International Journal of Cardiology 177 (2014) 529–531

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Letter to the Editor

An open-label study on long-term outcomes of bosentan for treating ulcers in thromboangiitis obliterans (Buerger's disease)☆ Joaquin De Haro ⁎, Silvia Bleda, Francisco Acin Angiology and Vascular Surgery Department, Hospital Universitario Getafe, Madrid, Spain

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Article history: Received 15 August 2014 Accepted 17 August 2014 Available online 23 August 2014 Keywords: Long-term effect Bosentan Buerger disease

Distal ischaemic ulcers are frequently observed in thromboangiitis obliterans (TAO), representing a disabling problem for these patients [1]. Only a very few pharmacological and surgical options (of controversial efficacy) are available to date. New therapeutic options with a higher efficacy than the current ones are clearly needed in order to properly manage these patients. Bosentan efficacy for preventing and treating ischaemic ulcers has been evaluated on the basis of several clinical observations in the short-term [2–6]. So far, data on long-term efficacy and safety of this oral dual endothelin receptor antagonist when administered to Buerger's disease patients who develop skin ulcers are lacking. A prospective, open-label study of patients with TAO and ulcers refractory to conventional treatment for off-label treatment with bosentan was performed. The study endpoints were clinical improvement rate, major or minor amputation rate, haemodynamic changes, and gradient in endothelial function (Table 1). Informed consent was obtained from each patient. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. Twelve out of 19 patients included were male (63%). Median age was 37 years (range 24–49). The median follow-up was 36 months (range 24–58). All patients were smokers. Fourteen (74%) were unable to completely abstain from smoking during the follow-up. Eleven patients with more than one ulcer in fingers or toes were included. Two patients presented lesions on the back of the foot at baseline. The upper extremity was involved in five patients (26%). Bosentan therapy consisted of a full-dose regimen (125 mg/12 h) maintained for four months or until total healing of the ulcers. ☆ Trial Registration:Clinical Trials Gov NCT01447550. ⁎ Corresponding author at: Ctra Toledo, Km 12,500, 28905 Getafe, Madrid, Spain. E-mail address: [email protected] (J. De Haro).

http://dx.doi.org/10.1016/j.ijcard.2014.08.107 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

During the follow-up, no new ischaemic lesions were observed in the target extremities in all but three patients whose ulcer had healed and who, six, 27 and 31 months respectively after the end of bosentan treatment, had a relapse of an ulcer on their toes. These relapses were treated with a new four-month course of bosentan which managed to heal the lesions. There was a significant decrease in the number of ulcers and pain visual score (Table 1). A significant improvement in the number of healed and improving with bosentan treatment ulcers was found during the follow-up (p = 0.001). Only two out of 22 (9%) extremities underwent major amputation (both below-the-knee) after bosentan treatment (Fig. 1). All patients experienced a statistically significant improvement in their BAFMD values (p = 0.01). No patient suffered serious adverse effects due to treatment with bosentan leading to withdrawal of the treatment. The only documented-associated adverse event was the occurrence of transient oedema in the lower extremities in 3 patients (16%), consistent with the vasodilatory effect of the distal bed associated with bosentan use. The present study is the first prospective study with long-term follow-up data on bosentan efficacy in TAO evaluating not only the number of healed and improving ulcers, but also endothelial function and haemodynamic measurements. Its findings show that bosentan therapy is associated with promising clinical and endothelial functionrelated outcomes in patients with TAO. Current evidence points to a greater, or faster, effect of bosentan on endothelium compared with its effect as an anti-fibrotic. It should be noted that both clinical improvement and complete healing of the ulcers were achieved in the majority of the target extremities despite the documented failure to give up smoking in the majority of the patients. Moreover, the only major amputations were performed in patients who gave up smoking definitively. These results compares favourably with a 19% major amputation rate in 69 patients who continued smoking, previously reported in a series involving 110 patients with TAO [7]. Concluding, bosentan may result in a long-term improvement of clinical and endothelial function outcomes for treating ischaemic ulcers in Buerger disease patients with an acceptable tolerability profile. Conflict of interest The authors declare that they have no conflict of interests regarding the issues related to this study.

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J. De Haro et al. / International Journal of Cardiology 177 (2014) 529–531

Table 1 Main outcomes of efficacy endpoints assessed in each per protocol scheduled visit during study. Clinical improvement rate (ulcer healing, complete healing of the ischaemic lesions, pain relief), major or minor amputation rate, haemodynamic changes as measured by means of anklebrachial index (ABI), and gradient in endothelial function as measured by means of the brachial artery flow-mediated dilation test (BAFMD). Six-month assessment (n = 19) There were significant improvements in the number of patients with healed ulcers (p = 0.01), and the number of ulcers completely healed and improving (p = 0.001), as well as a significant decrease in patients with active ulcers (p = 0.01). The improvement determined in the pain visual score (PVS) was also significant (p = 0.05). Likewise, the FMAD values were significantly increased (p = 0.01). One major amputation (below-the-knee) was performed after bosentan treatment in a patient with a worsening ulcer in the forefoot. Moreover, a minor amputation of one toe was performed with conservation of the extremity and healing of the ulcers of the other toes in one patient. One-year assessment (n = 19) A significant increase of healed ulcers, ulcers improving and FMAD were observed at one-year compared with the baseline assessments (p = 0.001). The ratio of patients with healed ulcers and PVS also significantly improved (p = 0.01). A decrease in the percentage of patients with active ulcers and a decrease in the pain visual score were also observed (p = 0.01), but without statistical significance compared with 6-month assessments. A non-significant improvement in the ratio of patients with healed ulcers and ulcers improving was noted when compared with 6-month assessments. However, a significant improvement was reached in FMAD determinations compared with 6-month assessments. Two patients underwent amputation (one major below-the-knee because of the worsening of an ulcer in the back of the foot and one minor in a toe) after bosentan treatment. Two-year assessment (n = 19) A significant improvement in the number of patients with healed ulcers, ulcers completely healed, PVS and FMAD was noted. No patients at this time presented active ulcers and no pain was reported. A minor amputation in the toe was performed. Three-year assessment (n = 10) Two patients suffered a relapse of an ulcer on their toes at 27 and 31 months. These relapses were treated with bosentan until the ulcers healed. Four-year assessment (n = 7) No ulcers and no pain were reported at four-year follow-up. The patients presented eight healed ulcers at this visit. A significant increase of FMAD values were observed meanwhile nonsignificant changes were found on ABI. One out of seven patients who completed the 4-year follow-up underwent a major amputation. One prior minor amputation was reported at this visit.

