22 Oct 2007 Bosentan for the treatment of pulmonary arterial hypertension associated with congenital heart disease
Background information of the condition
Pulmonary Arterial Hypertension (PAH) is a rare and potentially fatal disorder. It is manifested by dyspnea on exertion, syncope and signs and symptoms of right heart failure. In congenital heart disease (CHD) that involves left to right shunting, PAH generally develops due to increase in pulmonary blood flow causing microvascular change as the result of the heart defect. (Sitbon 2006) Some patients may live up to decades after diagnosis but they experience a significant reduction of functional capacity and quality of life due to the progressive nature of the disease. PAH/CHD patients are not a priority for transplantation due to the longer life expectancy.
Current treatments are usually symptomatic – oxygen, anticoagulants, prostanoid, and vasodilators. Bosentan is currently the only approved treatment for PAH/CHD in Canada. Sildenafil, epoprostenol and treprostinil are approved for idiopathic PAH and PAH associated with connective tissue disorder, but not for PAH associated with CHD. No clinical evidence was found to show that any of these treatments affect mortality, hospitalization or quality of life.
Drug (Product monograph)
Category: Dual endothelin receptor blocker
Mechanism of action: Bosentan competes with the binding of endothelin for both ETA and ETB receptors with a slightly higher affinity for ETA receptors. In animal model of pulmonary hypertension, chronic oral administration of bosentan reduced pulmonary vascular resistance and reversed pulmonary vascular and right ventricular hypertrophy. In an animal model of pulmonary fibrosis, bosentan reduced collagen deposition.
Indication(s):
- “Treatment of patients with WHO functional class III or IV idiopathic pulmonary arterial hypertension or PAH secondary to scleroderma”.
- “Treatment of patient with WHO functional class III or IV pulmonary arterial hypertension associated with congenital heart disease”.
Dose: initial dose at 62.5mg BID for 4 weeks and then increased to 125 mg BID.
Duration: not mentioned in the product monograph. The one DBRCT included in this review provides data for 16 weeks duration.
Note: U.S. FDA required all patients prescribed with bosentan to be tested for liver enzymes and pregnancy before treatment begins and every month during treatment. In mouse model, higher incidence of hepatocellular adenomas and carcinomas are reported with 450mg/kg/day (8 times of maximum dose) oral administration for 2 years.
Methodology of systematic review
Research question: In double blind randomized controlled trials (DBRCTs), does bosentan provide significant therapeutic advantage compared to placebo in treatment of WHO functional class III and IV in patients with pulmonary arterial hypertension associated with congenital heart disease?
Assessment principles: DBRCTs comparing bosentan to placebo in patients with WHO functional class III or IV pulmonary arterial hypertension associated with congenital heart disease will be critically appraised according to the following hierarchy of health outcomes – all cause mortality, non-fatal serious adverse events, rate of hospitalization, decrease in heart and lung transplantation, quality of life, improvement in functional capacity (six minute walk test), withdrawal due to adverse events and other adverse events.
Search strategy:Databases searched: (Medline 1966-Feb. 2007, Embase 1980-Feb. 2007, Cochrane database (CENTRAL), the manufacturer’s submission, and references of review articles.
Search findings: No DBRCTs were identified comparing bosentan to epoprostenol, sildenafil or treprostinil. One DBRCT (Galiè et al 2006) compared bosentan to placebo in adult patients with PAH/CHD.
Results:
One DBRCT of 16 weeks duration randomized 54 patients with PAH/CHD to Bosentan (N =37) or Placebo (N = 37). Ventricular septal defect was the most frequent congenital heart disease. All patients were WHO functional class III and baseline 6-minute walk test was markedly reduced compared with predicted normal values (332 to 366m). The mean age was 37.2 years in bosentan group and 44.2 years in the placebo group.
No deaths were reported. 5(14%) patients in bosentan group and 3(18%) patients in placebo group experienced at least one serious adverse event. Hospitalization data was not reported.
In the bosentan group, 13(35%) of patients improved from WHO class III to II compared to 2(13%) in the placebo group (ARR= 22% NNT=5 for 16 weeks). Patients who received bosentan showed a significant improvement in the 6-minute walk test as compared to placebo (53.1metres, p=0.008).
The study also reported significant improvement in physiologic measures -mean pulmonary arterial pressure, pulmonary vascular resistance index, mean systemic arterial pressure and systemic vascular resistance index. Two patients from the bosentan group and 2 patients from the placebo group discontinued treatment due to adverse events. Adverse event occurred in greater proportion of patients on bosentan than on placebo but were not statistically significant. They included peripheral edema (19% vs. 6%), headache (14% vs. 12%), palpitations (11% vs. 0%), dizziness (8% vs. 6%) and chest pain (8% vs. 0%).
Summary and rationale of conclusions
The goal of therapy is to improve functional capacity and quality of life. Bosentan showed a clinically significant improvement in functional capacity over a 16 week period but not in terms of quality of life. Longer duration studies are needed to assess mortality, hospitalization and transplantation rates.
Conclusions
Based on one DBRCT of 16 weeks duration, bosentan as compared to placebo provides clinically significant therapeutic advantage in terms of improvement in WHO functional class (ARR = 22%, NNT = 5 for 16 weeks) and a measurable improvement in 6-minute walk test (distance increased by 53 m, p=0.008) in adult patient with class III/IV PAH/CHD.
References:
- Sitbon O et al. Bosentan for the treatment of pulmonary arterial hypertension associated with congenital heart defects. European Journal of Clinical Investigation. 2006; 36:25-31.
- Product Monograph (e-CPS 2007)
- Galiè N et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicentre, double blind randomized placebo-controlled study. Circulation 2006; 114:48-54.
Additional information
WHO Functional Classification for PAH
Class I – Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.
Class II – Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class III – Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class IV – Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity.
Six- minute walk test (6MWT)
Six-minute walk test, as a surrogate outcome, is the most widely used test to assess the exercise capacity in PAH. It measures the distance in meter a patient can walk continuously for 6 minutes. The main advantage of using it is its ease of administration. It is a sub-maximal exercise test that can be performed by a patient with heart failure who is unable to tolerate maximal cardiopulmonary exercise testing
1 Comment