Figures
- Fig. 1—
Kaplan-Meier estimates with 99.9% confidence intervals and predicted survival using the D'Alonzo equation 9. The 99.9% confidence intervals of the Kaplan-Meier estimates do not approach the predicted survival, demonstrating a significant difference between the two curves. ----: observed survival; ––: predicted survival.
- Fig. 2—
Vital status and treatment at 12 and 24 months of follow-up. All 169 patients were followed for 12 months; 132 patients were followed for at least 24 months. Percentages are based on the number of patients followed.
: dead; └: alive, not on bosentan; ┘: alive, on bosentan and other treatments; □: alive, on bosentan alone. - Fig. 3—
Kaplan-Meier estimates of time to the first elevation of hepatic transaminases to greater than three times the upper limit of normal. About 90% of the cases of elevated liver transaminases occurred during the first 26 weeks of treatment. ALT/AST: alanine aminotransferase/aspartate aminotransferase. Patients at risk: 168, 139, 111, 50, 11, 0 at 0, 30, 60, 90, 120 and 150 weeks from treatment start, respectively.
Tables
- Table. 1—
1 Demographics and baseline characteristics
Bosentan-treated PPH patients NIH Registry PPH patients# Subjects n 169 187 Sex male/female % 21/79 37/63 Age yrs Mean±sd 46±16 36±15 Range 13–80 1–81 WHO functional class % I/II 1/8¶ 0/29 III/IV 82/9 71 Time from diagnosis months+ Mean±sd 32±41 Range 0.3–326 Haemodynamics mean±sd+ Cardiac index L·min−1·m−2 2.35±0.80 2.3±0.9 PVR Wood units 12.9±8.4 mPAP mmHg 57.1±16.0 60±18 mRAP mmHg 10.1±5.9 9.7±6.3 Walk test m Mean±sd 345±87 PPH: primary pulmonary hypertension; NIH: National Institutes of Health; WHO: World Health Organization; PVR: pulmonary vascular pressure; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure. #: data from Rich et al. 10 provided for context, NIH Registry data were not directly used in any analysis; ¶: all patients entered the pivotal studies in functional class III or IV, but 15 (9%) patients in the placebo group improved before being switched to bosentan in the extension study; +: time from diagnosis and haemodynamic data were available for 157–169 bosentan-treated patients, and for most of these patients were available only at the start of the placebo-controlled study.
- Table. 2—
2 Outcomes
Bosentan-treated PPH patients Subjects n 169 Duration of observation for survival Mean±sd 2.1±0.5 yrs Range 0.1–3.3 yrs Patients lost to follow-up 1 Lung transplantations 3 Deaths n (%) 20 (12)# Transfers to/additions of prostanoids or alternative oral PPH therapies n (%) 39 (23)¶ Patients who received alternative treatment 19 in addition to bosentan Discontinuations of bosentan without other event or treatment 4 PPH: primary pulmonary hypertension. #: includes the one patient lost to follow-up; ¶: includes the one patient lost to follow-up and three patients with a period of unknown treatment.
- Table. 3—
3 Kaplan-Meier (K-M) estimates and predicted survival using the D'Alonzo equation 9
Time months 0 6 12 18 24 30 36 K-M estimates % 100 98.8 96.4 90.5 88.5 85.6 85.6 Predicted survival % 76.3 69.2 62.8 57.3 52.4 48.2 Patients at risk n 169 167 163 153 113 23 16 - Table. 4—
4 Prognostic factors for mortality
Dichotomy/median Hazard ratio 95% Confidence limits Subjects n 169 WHO functional class IV 3.2 1.1–9.7 Cardiac index L·min·m−2 ≤2.25 1.5 0.6–3.6 mPAP mmHg ≤54 1.4 0.6–3.6 mRAP mmHg >8.5 1.9 0.7–4.8 6MWT m ≤358 4.0 1.3–12.2 WHO: World Health Organization; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure; 6MWT: 6-min walk test.
- Table. 5—
5 Adverse events noted by>10% of patients
Body system/adverse events n % Aggravated pulmonary hypertension 56 33.1 Headache 53 31.4 Upper respiratory tract infection 36 21.3 Chest pain 32 18.9 Dizziness (except vertigo) 29 17.2 Dyspnoea 27 16.0 Flushing 24 14.2 Nasopharyngitis 24 14.2 Diarrhoea 23 13.6 Syncope 23 13.6 Abnormal hepatic function 22 13.0 Bronchitis 20 11.8 Nausea 20 11.8 Cardiac failure 19 11.2 Leg oedema 19 11.2 Cough 18 10.7 Pain in limb 18 10.7 Arthralgia 17 10.1 Palpitations 17 10.1 Adverse events were collected from the 169 patients during adverse event reporting periods only. The mean duration of observation for adverse events was 78±28 weeks (±sd, median 77 weeks).
