Does rapid dose titration affect the hepatic safety profile of Bosentan?
BACKGROUND
Bosentan, a dual endothelin receptor antagonist, has proven efficacy in pulmonary hypertension. Due to an association with hepatic dysfunction, it is typically initiated at a sub-therapeutic dose for 4 weeks before titration to a therapeutic dose. At our institution some patients have undergone rapid titration, to potentially benefit from therapy earlier. This study assesses the impact of this practice on hepatic safety.


METHODS
All patients initiated on bosentan therapy before April 2005 were included. Rapidly titrated patients achieved a therapeutic dose by 3 days, whereas standard titration patients were titrated at 4 weeks. All patients were monitored with monthly liver function tests.


RESULTS
149 patients commenced bosentan, of which 55 were rapidly titrated. At baseline, the two groups were similar in age, BMI, diagnosis, 6-min walking distance, alanine aminotransferase (ALT), cardiac index and pulmonary artery pressures. The rapid group had elevated right atrial pressures (9.7 mm Hg versus 7.4 mm Hg, p = 0.016) and worse WHO functional class (p = 0.008) and included less females (31% versus 69%, p = 0.024). The incidence of hepatic dysfunction in all patients was 12.8% at 12 months. There was no statistical difference in incidence between the rapid and standard groups (4% versus 11% at 3 months, p = 0.211 and 6% versus 15% at 12 months, p = 0.219). Of all patients on bosentan, hepatic dysfunction was most significantly associated with a higher baseline ALT (p = 0.021), female sex (p = 0.003) and underlying connective tissue disease (p = 0.025). Subgroup analysis suggested these factors were not confounders when comparing rapid and standard titration.


CONCLUSIONS
Rapid and standard titration of bosentan resulted in similar hepatic safety profiles. Baseline ALT, female sex and the presence of connective tissue disease increased the risk of hepatic dysfunction independent of the titration method used.
Suntharalingam
J
J
Clinical Research Fellow, Pulmonary Vascular Diseases Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridgeshire, CB3 8RE, United Kingdom. jay.suntharalingam@papworth.nhs.uk
Hodgkins
D
D
Cafferty
F H
FH
Hughes
R J
RJ
Pepke-Zaba
J
J
D000410:Alanine Transaminase / Q000097:blood; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000077300:Bosentan; D003240:Connective Tissue Diseases / Q000150:complications; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy*; D015994:Incidence; D008107:Liver Diseases / Q000097:blood / Q000453:epidemiology / Q000209:etiology*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012737:Sex Factors; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D013449:Sulfonamides; D000410:Alanine Transaminase; D000077300:Bosentan