Published ahead of print on February 21, 2008, doi:10.1164/rccm.200712-1841OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200712-1841OC
Improved Outcomes in Medically and Surgically Treated Chronic Thromboembolic Pulmonary Hypertension1 Pulmonary Vascular Disease Unit, Papworth Hospital, Cambridge, United Kingdom; 2 Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom; 3 Department of Cardiology, Hammersmith Hospital, London, United Kingdom; 4 Northern Pulmonary Vascular Unit, Freeman Hospital, Newcastle-upon-Tyne, United Kingdom; 5 Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom; 6 Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, United Kingdom; and 7 Department of Cardiology, Royal Free Hospital, London, United Kingdom Correspondence and requests for reprints should be addressed to Dr. Joanna Pepke-Zaba, Ph.D., Pulmonary Vascular Disease Unit, Papworth Hospital, Cambridge CB23 3RE, UK. E-mail: joanna.pepkezaba{at}papworth.nhs.uk
Rationale: The management of chronic thromboembolic pulmonary hypertension (CTEPH) has changed over recent years with the growth of pulmonary endarterectomy surgery and the availability of disease-modifying therapies. Objectives: To investigate the prognosis of CTEPH in a national setting during recent years. Methods: All incident cases diagnosed in one of the five pulmonary hypertension centers in the United Kingdom between January 2001 and June 2006 were identified prospectively. Information regarding baseline characteristics, treatment, and follow-up was subsequently collected from hospital records. Measurements and Main Results: A total of 469 patients received a diagnosis, of whom 148 (32%) had distal, nonsurgical disease. One- and three-year survival from diagnosis was 82 and 70% for patients with nonsurgical disease and 88 and 76% for those treated surgically (P = 0.023). Initial functional improvement in patients with nonsurgical disease was noted but did not persist at 2 years. Significant functional and hemodynamic improvements were seen in surgically treated patients with an increase in six-minute-walk distance of 105 m (P < 0.001) at 3 months. Five-year survival from surgery in the 35% of patients who survived to 3 months but had persistent pulmonary hypertension was 94%. Conclusions: The prognosis in nonsurgical disease has improved. We have confirmed the previously described good outcome in surgically treated disease. However, we have also demonstrated that the long-term prognosis for patients who have persistent pulmonary hypertension at 3 months after surgery is good. The observed improvements in outcome during the modern treatment era reinforce the importance of identifying patients with this increasingly treatable condition.
Key Words: pulmonary hypertension • thromboembolism • endarterectomy • survival • drug therapy
Chronic thromboembolic pulmonary hypertension (CTEPH) is an increasingly recognized cause of pulmonary hypertension (PH). The true incidence is not known, with studies suggesting as many a 3.8% of patients develop the condition after an acute pulmonary embolism (1). Incomplete clot lysis, with subsequent organization of the obstructing material into vessel walls, causes continued obstruction to pulmonary vascular blood flow. A peripheral vasculopathy with microvascular changes indistinguishable from idiopathic pulmonary arterial hypertension can then occur even in the areas of the pulmonary vascular bed that have been unaffected by thromboembolism (2–4). Survival before the modern treatment era when effective treatments became available was poor, with 3-year survival as low as 10% in patients with a mean pulmonary artery pressure (mPAP) of greater than 30 mm Hg (5). The preferred treatment for CTEPH is surgical disobliteration of the pulmonary arteries by pulmonary endarterectomy (PEA). The current reported perioperative mortality is 5 to 10% in experienced centers, but there are significant improvements in pulmonary hemodynamics and self-reported functional class (6–9). Some patients, however, have thromboembolic disease that is too distal in the pulmonary arterial bed to be surgically accessible and/or have hemodynamic compromise out of proportion to the degree of segmental arterial obstruction present on imaging. Management of these patients was previously supportive. Because the histopathologic changes of pulmonary arterial hypertension are seen in patients with CTEPH, the disease-modifying therapies used in other forms of pulmonary arterial hypertension have been prescribed on a compassionate basis in the United Kingdom for patients with nonsurgical CTEPH. They have also been used as a bridge to surgery in selected patients with surgically accessible disease. There is only limited data from nonrandomized trials regarding the efficacy of these disease-modifying therapies in CTEPH (10–15), although the results of a placebo-controlled trial of the endothelin receptor antagonist (ERA) bosentan have recently been reported (16). Furthermore, there is a relative paucity of data regarding the natural history of patients with distal disease. Since 2001, the diagnosis, treatment and follow-up of all adult patients with CTEPH in the United Kingdom has been designated to five PH centers. One of these centers has also been designated as the single national center for PEA surgery. This has resulted in a unique opportunity to study the natural history of the disease in a single country and test the hypothesis that the outcome of patients with CTEPH has improved since the introduction of surgical and medical treatment. We have therefore performed a retrospective cohort study of all incident patients diagnosed with CTEPH within a 5.5- year period beginning in 2001. We aim to describe the natural history during the modern treatment era of all patients in the United Kingdom with both surgical and nonsurgical disease. Some of the results of this study have been previously reported in the form of an abstract (17).
