Home | News | Kontakt | Sitemap | Impressum

Medical > Therapy > Special indications

Chronic thromboembolic pulmonary hypertension (CTEPH)

Like pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH) is a disorder, which intrinsically involves the pulmonary circulation and belongs to category 4 of the Venice classification (1). CTEPH has many similarities with PAH. Symptoms and signs are comparable, and because of their non-specificity there is often a long latency period from the beginning of the first symptoms until correct diagnosis. Most probably the effective incidence of CTEPH is grossly underestimated. Unpublished data from Olmsted County (USA) indicate an annual incidence of 6 cases per million inhabitants, which is comparable to PAH. In the large randomised AIR study of inhaled iloprost (2), which included both PAH and CTEPH patients, the number of the latter category of patients was significantly lower (57 versus 102 patients). On the other hand, a recent study from Padua, Italy, following up 223 patients with acute pulmonary thromboembolism (PT) revealed a cumulative incidence of CTEPH of almost 4 percent after 10 years (3). Translated into the population of USA with a documented annual incidence of acute PT of 650 000, the calculated incidence of CTEPH should be almost 25 000 cases per year, which is in strong contradistinction with an incidence of about 2000, if one extrapolates the data of Mayo Clinic into the US population. This means that, although CTEPH is an orphan’s disease like PAH, It is most probably grossly underdiagnosed.

Pathogenesis of CTEPH
It is generally believed that CTEPH is a consequence of recurrent PT. The natural history of acute pulmonary embolism has been extensively studied more than 30 years ago. The Urokinase Pulmonary Embolism Trial showed that the most significant resolution of PT occurred within the first 14 days (4). However, a significant increase in resolution from 56 % to 74 % was observed between 14 days and 3 months. Thereafter, there was only minimal further resolution. A thorough follow-up study in 60 patients showed that after 2.5 years 65 % of the patients had complete resolution of their PT, whereas 23 % had minimal persistent PT, and 12 % persistent, unresolved PT (5).

Thus, incomplete resolution of PT is well documented. On the other hand, only about 60 % of patients with CTEPH do recall to have ever had an episode of acute PT. Moreover, traditional disorders of hypercoagulability are only rarely detected in these patients, and besides the lupus anticoagulans, such defects are not more frequent in CTEPH compared to the normal populations. Hence, nowadays many experts believe that CTEPH is in fact an intrinsic disorder of the pulmonary vessel wall (6).

Clinical presentation of CTEPH
The clinical presentation of CTEPH is comparable to that of PAH (7). Like in the latter disorder, the main diagnostic problem is that 1) the symptoms are non-specific, 2) the clinical signs are often overlooked and 3) the disorder is not well known because of its relative rarity.
The classical triad of disorders intrinsic to the pulmonary circulation is as follows: 1) increasing dyspnea on exertion, 2) normal spirometry, and 3) normal lung parenchyma on chest x-ray.
For further information about diagnosis of pulmonary hypertension see section on “Diagnosis”.

Surgical treatment of CTEPH
The treatment of choice in patients with CTEPH is pulmonary endarterectomy (PEA), which is potentially curative in these patients (8). The operability of the patients is determined 1) by the accessibility of the affected vessel and 2) by the absence of medical contraindications. Patients in whom the central or segmental arteries are involved represent good candidates for surgery. The distribution of the lesions is assessed by pulmonary angiography, which should only be performed at the centre that performs the PEA. The technical aspects of operability largely depend on the surgeon’s experience.

For further information about PEA see section on “Operative treatments”.

Contraindications for PEA
Besides the prerequisite of surgical accessibility, patients need to be suitable for the operation. The main medical contraindication for PEA is severe underlying chronic lung disease, especially chronic obstructive pulmonary disease (COPD) with a FEV1 below 50 percent of the predicted. Advanced age, renal or hepatic insufficiency as well as malignancy should be included in the risk assessment, but are not considered absolute contraindications. Indeed, renal and hepatic function can significantly improve after PEA in cases with severe right heart failure. Patients who suffer from a neoplastic disease but have a reasonable life expectancy may well benefit from the tremendous improvement in quality of life after PEA. Patients with concomitant coronary artery disease can undergo coronary artery bypass operation together with PEA.

Medical treatments for CTEPH
Since the seminal study by Moser in 1973, it is well known that CTEPH shares not only clinical but also pathological features with idiopathic PAH (9). Histologic examination in these patients discloses the full range of pulmonary hypertensive changes, including plexogenic lesions. A recent study demonstrated that CTEPH also shares vasoreactive properties with PAH with a comparable number of patients being responsive during acute vasodilator testing (10). Thus, in conjunction with the peculiar aspects of the natural history of CTEPH including the frequent absence of a clinical history of acute PT as well as coagulation disorders strongly suggest that in fact an intrinsic disorder of the pulmonary vessel wall, as mentioned above (6).

