Sutsch G.
(1998)⁹

RDBPC

• Hemodynamics
• Plasma neurohormones

Bosentan associated with:

On Day 1:
↓ MAP, PAMP, PCWP, RAP
↓ SVR and PVR
↑ CO (HR unchanged)

At 2 weeks:
Further ↑ CO
Further ↓ SVR and PVR

After bosentan:
↑ ET-1 levels
Unchanged other neurohormone levels

• Greater hemodynamic impairment in placebo group.
• One patient discontinued bosentan to hypotension.
• Reversible increase in hepatic transaminases.

Packer M.
(1998)¹⁰

REACH-1

RDBPC

Bosentan associated with:

• Efficacy no different from placebo
• ↑ likelihood of clinical improvement
  (B=27%, P=19%; p=0.045)
• ↓ likelihood of CHF deterioration
  (B=27%, P=43%; p=0.045)
• ↓ all-cause hospitalizations by 41%

• Study terminated early due to reversible elevations in transaminases; 47% of patients were followed for 6 months (B=16.5%, P=5.2%).¹¹
• Bosentan was associated with ↓ hematocrit

Krumm H.
(1999)¹¹

Open-label extension of REACH-1

86 patients from REACH-1 enrolled in open-label extension
(63 B and 23 P)

Less severe NYHA-FC than REACH-1

• Symptom status progressively improved during the trial:
  NYHA-FC IIIb/IV:
  21%/14% and 18%/7%, respectively.
  
  
• B 125 mg PO BID was associated with fewer deaths and hospitalization than B 500 mg PO BID and P

• One patient had an increase in hepatic transaminases (previously on placebo).
• Clinical improvement maintained with 125 mg PO BID and better tolerated.

Williamson D.
(2000)¹²

Open-label dose ranging

Bosentan associated with:

• Dose dependent ↓ in pulmonary resistance (p=0.01) and PAMP (p>0.05).
  
  
• Dose dependent ↓ SVR and MAP and ↑ in ET-1 levels.

• Part 2 terminated early when two patients in the placebo group developed hypotension and died within 36 hours of entering Part 2; rebound PHT was deemend unlikely.

Channick R.
(2001)¹³

RDBPC

62.5 mg PO BID for 4 weeks, then

125 mg PO BID if tolerated up to 12 weeks

Weeks 12 to 28 were not mandatory for all patients

• Bosentan was associated with increased 6-MWD:

  B=360 to 430 meters at week 12 (p<0.05)
  P=355 to 349 meters at week 12

  6-MWD mean change: 76m
  (95% CI: 12 to 139; p=0.021)

• PVR, PA, PCWP and MRAP were significantly ↓ with bosentan, whereas these parameters were ↑ in the placebo group.

• Functional class improved with bosentan: 43% (9/21) B patients improved to WHO class II from WHO class III at 12 weeks, and 57% (12/21) B remained class III; No patients deteriorated (p=0.0039).
• Bosentan ↑ time to clinical worsening compared to placebo (p=0.033)
• No hypotension or changes in hematological/
  biochemical parameters.
• Two bosentan patients had a transient increase in transaminases without symptoms; values returned to normal without discontinuation.

Rubin L
(2002)¹

RDBPC

BREATHE-1

62.5 mg PO BID ro 4 weeks then

125 mg PO BID or

250 mg PO BID for 12 additional weeks

• Bosentan was associated with a 44 m improvement in 6-MWD compared to placebo
  (95% CI: 21 to 67 m, p<0.001).
  
  
• Improvement more pronounced with
  B 250 mg PO BID than
  B 125 mg PO BID (54 m, 34m).
  No dose response ascertained.

• B 125 mg PO BID is the clinically preferable dose.
• Dose dependent liver abnormalities found with bosentan.
• Aminotransferases ↑ greater than 8 times ULN:

B 125 mg PO BID (n=2)

B 250 mg PO BID (n=5)