Correspondence

Bosentan for Pulmonary Hypertension

N Engl J Med 2002; 347:292-294July 25, 2002

Article

To the Editor:

We would like to express our concern about the conclusions reported by Rubin et al. (March 21 issue)1 in their article on bosentan therapy for pulmonary arterial hypertension. To prove the efficacy of bosentan for the treatment of pulmonary arterial hypertension, it would be logical to demonstrate a decrease in mean pulmonary-artery pressure. Such data have unfortunately not been presented. The authors have previously reported that bosentan significantly reduced mean pulmonary-artery pressure in patients with pulmonary arterial hypertension, but on close scrutiny of these data, the actual decrease in the pulmonary-artery pressure — from 54.0 to 52.4 mm Hg — seems clinically insignificant, although it was statistically significant.2 Second, the authors demonstrated that the distance walked in six minutes increased by 36 m in the overall group of patients who received bosentan, as compared with a decrease of 8 m in the placebo group (an actual difference of only 30 m). It is difficult to consider this decrease clinically significant because the standard deviation of more than 73 m in all groups suggests a wide variability in their base-line exercise capacity.

Third, the authors suggest that bosentan therapy reduced the Borg dyspnea index from 3.3 to 3.2, which, on a scale of 0 to 10, appears to be clinically irrelevant. Finally, the authors suggested that bosentan improved functional status. In fact, although 42 percent of the bosentan-treated patients had an improvement in functional class, so did 30 percent of the patients in the placebo group. This, along with the lack of a dose–response effect in the bosentan-treated patients, suggests that this is unlikely to be a bosentan-related effect. In conclusion, more studies of bosentan as a treatment for pulmonary hypertension must be conducted before claims about its efficacy can be made.

Brett N. Pereira, M.D.
Sundeep Salvi, M.D., Ph.D.
David Hide Asthma and Allergy Centre, Isle of Wight PO30 5TG, United Kingdom
brett.pereira@iow.nhs.uk

2 References

1. 1

   Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903[Erratum, N Engl J Med 2002;346:1258.]
   Full Text | Web of Science | Medline

2. 2

   Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119-1123
   CrossRef | Web of Science | Medline

To the Editor:

Rubin et al. report a high incidence of hepatic side effects during treatment with bosentan. However, the nature and extent of hepatotoxicity remain poorly defined as “abnormal hepatic function.” How many patients treated with bosentan had increases in aminotransferase to levels that were more than two times the upper limit of the normal range? Did the authors examine such factors as cholestasis or liver function in addition to aminotransferase levels? According to a recent report, at the molecular level, bosentan-induced hepatotoxic effects are due, at least in part, to inhibition of the major canalicular bile-salt–export pump.1 Thus, serum bile-salt levels (and alkaline phosphatase levels) are most sensitive, whereas γ-glutamyltransferase levels are typically not elevated in patients with inherited or acquired dysfunction of the canalicular bile-salt–export pump.2

The authors state, “Treatment with 125 mg of bosentan twice daily was not associated with a significant increase in adverse events or with a change in their nature.” However, in two patients, aminotransferase levels increased to more than eight times the upper limit of the normal range, which can be a sign of severe toxic hepatitis. We think that the risk of hepatotoxic effects should not be underestimated, especially since bosentan was administered for only 16 to 28 weeks in this study. Patients with pulmonary hypertension often present late in the course of disease, with right ventricular failure aggravating hepatic damage. The incidence and extent of liver injury may be higher in these patients and other subgroups of patients, indicating the need for comprehensive documentation of hepatic side effects.

Christoph G. Dietrich, M.D.
Andreas Geier, M.D.
Frank Lammert, M.D.
University Hospital, D-52057 Aachen, Germany

2 References

1. 1

   Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001;69:223-231
   CrossRef | Web of Science | Medline

2. 2

   Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 1999;117:1370-1379
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We disagree with Pereira and Salvi that the efficacy of treatment for pulmonary hypertension is dependent solely on the demonstration of a reduction in pulmonary-artery pressure. In pulmonary hypertension, both survival1 and clinical improvement are related less to the degree of elevation in pulmonary-artery pressure than to right-heart function. Despite only small reductions in mean pulmonary-artery pressure (mean change, 6.7 mm Hg), continuous intravenous epoprostenol therapy significantly improves exercise capacity and measures of right-heart function and prolongs survival among patients with primary pulmonary hypertension.2 Similar clinical and hemodynamic effects have been reported with bosentan by us and others.3

