C h ron i c Th ro m b o e m b o l i c Pulmonary Hypertension Peter S. Marshall, MD, MPHa,*, Kim M. Kerr, MDb, William R. Auger, MDb KEYWORDS  Chronic thromboembolic pulmonary hypertension  Pulmonary hypertension  Pulmonary embolus  Pulmonary thromboendarterectomy  Epidemiology  Diagnosis  Therapy  Percutaneous pulmonary angioplasty

KEY POINTS

INTRODUCTION AND DEFINITION Chronic thromboembolic pulmonary hypertension (CTEPH) or World Health Organization (WHO) class IV pulmonary hypertension is defined by a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg in the presence of organized, nonacute thrombus within the pulmonary vascular bed. The syndrome of chronic thromboembolic disease includes not only patients with overt thromboembolic pulmonary hypertension and right heart dysfunction, but those nonpulmonary hypertensive patients symptomatic because of dead space ventilation, referred to as thromboembolic-related respiratory insufficiency (TERRI).1,2

CTEPH arises from an initial thromboembolism or multiple events. However, 1 year after a thromboembolic event, patients are usually left with more than 90% of their pulmonary vascular bed unaffected.1 Some individuals do not completely resolve clot and experience a series of pathobiological changes that lead to chronic large vessel narrowing and distal small vessel vasculopathy causing increased pulmonary artery pressures. It is unclear whether these pathophysiologic changes have a genetic basis, are related to the anatomy involved, or involve alterations in fibrinolysis. The reasons for the failure to handle the clot burden and elucidation of the pathobiology are the subject of much research.

a Yale University School of Medicine, Section of Pulmonary, Critical Care & Sleep Medicine, 15 York Street, LCI 101, New Haven, CT 06510, USA; b Division of Pulmonary & Critical Care Medicine, University of California, San Diego Health Care System, 9300 Campus Point Drive, La Jolla, CA 92037, USA * Corresponding author. E-mail address: [email protected]

Clin Chest Med 34 (2013) 779–797 http://dx.doi.org/10.1016/j.ccm.2013.08.012 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

chestmed.theclinics.com

 Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon, but serious, complication of acute pulmonary embolus.  Several risk factors for the development of CTEPH have been identified and many are not directly associated with thrombophilia.  More research into the mechanisms whereby acute thrombus fails to resolve and results in increased pulmonary artery pressures is needed.  Presenting signs and symptoms of CTEPH are nonspecific.  The diagnostic evaluation confirms the diagnosis of CTEPH, helps determine the appropriateness for pulmonary thromboendarterectomy (also referred to as pulmonary endarterectomy), assesses for comorbidities, and determines prognosis.  Use of pulmonary arterial hypertension-modifying agents may improve hemodynamics and functional capacity but their role in CTEPH is yet to be determined.  Percutaneous pulmonary angioplasty may improve hemodynamics and functional capacity in patients who are not surgical candidates, but has significant procedural risk.  Pulmonary thromboendarterectomy is the treatment of choice in appropriate patients.

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Marshall et al EPIDEMIOLOGY Approximately 600,000 acute pulmonary emboli (PEs) occur yearly in the United States, resulting in 200,000 to 300,000 deaths.3 Only 150,000 of all patients with PE are diagnosed, indicating that thousands of PEs are undetected.4 Some patients with acute PE, whether diagnosed or undiagnosed, develop chronically increased pulmonary artery pressures. Registry data suggest that the incidence of CTEPH is between 3 and 30 per 1 million in the general population.5 There are an estimated 500 to 2500 new cases of CTEPH in the United States each year and only 60% to 74.8% of patients diagnosed with CTEPH have a history of documented acute PE, reinforcing the concept that acute PE may go undiagnosed.6–9 The lack of documented PE in some patients has prompted some investigators to suggest that thromboembolism may not always be the inciting event in CTEPH.10 The percentage of patients with acute PE who develop CTEPH is unknown but ranges from 0.6% to 8.8%.11–14 A prospective study identified 223 eligible patients with acute PE and followed patients for up to 10 years.14 Patients with conditions that predisposed them to nonthromboembolic pulmonary hypertension were not included in the analysis (N 5 81). The cumulative incidence of CTEPH at 6 months was 1% (95% confidence interval [CI], 0.0–2.4), at 1 year 3.1% (95% CI, 0.7–5.5), and at 2 years 3.8% (95% CI, 1.1–6.5). Predictors for the development of CTEPH included multiple episodes of PE, larger perfusion defect, and younger age. No new cases of CTEPH were identified after 2 years of follow-up. A screening program for CTEPH was devised for 866 unselected patients with acute PE. The overall incidence of CTEPH was 0.57% (95% CI, 0.02– 1.2).15 In patients with provoked PE the incidence of CTEPH was 0, and in patients with unprovoked PE it was 1.5% (95% CI, 0.08–3.1). Only 68% of the original cohort completed the study. CTEPH could not be definitively excluded in the deceased or those not reporting for follow-up and this may have underestimated the incidence of CTEPH. In addition, the inclusion of patients with conditions predisposing them to pulmonary hypertension in the screening program may have resulted in an underestimation of the incidence of CTEPH compared with the results of other studies.12,13 Studies offering higher estimates of the incidence of CTEPH used only echocardiography to detect CTEPH in symptomatic (and asymptomatic) patients, which may account for the higher estimates, whereas all cases in the screening program cohort were confirmed by right heart catheterization.13,15

