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Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina; and Department of Respiratory Medicine, Hospital Antoine Béclère, Clamart, France
Correspondence and requests for reprints should be addressed to Victor F. Tapson, M.D., Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710. E-mail: tapso001{at}mc.duke.edu
ABSTRACT
The incidence and prevalence of chronic thromboembolic pulmonary hypertension (CTEPH) are yet to be accurately determined and may be significantly underestimated. Historically, the occurrence of CTEPH in patients diagnosed with acute pulmonary embolism (PE) has been considered rare. Data from autopsy studies estimated the incidence of CTEPH at 1–3% overall and at 0.1–0.5% in patients surviving acute PE. Data indicate that each year in the United States, approximately 600,000 individuals suffer an acute pulmonary embolic event and that the annual number of new CTEPH cases in the United States is between 500 and 2,500. This may underestimate the true frequency of CTEPH because the disease is often misdiagnosed due to nonspecific symptoms and variable disease course. A monocenter, prospective, longitudinal study assessing symptomatic CTEPH in patients with acute PE but without prior venous thromboembolism recently estimated the cumulative incidence of CTEPH to be 1.0% 6 mo after PE, 3.1% after 1 yr, and 3.8% after 2 yr; overall post-PE incidence was approximately 3%. Further studies are needed to better define the true rate of CTEPH. Acute embolic events can occur without symptoms, and symptomatic PE is often overlooked or misdiagnosed in practice. CTEPH is often identified during diagnostic work-up in patients with unexplained pulmonary hypertension, many of whom lack medical history suggesting previous PE. In a recent study in 142 consecutive patients with CTEPH, 90 (63%) had no previous history of symptomatic venous thromboembolism. Further prospective epidemiologic studies are needed to better define the incidence and prevalence of CTEPH.
Key Words: deep vein thrombosis • pulmonary embolism • pulmonary hypertension • thromboembolism • venous thromboembolism
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition characterized by single or recurrent pulmonary thromboemboli that obstruct or obliterate the pulmonary vascular bed as unique organized tissue, promoting increased pulmonary vascular resistance and progressive pulmonary hypertension and right-heart failure (1–4). The involvement of pulmonary microvascular changes in the form of general pulmonary hypertensive arteriopathy has been defined relatively recently and is gaining increased recognition as a contributor to disease progression in CTEPH (5–7).
The symptomatic history of CTEPH has been well characterized (8). Many patients with CTEPH present late in the course of disease with progressive dyspnea on exertion, hemoptysis, and general clinical deterioration that parallels loss of right ventricular functional capacity. The early natural history of the condition has not been adequately characterized (9). Nonspecific symptoms and lack of medical history of previous venous thromboembolism (VTE) often complicate accurate diagnosis and, as a result, CTEPH is frequently misdiagnosed and is underrecognized in practice (10). Consequently, CTEPH occurrence is poorly documented.
Although recent studies have greatly improved our understanding of CTEPH in terms of its pathophysiology and, to some degree, its natural history, the incidence and prevalence of the condition are yet to be fully documented. In this article, we explore the natural history of CTEPH; discuss studies on the occurrence of and interrelationships between VTE, pulmonary embolism (PE), and CTEPH; and highlight recent findings that underline the underestimation and/or underrecognition of the disease.
VTE, PE, AND CTEPH: THE SCOPE OF THE PROBLEM
There has been debate on the principal source of initiating thromboembolic events that contribute to development of CTEPH, and this is important in studying the incidence of the condition because it is key in defining which patients should be looked at. In accord with the "thrombotic hypothesis," PE arising from sites of deep vein thrombosis (DVT) is generally accepted as the initiating event in CTEPH, and this has strongly influenced the diagnosis and management of the condition since the 1960s. This suggests that patients at increased risk of PE, such as those with previous DVT and/or PE, are appropriate populations for monitoring the rate of CTEPH occurrence (11). Lang and colleagues (10) reported that a history of VTE can be documented in approximately 60% of patients.
According to the American Heart Association, VTE is the third most common vascular disease in the United States, with approximately 2 million cases per year (12). There are 600,000 hospitalizations per year for DVT in the United States, with 250,000 cases requiring 5 d or more of treatment with intravenous heparin (13, 14). Studies from other countries, including countries in Asia where DVT is perceived to be rare, suggest that it is a worldwide problem (15–17). Although a significant minority of patients with acute proximal DVT have been shown to have asymptomatic (i.e., "silent") PE (18), annual mortality rates associated with VTE/PE range from 60,000 to 200,000 (19, 20). To put this in context, data from the same time period show that in the United States, PE-related mortality equaled that for AIDS, breast cancer, and road traffic accidents combined (20–23). In 20–40% of patients who develop acute PE, hemodynamic failure and death have been reported to occur within 1 h of the event (19).