Patients with active ulcers (%) Patients with healed ulcers (%) Ulcers improving (%) Ulcers completely healed (%) Pain visual score (mm, mean ± SD) Give up smoking (%) Minor amputation (%) Major amputation (%) ABI (mean ± SD) BAFMD (mean ± SD)

Baseline (n = 19)

6 months (n = 19)

12 months (n = 19)

18 months (n = 19)

24 months (n = 19)

30 months (n = 15)

36 months (n = 10)

42 months (n = 8)

48 months (n = 7)

19 (100)

7 (37)

4 (21)

1 (5)

0 (0)

1 (6)

1 (10)

0 (0)

0 (0)

0 (0)

13 (68)

15 (79)

16 (84)

16 (84)

13 (87)

9 (90)

9 (90)

5 (71)

0/34 (0) 0/34 (0)

29/32 (90) 16/32 (50)

28/29 (96) 24/29 (83)

28/29 (96) 27/29 (93)

28/28 (100) 28/28 (100)

20/21 (95) 20/21 (95)

12/13 (92) 12/13 (92)

10/10 (100) 10/10 (100)

8/8 (100) 8/8 (100)

81 ± 7

63 ± 6

41 ± 9

12 ± 13

0

9 ± 21

10 ± 18

0

0

0 (0) 0 (0) 0 (0) 0.49 ± 0.13 1.9 ± 0.6

5 (26) 1 (5) 1 (5) 0.51 ± 0.15 5.6 ± 0.9

7 (37) 2 (10) 2 (10) 0.50 ± 0.16 11.5 ± 1.0

6 (31) 2 (10) 2 (10) 0.48 ± 0.17 10.7 ± 1.3

7 (37) 3 (15) 2 (10) 0.49 ± 0.14 9.9 ± 1.9

5 (33) 3 (20) 2 (13) 0.53 ± 0.13 8.8 ± 2.1

5 (50) 1 (10) 1 (10) 0.52 ± 0.13 10.1 ± 2.2

4 (50) 1 (12) 1 (12) 0.54 ± 0.16 9.2 ± 2.9

3 (43) 1 (14) 1 (14) 0.54 ± 0.17 9.7 ± 2.8

Abbreviations: BAFMD: brachial artery flow-mediated dilation test; ABI: ankle-brachial index.

Authors' contributions All authors accept full responsibility for the design and conduct of the study, and had full access to the data and controlled the decision to publish them. All co-authors agree with this and have participated in the study to a sufficient extent to be named as authors. All authors read and approved the final manuscript. Funding This work was supported by Fundacion Investigacion Biomedica del Hospital Universitario de Getafe, Madrid, Spain. Disclosure statement Written consent for publication was obtained from the patient(s) or their relative(s).

References [1] Shionoya S. Diagnostic criteria of Buerger's disease. Int J Cardiol 1998;66(Suppl. 1): S243–5. [2] Korn JH, Mayes M, Matucci-Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004;50:3985–93. [3] Humbert M, Cabane J. Successful treatment of systemic sclerosis digital ulcers and pulmonary arterial hypertension with endothelin receptor antagonist bosentan. Rheumatology 2003;42:191–3. [4] Ramos-Casals M, Brito-Zeron P, Nardi N, et al. Successful treatment of severe Raynaud's phenomenon with bosentan in four patients with systemic sclerosis. Rheumatology 2004;43:1454–6. [5] Launay D, Diot E, Pasquier E, Mouthon L, Boullanger N, Fain O. Bosentan for treatment of active digital ulcers in patients with systemic sclerosis. Presse Med 2006;35: 587–92. [6] Tillon J, Herve F, Chevallier D, Muir JF, Levesque H, Marie I. Successful treatment of systemic sclerosis-related digital ulcers and sarcoidosis with endothelin receptor antagonist (bosentan) therapy. Br J Dermatol 2006; 154:1000–2. [7] Ohta T, Ishioashi H, Hosaka M, Sugimoto I. Clinical and social consequences of Buerger disease. J Vasc Surg 2004;39:176–80.

J. De Haro et al. / International Journal of Cardiology 177 (2014) 529–531

Fig. 1. Kaplan–Meyer curves regarding survival free of major amputation and ulcer healing in our cohort of Buerger's disease patients with ulcers treated with bosentan.

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