All patients diagnosed with CTEPH at a U.K. PH center from January 1, 2001, until June 31, 2006, were identified prospectively. One investigator (R.C.) subsequently visited each site to examine patient records and results to confirm the diagnosis and to record baseline, treatment, and follow-up data. Date of diagnosis was taken as the date of initial right heart catheter or date of first visit in cases in which catheter details could not be located. The diagnosis of CTEPH was made by experienced pulmonary vascular physicians and radiologists. Operability was assessed by a review of clinical data and radiologic investigations by the surgical multidisciplinary team at the national PEA center. Pulmonary hemodynamics, clinical state, and appearances on at least two radiologic modalities were taken into account when deciding on surgical suitability. Patients with other causes for the radiologic appearance of CTEPH—for example, sarcoma and vasculitis—were excluded from the cohort. Surgery was performed using the principles described by Jamieson and colleagues (7). Patients were followed up until either their date of death or the censoring date of January 26, 2007 if still alive. Mortality status at this date was checked from PH center records, by contacting general practitioners, and by using the National Health Service strategic tracing service. In 9% of cases, the definite cause of death could not be ascertained. A small number of patients were untraceable or had undergone transplantation. In these cases, the date of last known contact or transplant was used as their censor date. The first oral disease-modifying therapy became available in the United Kingdom in December 2002. We therefore separately analyzed the survival of distal, nonsurgical patients who entered the cohort during 2001/2002 and 2003 onward. Because a learning effect is well recognized in PEA programs, survival in patients with surgical disease was also analyzed separately during these two periods. Because this study was designed and conducted to define current care, formal ethics approval was not required. The national Patient Information Advisory Group was fully informed regarding the use of patient data.
Statistical Analysis
Study Population Patient numbers are shown in Figure 1. All patients had been investigated with computed tomography pulmonary angiography. A majority of patients had also had at least one of pulmonary and/or magnetic resonance angiography and isotope perfusion scanning performed. Right heart catheter details were located for 97% of patients. In the remainder, echocardiography showed clear evidence of significant PH. In 19% of patients, difficulty obtaining a pulmonary capillary wedge pressure was experienced. In all these cases, the total pulmonary resistance was significantly elevated and left ventricular systolic function was assessed to be normal on echocardiography. Survival was identical in those with and without a reliable wedge pressure. The patients without a wedge pressure were therefore included, but only their total pulmonary resistance used for analysis. The six-minute-walk test (6MWT) was used to assess baseline exercise capacity for 69% and the incremental shuttle-walking test for 20% of patients. Baseline characteristics of all patients are shown in Table 1. The outcomes of those with surgically treated and those with nonsurgical disease are described below.