A large retrospective study reviewing the medical records of 2,218 patients with incident DVT or PE over 25 yr was conducted in Olmsted County, Minnesota, between 1966 and 1990 (24). The incidence of VTE in the general population was estimated at 0.117% (0.048% DVT and 0.069% PE). An average annual incidence of 1 acute PE per 1,000 population was stated. The overall incidence of VTE increased with age, with the greatest proportional contribution seen from patients with PE. A similar study conducted in Worcester, Massachusetts, between 1985 and 1986 estimated the incidence of DVT at 0.048% and that of PE at 0.029%, with a similar association between PE and age (20).
Although annual mortality rates from PE have been reported to increase between the 1960s to the mid-1980s in the United States, likely due to improved diagnostic procedures, the incidence of PE was 45% lower for the period 1976–1990, compared with 1966–1975 in the Olmsted County study, and the authors concluded that, overall, the incidence of PE decreased in this time interval (24). Greater health awareness and lifestyle changes within susceptible age groups could be among a number of factors providing this improvement. However, as valuable as the Olmsted County study data are, this study compared a 15-yr time period starting 30 yr ago with the subsequent time period ending 15 yr ago. Medical wards have changed substantially over the past 15 yr, and patients in the hospital tend now to have more severe disease. Prophylaxis is still dramatically underused, and it is considered debatable whether the incidence of PE is lower now than it was 15 yr ago.
Studies in Japan have identified an increase in the incidence of mortality related to PE (25). Improved diagnostic procedures may have led in part to an apparent increase: the clinically diagnosed rate in autopsy cases in which PE is the main diagnosis or cause of death increased from 28.7% in 1987 to 45.3% in 1997 in Japan. Westernization of lifestyle in Japan during the last 50 yr up to 2000, including diet, has also been suggested as contributing to the increase in fatal PE in this region.
The risk of death from right-heart failure in patients with undiagnosed or untreated CTEPH is high, with survival inversely related to pulmonary artery pressure at diagnosis: mortality rates are approximately 70% among patients with a mean pulmonary artery pressure > 40 mm Hg, increasing to 90% at > 50 mm Hg (3). The significant morbidity and mortality related to VTE, PE, and CTEPH represent a substantial health care challenge.
CTEPH INCIDENCE AND RELATED FINDINGS
The weight of evidence suggests that the development of CTEPH is an extension of the natural history of acute PE, although it occurs in only a minority of patients. CTEPH has been estimated to occur in 0.1–0.5% of patients who survive an episode of PE (19, 26), which equates to 500–2,500 annual cases in the United States alone (26). More recent data indicate that the incidence of CTEPH may be much higher than these studies suggest.
In the vast majority of patients, the usual natural history of PE includes restoration of normal hemodynamics and gas exchange, and total resolution of thromboemboli or resolution with minimal "residua" by mechanical changes in thrombus location and endogenous thrombolysis within 30 d (5, 10). Exercise tolerance also returns to normal or near normal in most patients (15). Measurement of right-heart pressures during serial follow-up catheterization has shown restoration of normal right-heart function in 90% of patients within 10–21 d after acute PE (26). However, incomplete recovery from PE has been observed in a substantial proportion of patients. Echocardiographic and lung perfusion data indicate that up to 25% of patients show persistent pulmonary hypertension or abnormal lung perfusion patterns up to several months after PE (27–29). This indicates that incomplete anatomic and hemodynamic recovery from acute PE is more common than is generally recognized, and a significant number of post-PE patients may be at risk of developing CTEPH (5).
Early thrombotic resolution reduces vascular obstruction after PE, after which organization and recanalization further alleviate impaired blood flow. However, there is little angiographic or hemodynamic data from sequential follow-up studies in post-PE patients, and the impact of significant organized thromboembolic residua on lung perfusion is not fully known. Pulmonary vessels can reperfuse even when as little as 20% of the normal luminal diameter is patent and therefore may appear normal in scans, even though they remain as high-resistance vessels contributing to greater pulmonary vascular resistance (11). In a prospective study of 78 survivors of acute PE incorporating 1 yr of echocardiographic follow-up and 5 yr of clinical follow-up, Ribeiro and colleagues (27) shed light on the frequency of postembolic subclinical pulmonary hypertension. Data showed an early 38-d dynamic phase followed by a stable phase of pulmonary artery pressure decline. Persistent pulmonary hypertension and/or right ventricular dysfunction were present in 44% of patients after 1 yr. Four patients (5.1%) developed definite CTEPH, and three patients (3.8%) underwent pulmonary thromboendarterectomy (27). An important finding was that a pulmonary artery pressure of > 50 mm Hg, documented by echocardiography at the time of diagnosis of acute PE, was associated with a threefold higher risk of persistent pulmonary hypertension after 1 yr. As indicated in previous studies, age over 70 yr was also identified as a risk factor for persistent pulmonary hypertension (27).