There are numerous uncontrolled studies showing some benefit of treatment with almost all vasoactive drugs in patients with CTEPH. Nagaya et al. demonstrated a significant improvement of hemodynamic parameters with continuous intravenous epoprostenol in 12 patients with severe CTEPH during about 7 weeks before PEA (11). This results were confirmed in a group of 27 cases with inoperable distal CTEPH (12). In addition, there was an improvement in NYHA/WHO functional class (FC) and an increase in 6-minute walking distance (6-MWD) of 66 m. These effects were maintained after 30 months in 17 patients. Comparable effects on all these parameters have been shown for subcutaneous treprostinil in 25 patients after a mean follow-up of 2 years, with an increase in 6-MWD of 59m. Also with the orally active prostacyclin analogue beraprost there was some improvement in hemodynamics and FC in 20 cases (13). Compared with a historical control of 23 patients, those treated had a better survival (765 versus 46 % at 5 years. Data on 6-MWD were not given. In contrast, the subgroup of 57 patients included in the above mentioned AIR study of inhaled iloprost showed no significant benefit (2).

An open trial of oral sildenafil resulted in an improvement in hemodynamics and 6-MWD (54m) in 12 patients with inoperable CTEPH after a follow-up of about 6 months (14).

Oral bosentan improved hemodynamics and 6-MWD (73m) in 19 patients with inoperable CTEPH (15). Whereas FC did not change significantly, it improved in another open trial of 16 cases (16). The 6-MWD increased by 92 m in these patients. Comparable results have been found in the recently concluded Swiss BOCTEPH trial (Ulrich S. Personal communication). Also on the long term, bosentan might have a beneficial effect, as shown by Seyfarth et al. who found an increase in 6-MWD by 61m and a decrease in the Tei index after 24 months (17).

Recently, the initial results from the double-blind, placebo-controlled, multicenter study BENEFiT (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension) in 157 patients have been reported (Actelion, press release). The study met its primary objective, as treatment with bosentan was associated with a significant reduction in pulmonary vascular resistance by -193 dyn x sec x cm-5 (p<0.0001). The six-minute walk test remained stable over the four months of blinded evaluation in both treatment groups. This lack of difference between the two groups of patients most probably is due to their advanced age (about 20 years older than patients in other PAH trials), the high prevalence of concomittant co-morbidities, and the relatively short duration of the study. Patients on bosentan, however, showed a significant improvement in breathlessness (Borg dyspnoea score) with exercise and there was a trend in favor of bosentan towards prevention of worsening WHO functional class.


References:

1. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S-12S.

2. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, Nikkho S, Speich R, Hoeper MM, Behr J, Winkler J, Sitbon O, Popov W, Ghofrani HA, Manes A, Kiely DG, Ewert R, Meyer A, Corris PA, Delcroix M, Gomez-Sanchez M, Siedentop H, Seeger W. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-329.

3. Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P, Thromboembolic Pulmonary Hypertension Study G. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. New England Journal of Medicine 2004;350:2257-2264.

4. The Urikinase Pulmonary Embolism Trial. Circulation 1973;47 (Suppl II):1-108.

5. Paraskos JA, Adelstein SJ, Smith RE, Rickman FD, Grossman W, Dexter L, Dalen JE. Late prognosis of acute pulmonary embolism. N Engl J Med 1973;289:55-58.

6. Fedullo PF, Rubin LJ, Kerr KM, Auger WR, Channick RN. The natural history of acute and chronic thromboembolic disease: the search for the missing link. Eur Respir J 2000;15:435-437.

7. Dartevelle P, Fadel E, Mussot S, Chapelier A, Herve P, de Perrot M, Cerrina J, Ladurie FL, Lehouerou D, Humbert M, Sitbon O, Simonneau G. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004;23:637-648.

8. Mayer E. Surgical treatment of chronic thromboembolic pulmonary hypertension. Swiss Med Wkly 2006;136:491-497.

9. Moser KM, Bloor CM. Pulmonary vascular lesions occuring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993;103:685-692.

10. Ulrich S, Fischler M, Speich R, Popov V, Maggiorini M. Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties. Chest 2006;130:841-846.

11. Nagaya N, Sasaki N, Ando M, Ogino H, Sakamaki F, Kyotani S, Nakanishi N. Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 2003;123:338-343.

12. Cabrol S, Souza R, Jais X, Fadel E, Ali RH, Humbert M, Dartevelle P, Simonneau G, Sitbon O. Intravenous epoprostenol in inoperable chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant 2007;26:357-362.

13. Ono F, Nagaya N, Okumura H, Shimizu Y, Kyotani S, Nakanishi N, Miyatake K. Effect of orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Chest 2003;123:1583-1588.

14. Ghofrani HA, Schermuly RT, Rose F, Wiedemann R, Kohstall MG, Kreckel A, Olschewski H, Weissmann N, Enke B, Ghofrani S, Seeger W, Grimminger F. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003;167:1139-1141.

15. Hoeper MM, Kramm T, Wilkens H, Schulze C, Schafers HJ, Welte T, Mayer E. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2363-2367.

16. Bonderman D, Nowotny R, Skoro-Sajer N, Jakowitsch J, Adlbrecht C, Klepetko W, Lang IM. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 2005;128:2599-2603.

17. Seyfarth HJ, Pankau H, Hammerschmidt S, Schauer J, Wirtz H, Winkler J. Bosentan improves exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy. Chest 2005;128:709-713.

Back to > Medical > Therapy > Special indications