international guidelines, implementation of screening programme with follow-up echocardiography within 24 months after an acute episode of pulmonary embolism could be helpful

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Prevalence of undiagnosed chronic thromboembolic pulmonary hypertension after pulmonary embolism.

Chronic thromboembolic pulmonary hypertension is associated with adverse prognosis. Early diagnosis is important to better identify patients who would...
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