A prospective, long-term, longitudinal follow-up study conducted by Pengo and colleagues (30) recently provided direct evidence that the incidence of pulmonary hypertension after acute PE may be higher than that seen in previous studies (19, 26). Pengo and colleagues (30) assessed the incidence of symptomatic CTEPH in consecutive patients diagnosed with acute PE but without prior VTE, with a median follow-up of nearly 8 yr. Patients with unexplained persistent dyspnea underwent transthoracic echocardiography followed by ventilation–perfusion lung scanning and pulmonary angiography. CTEPH was considered present if systolic and mean pulmonary artery pressures exceeded 40 mm Hg and 25 mm Hg, respectively; if pulmonary capillary wedge pressure was normal; and if there was angiographic evidence of disease. Symptomatic CTEPH was shown to affect approximately 4% of patients within 2 yr after a first episode of symptomatic PE. The cumulative incidence of symptomatic CTEPH was 1.0% at 6 mo, 3.1% at 1 yr, and 3.8% at 2 yr (Figure 1).
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UNDERRECOGNITION OF PE AND UNDERESTIMATION OF CTEPH
In general, prospective studies provide higher incidence values compared with retrospective studies, and there are several possible reasons why the incidence of CTEPH has been underestimated in the past. VTE has been shown to be asymptomatic (silent PE) in a substantial proportion of patients who may go on to develop CTEPH. Lang (10) recently conducted a study in 142 consecutive patients with diagnosed CTEPH at the Medical University of Vienna and showed that 90 patients (63%) did not have a history of symptomatic VTE at presentation. Autopsy studies frequently show that most cases of fatal PE are unrecognized and/or undiagnosed, and data from studies screening for PE in patients with DVT and in postoperative patients suggest that many patients with PE are asymptomatic and that PE often goes unrecognized (31). Passarino and colleagues (32) reported that of 546 autopsy-confirmed cases of death associated with PE, correct diagnoses were seen only in 8.4% of cases. Meignan and colleagues (18) performed perfusion lung scans in 622 outpatients with no clinical indication of PE and with proximal DVT confirmed by venography and showed that 40–50% had silent PE. These findings provide compelling evidence that VTE is extensively overlooked and that PE is frequently undetected by physicians.
Although the study conducted by Pengo and colleagues (30) provides the most robust data regarding the incidence of CTEPH after PE, there is ongoing debate on whether their findings represent the true incidence of CTEPH. Many believe that CTEPH incidence may have been underestimated because only patients with symptomatic PE and without VTE were included, arguing that because only patients with acute PE were included in the primary analysis, those who never presented with PE but have developed CTEPH would naturally have been excluded. Pengo and colleagues also excluded patients with preexisting exertional dyspnea or with a history of other disease known to be associated with pulmonary hypertension and recommended that their overall incidence estimate be regarded as the lower limit (30). Some experts have disputed the data of Pengo and colleagues (30), suggesting that it may represent an overestimate.
Following a cohort of patients for a given amount of time while looking for defined signs of a disease may lead to detection of early, and sometimes asymptomatic, cases. Patients may have a shorter than normal time from symptom onset to diagnosis (i.e., "lead-time bias"). In the study by Pengo and colleagues, the time from CTEPH symptom detection to diagnosis was less than 8 mo in all but two patients (30), but many patients with CTEPH are symptomatic for much longer than this before diagnosis in the clinic. In addition, some milder cases (12 of 18 patients in this cohort with class II symptoms) might not ever have gotten worse or ever presented to a pulmonary hypertension center to be evaluated for CTEPH. Patients included in the study may have been less severely ill than those commonly seen in practice, and the incidence of severe CTEPH may be less common than the study might suggest at first glance. Further research is needed to better define CTEPH incidence and perhaps to stratify patients according to disease severity.
The length of time required for the development of symptomatic CTEPH, the lack of predictability of hemodynamic deterioration post-PE, and the frequent asymptomatic nature of VTE/PE and early persistent post-thromboembolic pulmonary hypertension represent major challenges for establishing definitive estimates of CTEPH incidence. In future studies, it may be useful to apply assessments of risk factors for possible pulmonary hypertension in patients with suspected chronic thromboembolic disease or CTEPH (34). Potential risk factors identified by Pengo and colleagues (30) in symptomatic post-PE patients included multiple episodes of PE, larger perfusion defect, younger age, and idiopathic presentation of PE. Other reported risk factors include splenectomy, chronic inflammatory disorders, myeloproliferative syndromes, and ventriculoatrial shunt, all of which represent an opportunity for physicians to consider CTEPH as a clinical possibility (33–35). In clinical practice, physicians should be vigilant for persistent or recurrent dyspnea in patients who have had a recent PE. The key to improving the diagnosis and management of CTEPH is not only to raise awareness of the disease among physicians but also to develop diagnostic and treatment guidelines for effective multidisciplinary management of post-PE patients (10).