Survival As noted above, the presented survival data are for incident cases diagnosed after January 2001. One- and three-year survival from the date of diagnosis over the whole period was 88 and 76% for those treated with PEA and 82 and 70% for those with nonsurgical disease (P = 0.023; Figure 2). Survival curves of patients diagnosed during the first 2 years compared with those diagnosed subsequently are shown in Figures 3A and 3B. Surgically treated patients diagnosed in the earlier rather than later period had a significantly higher mPAP (51.1 ± 10.7 vs. 47.9 ± 10.8 mm Hg, P = 0.04) and total pulmonary resistance (1,220 ± 553 vs. 1,039 ± 392 mm Hg, P = 0.01). There was no statistically significant difference in time from diagnosis to surgery between the two time periods (median, 189 [299] vs. 220 [156] d; P = 0.36). For those with nonsurgical disease, there was no significant difference in hemodynamics between the two time periods; however, the proportion of distal patients with World Health Organization (WHO) class IV disease was 30% in the earlier group compared with 11% in the later group (P = 0.008).
Disease-modifying Therapies Of those undergoing PEA, 29% of the earlier group received disease-modifying therapy with a prostanoid, an ERA, or a phosphodiesterase-5 inhibitor before surgery, compared with 65% of the later group (P < 0.001). In patients with nonsurgical disease, 70% of the earlier group received disease-modifying therapies compared with 90% of the later group (P = 0.005). Of those with nonsurgical disease diagnosed during 2001/2002 and receiving monotherapy, 17% were treated with an ERA and 83% with a prostanoid. In those diagnosed from 2003 onward, 56% received an ERA, 33% a phosphodiesterase-5 inhibitor, and only 11% a prostanoid (P < 0.05).
Nonsurgical Outcome
Surgical Outcome Perioperative mortality, as defined by survival to hospital discharge, was 16% over the whole period, whereas in the subgroup of patients diagnosed from 2003 onward the figure was 11.5%. In those operated on in 2006, this perioperative mortality rate was still lower at 5.4%. Hemodynamic data were obtained in 162 (83%) of PEA survivors at 3 months after surgery, 142 of whom had performed a baseline 6MWT (Table 3). There was no significant difference in subsequent survival between those with or without a 3-month right heart catheter. At 12 months these improvements were either maintained or had improved further (data not shown). In those who survived surgery to 3 months, the proportion with WHO functional class I or II disease increased from 12% at baseline to 88% at 3 months (Figure 4).
Persistent PH after Surgery One hundred and sixty-two of the 198 patients who survived PEA to discharge had a repeat right heart catheter at 3 months after surgery. Seventy of these (35% of those who survived PEA) had both an mPAP of 25 mm Hg or greater and pulmonary vascular resistance of 240 dyn · s · cm–5 or greater, and so were diagnosed with persistent PH. The group with persistent PH had worse preoperative hemodynamics than those without persistent PH, with an mPAP of 50.5 ± 9.4 versus 46.5 ± 10.4 mm Hg and a total pulmonary resistance of 1,144 ± 475 versus 934 ± 344 dyn · s · cm–5 (P, both <0.05). One- and three-year survival was 99 and 94% for those with and 98 and 93% for those without persistent PH (Figure 5). Using treatment criteria of mPAP of 30 mm Hg or greater and/or WHO class III or worse, 8% of survivors were receiving disease-modifying therapy at 3 months, 14% by 1 year, and 18% by 2 years after surgery. Using an intention-to-treat analysis of patients with a baseline 6MWT, the mean improvement in walk distance was 97.0 ± 14.6 m at 3 months and 103.1 ± 22.7 m at 12 months after surgery. In those with persistent PH, the proportion in WHO class I or II increased from 4% at baseline to 82% at 3 months (Figure 6).
Incidence of CTEPH Sixty-one patients in 2001 and 105 patients in 2005 were diagnosed with CTEPH. Assuming a U.K. population of 60 million, the overall national incidence of CTEPH that had been diagnosed and treated by the U.K. PH service was therefore 1.02 cases/year per million individuals in 2001, rising to 1.75 cases/year per million individuals in 2005.