Although in our study the Borg dyspnea index decreased only slightly from the base-line value in the patients treated with bosentan, this finding should be viewed in the context of the clinically and statistically significant difference between the bosentan and placebo groups in the change from base line with regard to the distance walked in six minutes (a difference of 44 m between the two groups), suggesting that the patients treated with bosentan were capable of walking farther with less dyspnea. Additional data supporting the efficacy of bosentan include the demonstration of sustained responses with long-term treatment4 and improvement in echocardiographic findings with regard to right ventricular function.5 The absence of a dose–response effect is not surprising in the light of the efficacy of endothelin-receptor blockade by bosentan in low doses. Thus, the efficacy of bosentan therapy for pulmonary hypertension has been demonstrated on the basis of hemodynamic data, exercise tolerance, and clinical status.

We agree that the risk of liver injury should not be underestimated. The Food and Drug Administration requires that patients taking bosentan be monitored by means of monthly liver-function tests.

Ten patients treated with 125 mg of bosentan twice a day had increases in aminotransferase levels to more than three times the upper limit of the normal range. Two of these patients had an increase in the alkaline phosphatase level that was more than twice the upper limit of the normal range, but bilirubin levels did not increase to values that were more than twice the upper limit of the normal range. Bosentan therapy was continued in all 10 patients, either at the same dose or at a dose of 62.5 mg twice a day. Aminotransferase levels returned to values that were less than twice the upper limit of the normal range in seven patients and decreased progressively in the other three patients. All 10 patients participated in the open-label extension study.

The mechanism responsible for the increase in liver aminotransferase levels has not been fully elucidated. On the basis of preclinical studies, an accumulation of bile acids in hepatocytes due to competitive inhibition of the bile-salt–export pump could play a part. However, hepatocellular injury and mixed hepatocellular and cholestatic injury have both been observed.

Lewis J. Rubin, M.D.
University of California, San Diego, La Jolla, CA 92037
ljrubin@ucsd.edu

Nazzareno Galiè, M.D.
Università di Bologna, 40138 Bologna, Italy

Gérald Simonneau, M.D.
Hôpital Antoine Béclère, 92141 Clamart, France

for the Bosentan Randomized Trial of Endothelin Antagonist Therapy Study Investigators

5 References

1. 1

   D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343-349
   Web of Science | Medline

2. 2

   Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-302
   Full Text | Web of Science | Medline

3. 3

   Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119-1123
   CrossRef | Web of Science | Medline

4. 4

   Sitbon O, Channick RN, Simonneau G, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension (PAH): an open-label long term follow-up study. Am J Respir Crit Care Med 2002;165:A578-A578 abstract.
   

5. 5

   Galie N, Hinderliter AL, Torbicki A, et al. Effects of the oral endothelin receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2002;39:Suppl A:224A-224A abstract.
   CrossRef | Web of Science

Citing Articles (5)

Citing Articles

1. 1

   Bruno Stieger, Andreas Geier. (2011) Genetic variations of bile salt transporters as predisposing factors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis. Expert Opinion on Drug Metabolism & Toxicology 7:4, 411-425
   CrossRef

2. 2

   Anna M. Hackman, Thomas E. Lackner. (2006) Pharmacotherapy for Idiopathic Pulmonary Arterial Hypertension During the Past 25 Years. Pharmacotherapy 26:1, 68-94
   CrossRef

3. 3

   Shigetake Sasayama, Takeyoshi Kunieda, Hitonobu Tomoike, Masunori Matsuzaki, Kunio Shirato, Takayuki Kuriyama, Tohru Izumi, Hideki Origasa, Paul LM van Giersbergen, Jasper Dingemanse, Satoshi Tanaka. (2005) Effects of the Endothelin Receptor Antagonist Bosentan on Hemodynamics, Symptoms and Functional Capacity in Japanese Patients With Severe Pulmonary Hypertension. Circulation Journal 69:2, 131-137
   CrossRef

4. 4

   &NA;. (2003) Bosentan: profile report. Drugs & Therapy Perspectives 19:1, 5-6
   CrossRef

5. 5

   Martin R. Wilkins, Gideon Paul. (2002) Bosentan. American Journal of Cardiovascular Drugs 2:5, 343
   CrossRef