UPDATED THINKING ON CTEPH PROGRESSION
Evidence highlighting differences between VTE/PE and CTEPH has led to some speculation on whether CTEPH originates from thromboembolic disease in all cases (36). For instance, VTE is more common in the elderly, whereas CTEPH often affects younger adults (37). CTEPH is difficult to replicate through induced PE in experimental studies, and there are striking differences between the organized thrombotic material removed during pulmonary thromboendarterectomy in CTEPH and that retrieved during embolectomy in patients with acute PE (10). In addition, many conditions that predispose to VTE do not seem to cause CTEPH, suggesting that the two conditions may be unrelated (36). For instance, as covered in detail elsewhere in this issue (34), markers of congenital thrombophilia are acknowledged as risk factors for VTE but are not unduly prevalent in CTEPH (36). No clear link has been established between CTEPH and the occurrence of antithrombin, protein S, protein C, or factor II or factor V Leiden (34).
As covered in detail by others (6, 34), opinion on the pathogenesis and natural history of CTEPH has evolved, and it is becoming increasingly acknowledged that although organized central thrombi are the most likely disease-initiating event, progressive small pulmonary vessel arteriopathy may contribute to the long-term progression of pulmonary hypertension (4, 6, 7). Studies also suggest that local (in situ) pulmonary thrombosis may contribute to disease progression, promoting the stabilization and growth of thromboemboli (7, 36). Further, it has been proposed that CTEPH may represent part of a spectrum of disease associated with PE, with complete hemodynamic and anatomic resolution in a minority of patients, partial resolution with normal clinical status in most, and progression to CTEPH in the remaining few (11). Recent studies have addressed this debate to some degree, but questions regarding pathophysiologic changes between VTE and CTEPH diagnosis remain and require further study.
Studies on the epidemiology and etiology of CTEPH have also highlighted some findings that may indicate predisposing factors. The approximate 2:1 predominance of CTEPH among women and the higher overall incidence of chronic pulmonary thromboembolism in Japanese patients compared with cohorts in the United States indicate some possible differences in the spectrum of prevailing etiologic factors. For instance, based on serologic genotyping, Tanabe and colleagues (38) suggested that certain HLA polymorphisms in Japanese patients seem to affect the occurrence of DVT and therefore may affect patient susceptibility to and clinical characteristics of CTEPH. Whether such factors are relevant in interpreting data on trends in incidence of PE-related mortality is not known and requires further study.
CONCLUSIONS
The incidence of CTEPH is difficult to assess and, historically, has been underestimated. Although initial autopsy studies indicated the CTEPH incidence to be 0.1–0.5%, recent prospective epidemiologic data indicate an incidence of approximately 4% after acute, symptomatic PE. Further epidemiologic studies of post-PE patients and others considered at risk of persistent pulmonary hypertension related to thromboembolic disease are required to clearly define the incidence and prevalence of CTEPH.
Physicians need to be more aware of the long-term risks of CTEPH associated with PE, even in post-PE patients who show no clinically obvious symptoms (e.g., exertional dyspnea). Analysis of the time course of changes in pulmonary artery pressure versus right ventricular function could aid early identification of persistent pulmonary hypertension and right-heart dysfunction in monitoring for possible CTEPH. Pulmonary artery pressure > 50 mm Hg has been suggested as predictive of greater risk of persistent pulmonary hypertension (26). Echocardiography in patients with acute PE has enabled monitoring of progression or resolution of thromboembolic pathology (27, 30). Further analyses and initiatives are required to enable the early identification of CTEPH and to increase our understanding of the mechanisms and natural history of the disease.
FOOTNOTES
Supported by an unrestricted educational grant from Actelion Pharmaceuticals.
Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form May 10, 2006; accepted in final form June 26, 2006)
REFERENCES
This article has been cited by other articles:
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 L. J. Rubin, M. M. Hoeper, W. Klepetko, N. Galie, I. M. Lang, and G. Simonneau Current and Future Management of Chronic Thromboembolic Pulmonary Hypertension: From Diagnosis to Treatment Responses Proceedings of the ATS, September 1, 2006; 3(7): 601 - 607. [Abstract] [Full Text] [PDF]
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