Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension (PPH), is a disease of unknown aetiology, characterised by progressive pulmonary vascular remodelling, ultimately leading to right heart failure and death 1. Without targeted treatment, IPAH carries a grave prognosis, with a median survival of 2.8 yrs after diagnosis 3.

In the last few years, a number of novel treatments for this devastating disease have been developed and are now in use. Intravenous epoprostenol has been shown in several studies to improve haemodynamics, exercise tolerance and survival 4–6. To circumvent the risks, inconveniences and costs associated with continuous intravenous epoprostenol, stable prostacyclin analogues have been introduced that can be administered orally, subcutaneously or by inhalation 7. In patients with IPAH, all these substances have been shown to improve exercise tolerance and haemodynamics in relatively short-term clinical studies 8–10, but the effects on long-term survival have not been thoroughly investigated.

Besides prostaglandins, novel substances with different mechanisms of action have been introduced in recent years. The dual endothelin receptor antagonist bosentan has been approved throughout the western world for treatment of pulmonary arterial hypertension (PAH) 11. In addition, several case series and one small controlled study have suggested that phosphodiesterase-5-inhibitors, such as sildenafil, may have beneficial effects in PAH 12.

Despite the fact that all of these substances have positive effects in IPAH, they do not provide a cure and, in many patients, the disease will eventually progress. The optimal management for patients who exhibit clinical deterioration despite targeted treatment is unclear. The introduction of intravenous epoprostenol is an option for patients in whom treatment with endothelin receptor antagonists, nonintravenous prostanoids or sildenafil fails. Another option is combination treatment 14. A few uncontrolled clinical studies have suggested that combinations of aerosolised iloprost and sildenafil, as well as aerosolised iloprost and bosentan, are safe and effective in selected patients with progressive disease despite prostanoid treatment 15. Combining bosentan and sildenafil may also be an attractive choice, since both substances are orally available, act via different mechanisms and are usually well tolerated. This paper describes the clinical course of nine patients with severe and progressive IPAH who were treated with a combination of bosentan and sildenafil.

Patients and methods

Between January 2002 and December 2003, 58 patients received bosentan for treatment of IPAH at Hannover Medical School (Hannover, Germany). Bosentan was used either as first-line therapy or in addition to a prostanoid (i.e. inhaled iloprost, oral beraprost or intravenous iloprost). Treatment efficacy was monitored primarily by the 6-min walk distance (6MWD) and cardiopulmonary exercise testing(CPET), and was targeted to reach pre-defined goals based on prognostically relevant variables: a 6MWD >380 m 6 and a peak oxygen uptake measured during CPET >10.4 mL·min⁻¹·kg⁻¹ 17. Patients who did not reach these goals on two consecutive visits were offered additional treatment with sildenafil. There was no formal study protocol. All patients were informed about the fact that this approach was investigational, that long-term data on safety and efficacy of sildenafil in PAH were not available, that there were no experiences with the combination of bosentan and sildenafil, and about the alternative option to receive intravenous prostacyclin treatment.

Results

Within the observation period, 2002–2003, nine out of 58 patients with IPAH, initially treated with bosentan or a combination of bosentan and a prostanoid, fulfilled the predefined criteria of clinical worsening as defined above. These patients suffered from severe and progressive pulmonary hypertension, and were in New York Heart Association (NYHA) functional class III or IV before treatment was started. All patients were nonresponders to acute vasodilator challenge. The baseline characteristics and haemodynamics of these patients are shown in table 1⇓.

Six-min walk distance

As shown in figure 1⇓ and table 2⇑, the 6MWD at baseline was 346±66 m. After introduction of bosentan treatment, the 6MWD improved by 57 m to 403±80 m (p=0.0003). However, this effect was not sustained and, after an interval of 11±5 months, the walk distance had declined to 277±80 m. At this point, sildenafil was added to bosentan. Three months later, the 6MWD had increased to 392±61 m (p=0.007) and the patients remained stable throughout the median follow-up of 9 months (range 6–12).

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Fig. 1.—

Six-min walk distance (6MWD) of nine patients with idiopathic pulmonary arterial hypertension at baseline 1 (before treatment with bosentan), 3 months after introduction of bosentan, baseline 2 (11±5 months later before addition of sildenafil), 3 months later and 6–12 months later. Open arrow: bosentan started; closed arrow sildenafil started.