This is the first study involving long-term objective follow-up of a national cohort of patients with CTEPH. It is also the first study to describe the long-term outcome of patients with distal disease and persistent postoperative PH. We have demonstrated that survival of patients with nonsurgical disease in the era of disease-modifying therapies is superior to that reported in historical series, with 1- and 3-year survival rates of 82 and 70%, respectively. In a study of 26 patients who were not treated with surgery or disease-modifying therapies, 2-year survival was only 10% in those with an mPAP of over 50 mm Hg (18). Similarly, a study of 49 patients treated with anticoagulation, and in four cases PEA, found a 3-year survival of only 10% in those with an mPAP of over 30 mm Hg (5). Despite another study involving 48 Japanese patients who had an mPAP of 50 mm Hg that reported a median survival of almost 6 years (19), it is generally recognized that most patients with CTEPH treated with anticoagulation alone have progressive disease (2). In the above studies, no clear distinction between the survival in surgical and nonsurgical disease was made. In the current study, the survival beyond 1 year of both nonsurgical and surgical patients was better in those diagnosed from 2003 onward. In patients with nonsurgical disease, 1- and 3-year survival in this period was 83 and 76%, respectively. Although there was no difference in pulmonary hemodynamics and exercise tolerance between the earlier and later group, a significantly higher proportion of the latter were treated with disease-modifying therapy, in particular oral treatments. Suntharalingam and colleagues recently reported on a group of 35 patients with distal CTEPH who were diagnosed between 1994 and 2005, of whom 68% had been treated with disease-modifying therapies. One- and three-year survival rates were 77 and 53%, respectively (20). In contrast, in a study of 47 patients with nonsurgical disease or persistent PH postsurgery who had a mean mPAP of 51 mm Hg and who were all treated with bosentan, the 1-year survival was 96% (13). The improved survival seen in the second study supports the notion that an increased use of disease-modifying therapies may improve long-term outcome in nonsurgical disease. The short-term beneficial effects of disease-modifying therapies have recently been reported in the randomized controlled BENEFiT trial, which involved 157 patients with CTEPH with either nonsurgical disease or persistent postoperative PH receiving 16 weeks of either bosentan or placebo (16). Although no significant effect on the coprimary endpoint of six-minute-walk distance was found, significant improvements in the other primary endpoint of pulmonary vascular resistance, as well as in the secondary endpoints of cardiac index and total pulmonary resistance, were observed. The increased survival of surgical patients that was observed in the present study during the later period of 2003 onward may have been due to a combination of the improvements in surgical selection and perioperative management over time, which are typical of centers undertaking PEA surgery, together with an increased use of disease-modifying therapy before surgery. In a series of 1,500 patients treated with PEA, Jamieson and colleagues observed that perioperative mortality fell from 8.8% in those who had the operation between 1994 and 1998 to 4.4% in those operated on between 1998 and 2002 (7). In nonsurgical disease, in which the majority (85%) of patients received disease-modifying therapy, there was evidence of an increase in exercise capacity at 3 and 12 months after diagnosis. Follow-up was less standardized than in surgical disease and so data were not complete. However, those with and without recorded walk distances had the same survival, suggesting that the improvements seen are representative of the whole group. Although average exercise capacity had returned to baseline by 24 months, this can still be seen as a favorable outcome in a condition in which the outcome was historically so poor. The improvement in exercise capacity noted in patients still alive at each follow-up time point suggests that a proportion of patients do have an important and sustained response to disease-modifying therapy. In surgically treated patients, improvements seen elsewhere in pulmonary hemodynamics (21, 22), functional class (6, 9), and exercise capacity (23) were confirmed. For example, our finding that almost 90% of patients were in functional classes I and II at 1 year after surgery is comparable to the 93% of 308 questionnaire responders whom Archibald and coworkers found to be in these two classes at the same point in time (9). An important finding of our study is that survival in patients with persistent PH 3 months after PEA, who were treated with disease-modifying therapy in selected cases, was excellent. Furthermore, functional improvements in this group were still clinically significant. Baseline hemodynamics, especially the pulmonary vascular resistance, were worse in the group who developed persistent PH. This would be in keeping with a greater degree of distal disease and pulmonary vasculopathy in those whose hemodynamics did not normalize after