The incidence of CTEPH after acute PE is probably 0.5% to 3.8%, with few cases identified more than 2 years after acute PE. The relationship between prior thromboembolism and CTEPH is stronger in patients with a prior episode of deep vein thrombosis (DVT), whose incidence of CTEPH is 5.2%, and in patients with a prior episode of PE, whose incidence is 33%.14 It is widely accepted that incompletely resolved PE is a risk factor for the development of CTEPH after acute PE, and that larger perfusion defects are correlated with the development of CTEPH.11,14,16,17 The development of CTEPH after acute PE may also be related to the degree of increase in pulmonary pressures at diagnosis of acute PE. A cohort of 78 patients was followed for 5 years and those who had persistent increases in pulmonary artery pressures after 1 year had significantly higher pulmonary pressures at the time of diagnosis.17 In other studies, patients with a right ventricular systolic pressure (RVSP) greater than 50 mm Hg at PE diagnosis had a 3-fold to 5-fold greater increase in persistent pulmonary hypertension by transthoracic echocardiography (TTE).17,18 Reidel and colleagues19 noted that a mPAP greater than 30 mm Hg at PE diagnosis was associated with further increases in pulmonary artery pressure during long-term follow-up. Although data are limited, there is some evidence that use of lytic therapy in those PE patients with significant pulmonary hypertension at presentation may reduce the occurrence of sustained increases in pulmonary artery pressures, although this remains controversial.18,20 Factors other than thromboembolic disease have been identified for the development of CTEPH.7,21 A cohort of patients with CTEPH was compared with a cohort of patients with precapillary nonthrombotic pulmonary arterial hypertension (PAH).7 In addition to prior venous thromboembolism and recurrent venous thromboembolism, multivariate analysis revealed that independent risk factors for the development of CTEPH included thyroid replacement (odds ratio [OR], 6.10; 95% CI, 2.73–15.05), a history of malignancy (OR, 3.76; 95% CI, 1.47–10.43), ventriculoatrial shunt (for hydrocephalus) and infected pacemaker (OR, 76.40; 95% CI, 7.67–10351), and a history of splenectomy (OR, 17.87; 95% CI, 1.56–2438). These risk factors are relevant to those without PE or DVT because only 40% of the patients in this cohort had a history of prior thromboembolic disease. Other risk factors include the presence of antiphospholipid antibodies/lupus anticoagulant, inflammatory bowel disease, chronic osteomyelitis, infected tunneled catheter systems, fibrinogen variants resistant to

Chronic Thromboembolic Pulmonary Hypertension lysis, histocompatibility locus antigen (HLA) polymorphisms, and non-O blood groups.7,22–25 The concept that prothrombotic states may predispose patients to the development of CTEPH is supported by several observations. First, prior venous thromboembolism is clearly associated with the development of CTEPH (OR, 4.5; 95% CI, 2.4–9.1), as is recurrent venous thromboembolism (OR, 15; CI, 95% 5.4–43).7,22 Increased levels of factor VIII have been identified in a greater proportion of individuals with CTEPH (41%) than patients with nonthromboembolic pulmonary hypertension (22%; P 5 .022) and healthy controls (5%; P1000 dyn/s/cm 5), major comorbid conditions, and significant lung disease in areas of lung reperfused by PTE. Advanced age is also a predictor of poor outcome but not a contraindication to PTE. Mortality after PTE is high among those with residual increase in PVR (>500 dyn/s/cm 5). Before surgery, an attempt should be made to determine the extent of distal disease versus more proximal disease or upstream disease because patients with more distal disease often have residual increase in PVR after PTE. The role of nonsurgical therapy in CTEPH has yet to be defined. Use of PAH disease-modifying

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Chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with high mortality and few treatment options. This article reviews the epidemiolog...
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