Discussion

This case series may serve as a pilot trial showing that combining bosentan and sildenafil might be feasible in patients with IPAH. This combination was well tolerated by all patients and proved to be highly efficient. Of note, this patient population consisted of a “negatively” selected subgroup of young patients with very severe and rapidly progressive IPAH. Before targeted treatment was initiated, allpatients were in functional class NYHA III or IV, and haemodynamic assessment confirmed the presence of advanced pulmonary hypertension with a mean pulmonary artery pressure of 62±12 mmHg, a cardiac index of 1.6±0.3 L·min⁻¹·m⁻² and a pulmonary vascular resistance of 1,549±440 dynes·s·cm⁻⁵. In accordance with current recommendations 7, bosentan was started as first-line treatment, resulting in clinical improvement and increased exercise tolerance as determined by 6MWD and CPET. However, in contrast to the majority of patients receiving treatment with bosentan, this effect was not sustained. After an average period of close to 1 yr, the patients showed clinical deterioration and a marked decline in 6MWD, as well as in V′_O2,peak. It is the unfortunate clinical reality that, even with the novel targeted treatments available for PAH, a certain proportion of patients are going to deteriorate after initial improvement. Those patients are very likely to die from their underlying disease and they do require aggressive treatment. The most recent world conference on pulmonary hypertension recommended that prostacyclin treatment or, alternatively, combination treatment should be initiated in patients not responding sufficiently to treatment with endothelin receptor antagonists or nonintravenous prostanoids 14. Since bosentan clearly had a beneficial effect in all of the patients in the current study, the authors decided to initiate combination treatment, reserving intravenous prostacyclin for treatment failures. For reasons discussed below, sildenafil was chosen as an add-on treatment. The combination of bosentan and sildenafil was surprisingly well tolerated by all patients and resulted in marked clinical improvement. The pre-defined treatment goals (6MWD >380 m and V′_O2,peak >10.4 mL·min⁻¹·kg⁻¹) were reached in six out of nine patients. The remaining patients were judged as sufficiently stable and showed a tendency towards further improvement during follow-up, so that introduction of intravenous prostacyclin was not deemed immediately necessary. It is noteworthy that none of the patients died during the observation period of 21±3 months, even though the expected 1-yr and 2-yr survival probabilities of these patients based on their baseline haemodynamics according to the formula of the National Institutes of Health were 0.64 and 0.51, respectively 3.

Obviously, this observational report has several inherent limitations: there was no control group, the patient population was small and the overall observation time was rather limited. In addition, treatment with bosentan and sildenafil was not part of a formal study protocol, and serial right heart catheter examinations were not performed and, therefore, haemodynamic follow-up data were not available. Although these data would be of value, it is the authors' practice to base most therapeutic decisions on the results of patient's self reporting (functional classification), clinical examination, 6MWT and CPET, and to reserve right heart catheterisation for open questions or for certain therapeutic decisions, such as listing for highly urgent lung transplantation.

Bosentan and sildenafil were combined rather than bosentan and a prostanoid for several reasons: at the time when combination treatment was initiated in the patients, bosentan was the only drug approved for treatment of IPAH in Germany (sildenafil, beraprost and treprostinil have not been approved in Germany, and aerosolised iloprost was officially introduced in January 2004); beraprost or treprostinil were not considered as first choices for combination treatment because the former drug has not been shown to exhibit long-term clinical efficacy 19 and the latter one commonly causes substantial infusion site pain 10; compared to inhaled iloprost, sildenafil has the practical advantage of being orally administered rather than requiring six to nine inhalations daily; and in addition, although it has been shown that inhaled iloprost and sildenafil have synergistic effects 15, it was hypothesised that the combination of substances with different intracellular modes of action might be advantageous in the long run, although comparative studies are required to resolve this issue.

Economical considerations also contributed to the decision to combine bosentan and sildenafil. In Germany, the annual treatment costs for a single patient are ∼45,000 for bosentan, 70,000 for inhaled iloprost and 5,000–10,000 (depending on the dose) for sildenafil. Thus, the annual costs for combining bosentan and sildenafil are 50,000–55,000, compared to 75,000–80,000 for inhaled iloprost plus sildenafil and 115,000 for inhaled iloprost plus bosentan. In comparison, in Germany, the annual treatment costs for intravenous epoprostenol are 230,000 (at a dose of 25 ng·kg⁻¹·min⁻¹, which is a typical average dose in patients receiving epoprostenol for >1 yr 5) and those for intravenous iloprost are 180,000 (at a dose of 2 ng·kg⁻¹·min⁻¹, a typical average dose for intravenous iloprost 16). Thus, when the clinical situation mandates combination treatment or the introduction of intravenous prostacyclin, the annual savings with the combination bosentan and sildenafil are >100,000 for every patient, meaning that the approach in this study resulted in savings of>1,000,000 just based on the nine patients described.

Despite these considerations, many open questions remain: it is unknown whether combination treatment is truly more efficient than single treatment (although theoretical reasoning clearly favours combination treatment, switching to sildenafil may have been equally effective as combining bosentan and sildenafil); it is unknown which combination regimens exert favourable long-term results (this will be difficult to answer as the number of potentially useful combinations is exponentially increasing with the introduction of novel treatments for PAH); and finally, so far, the combination of bosentan and sildenafil has only been used in patients with IPAH, and it is unknown whether these observations also apply to other forms of pulmonary hypertension.

In conclusion, the data presented here provide preliminary evidence that the combination of bosentan and sildenafil may be safe and effective in selected patients with idiopathic pulmonary arterial hypertension.