surgery. The proportion of patients with persistent PH is consistent with the 35% noted previously (21). The true incidence of CTEPH within the whole population is not known. The present study is the first to report an incidence of CTEPH based on the number of diagnosed and treated cases within a national population. The observed incidence increased by 75% over a period of 5 years, which is most likely to be due to increased awareness of the condition over that period. The figure of 1.75 cases/year per million individuals is conservative because it does not include patients who had received a diagnosis but had not been referred to a PH center, or those who had not received a diagnosis. Both these groups of patients will not, however, have received appropriate management. A limitation of this study is its largely retrospective, observational nature. This means that we cannot confidently ascribe causes to the improvements in survival seen; rather, we can only describe associations between treatments and outcome. Furthermore, there are unavoidable gaps in the data. As discussed, it is possible that there are patients in the United Kingdom who have had a diagnosis of CTEPH made in other hospitals but have not been referred to a national PH center. However, the number of such patients receiving disease-modifying therapies or undergoing PEA elsewhere during the study period is likely to be extremely small. In conclusion, first we have shown that the survival of nonsurgical patients is superior to that seen in historical series. Second, we have confirmed that the outcome in surgically treated patients is good in terms of both survival and functional improvements. However, we have additionally demonstrated that patients with persistent PH after the perioperative period have a good prognosis in terms of both function and survival. The improvements in outcome during the modern treatment era, which are described in the present article, highlight the importance of identifying patients with this increasingly treatable condition.
The authors acknowledge the contribution of the following staff of Papworth Hospital in the treatment of the patients involved: Mr. John Dunning, Dr. Rey Latimer, Dr. Alain Vuylsteke, Dr. Roger Hall, Dr. Nick Screaton, Dr. Deepa Gopalan, Professor Nick Morrell, and Mrs. Maureen Rootes.
Supported by unrestricted educational grants from Actelion, LungRx, Pfizer, and Schering. Originally Published in Press as DOI: 10.1164/rccm.200712-1841OC on February 21, 2008 Conflict of Interest Statement: R.C. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. D.G.K. has received consultancy and lecturing fees and been funded to attend conferences from Actelion, GlaxoSmithKline, Pfizer, Encysive, and Schering Pharmaceuticals. J.S.R.G. has served on advisory boards for Actelion Pharmaceuticals, Encysive Pharmaceuticals, Pfizer, and GlaxoSmithKline. P.A.C. has been reimbursed by Encysive, Pfizer, and Actelion. A.J.P. has received consultancy fees from Actelion, GlaxoSmithKline, Pfizer, and Encysive totaling under $20,000 over the last 2 years. D.P.J. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. D.H. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. K.G. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. R.J.H. has been sponsored by Encysive UK, Actelion UK, and Schering to attend scientific meetings; has worked as a consultant for Actelion UK and Encysive UK; and has received fees for lecturing from Actelion UK. K.S. has received unrestricted educational and travel grants to attend scientific meetings from Actelion, Encysive, Pfizer, United Therapeutics, and GlaxoSmithKline. S.S.L.T. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. I.J.A. has been reimbursed by Actelion, Pfizer, and Encysive for attending several international conferences. Actelion has paid honoraria for a number of educational meetings. C.T. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. R.C. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. C.M.C. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. C.D. does not have a commercial relationship with a commercial entity that has an interest in the subject of this manuscript. J.G.C. provides consultancy services for Actelion and Encysive, as well as speaking at conferences and meetings sponsored by them. J.G.C. has received £15,750 for these services over the last 3 years, in addition to the nurses in the unit that are funded by Actelion and Encysive. J.P.Z. has participated as a speaker in scientific meetings or courses and by several pharmaceutical companies (Actelion, Bayer, Schering, Pharma, Pfizer, and GlaxoSmithKline); has been serving on an advisory board for Actelion, Encysive, and Pfizer; has been reimbursed by Encysive for attending the ATS 2007 conference, has received £75,000 in a joint educational grant from Actelion, LungRx, Pfizer, and Schering for research leading to this manuscript. Received in original form December 17, 2007; accepted in final form February 19, 2008
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ABSTRACT
AT A GLANCE COMMENTARY
2 test. Survival was estimated using Kaplan-Meier methods with comparisons performed by the log-rank test. A P value of 0.05 or less was taken as significant throughout. 
