Table 3 Algorithm for reducing dosage or discontinuation of bosentan depending on hepatic transaminases and systolic blood pressure

 > 3 and ≤ 5 × LSN

Reduce the daily dose by half (i.e. 62.5 mg morning and evening in this trial) and check transaminase level at least every 2 weeks.

If the level returns to its starting value, continue or resume bosentan treatment if applicable.

 > 5 and ≤ 8 × LSN

Interrupt treatment and verify transaminase level at least every 2 weeks.

Once the rate has returned to starting value, resume bosentan treatment.

 > 8 × LSN

Definitively interrupt bosentan treatment.

In case of high transaminase level with clinical signs of liver disorder (e.g. nausea, vomiting, fever, abdominal pain, jaundice or unusual lethargy or fatigue) or high bilirubin level equal to or greater than twice the LSN, bosentan treatment should be interrupted definitively.

 SBP < 100 mmHg

Re-verify BP at investigating centre

 90< SBP < 100 mmHg

Verify BP the next day at investigating centre

 Persistent 90< SBP < 100 mmHg

Self-measurement verification of BP every week until normalisation

 SBP < 90 mmHg

Reduce dose (bosentan/placebo 125 mg) by half to (bosentan/placebo 62.5 mg)

Check SBP for 3 days by self-measurement = medical verification of self-measurement results (patient brings device to hospital)

SBP < 90 mmHg = discontinue treatment

SBP > 90 mmHg = continue half dose

 SBP < 90 mmHg more than 20 mmHg lower than SBP compared to screening

Immediately reduce dose of (bosentan/placebo 125 mg) by half (bosentan/placebo 62.5 mg)

Monitor BP for 3 additional days with self-measurement after dose reduction, then medical verification of self-measurement results (patient brings device to hospital)

If hypotension SBP < 90 mmHg is maintained: discontinue treatment

If SBP > 90 mmHg = continue half dose