Background
Methods
Study design
Patients
Outcome measures and statistical considerations
Results
Placebo (n = 53) | Sildenafil (n = 50) | |
---|---|---|
Men, n (%) | 12 (23) | 13 (26) |
Age, mean ± SD, y | 56.9 ± 14.1 | 55.2 ± 15.1 |
Ethnicity, n (%) | ||
White | 45 (85) | 44 (88) |
Asian | 2 (4) | 4 (8) |
Other or unspecified | 6 (11) | 2 (4) |
Primary diagnosis, n (%) | ||
IPAH/HPAH | 32 (60) | 35 (70) |
Duration since diagnosis, median (range), y | 1.3 (0.3–10.5) | 1.5 (0.4–19.3) |
APAH-CTD | 21 (40) | 15 (30) |
Duration since diagnosis, median (range), y | 2.0 (0.3–8.1) | 1.5 (0.3–7.2) |
Scleroderma | 19 | 10 |
Othera
| 2 | 5 |
Bosentan treatment | ||
Dosage, n (%) | ||
62.5 mg BID | 3 (6) | 2 (4) |
125 mg BID | 49 (93) | 47 (94) |
Other or missing | 1 (2) | 1 (2) |
Duration, median (range), mo | 11.4 (3.1–90.9) | 11.2 (3.2–65.3) |
≤ 1 y, n (%) | 27 (51) | 26 (52) |
> 1 y, n (%) | 26 (49) | 24 (48) |
6MWD, mean ± SD, m | 350.4 ± 87.6 | 354.4 ± 73.1 |
<325 m, n (%) | 17 (32) | 15 (30) |
≥325 m, n (%) | 36 (68) | 35 (70) |
Strata (aetiology, baseline 6MWD), n (%) | ||
IPAH/HPAH, <325 m | 7 (13) | 10 (20) |
IPAH/HPAH, ≥325 m | 25 (47) | 25 (50) |
APAH-CTD, <325 m | 10 (19) | 5 (10) |
APAH-CTD, ≥325 m | 11 (21) | 10 (20) |
WHO functional class, n (%) | ||
II | 15 (28) | 20 (40) |
III | 38 (72) | 29 (58) |
IV | 0 | 1 (2) |
Borg dyspnoea score, mean ± SD, median (range) | 4.2 ± 1.9 4.0 (0.5–8.0) | 4.1 ± 2.3 4.0 (0–8.0) |
mPAP, mean ± SD, mmHg | 44.9 ± 13.3 | 46.9 ± 12.5 |
Change from baseline at week 12 | Change from baseline at week 64 | Change from week 12 to week 64 | ||||
---|---|---|---|---|---|---|
Endpoint | Placebo (n = 53) | Sildenafil (n = 50) | Placebo (n = 53) | Sildenafil (n = 50) | Placebo (n = 48) | Sildenafil (n = 43) |
Borg dyspnoea score (LOCF) | ||||||
n | 53 | 49 | 53 | 49 | 47 | 36 |
Median change (range) | 0 (−3, 6) | 0 (−6, 2) | 0 (−3, 7) | 0 (−4, 4) | 0 (−7, 8) | 0 (−2, 4) |
WHO functional class (LOCF), n (%) | ||||||
Worsened 1 class | 1 (2) | 0 (0) | 4 (8) | 5 (10) | 4 (8) | 8 (19) |
No change | 45 (85) | 39 (78) | 34 (64) | 34 (68) | 34 (71) | 28 (65) |
Improved 1 class | 7 (13) | 10 (20) | 15 (28) | 10 (20) | 9 (19) | 3 (7) |
Died | 0 | 1 (2) | 0 | 1 (2) | 0 | 1 (2) |
Missing | 0 | 0 | 0 | 0 | 1 (2) | 3 (7) |
BNP | ||||||
n | 35 | 33 | 24 | 18 | 21 | 21 |
Median change (min, max), pg/mL | 8.0 (−217.5, 254.4) | −1.0 (−436.5, 268.7) | 3.0 (−125.4, 738.0) | 34.3 (−618.2, 1141.8) | −6.1 (−166.9, 652.0) | 20.1 (−643.7, 1218.8) |
N-terminal pro-BNP | ||||||
n | 14 | 19 | 9 | 10 | 9 | 12 |
Median change (min, max), pg/mL | 14.3 (−2227.0, 600.0) | −94.1 (−1277.0, 221.0) | 7.8 (−1761.0, 561.3) | −121.7 (−895.3, 5519.4) | 55.0 (−1029.0, 466.0) | −13.2 (−459.4, 5656.2) |
Adverse events (AEs)a
| Placebo (n = 53) | Sildenafil (n = 50) | ||
---|---|---|---|---|
All causality | Treatment related | All causality | Treatment related | |
Patients with AEs, n (%) | 41 (77) | 13 (25) | 34 (68) | 17 (34) |
Patients with serious AEs, n (%) | 12 (23) | 0 | 9 (18) | 1 (2) |
AEs | ||||
Headache | 5 (9) | 3 (6) | 6 (12) | 6 (12) |
Flushing | 1 (2) | 1 (2) | 5 (10) | 5 (10) |
Diarrhoea | 3 (6) | 1 (2) | 5 (10) | 3 (6) |
Nasopharyngitis | 5 (9) | 0 | 4 (8) | 0 |
Vertigo | 0 | 0 | 3 (6) | 0 |
Vision blurred | 0 | 0 | 3 (6) | 2 (4) |
Oedema, peripheral | 2 (4) | 1 (2) | 3 (6) | 1 (2) |
Pulmonary arterial hypertension | 5 (9) | 0 | 2 (4) | 0 |
Back pain | 4 (8) | 0 | 1 (2) | 0 |
Bronchitis | 4 (8) | 0 | 1 (2) | 0 |
Upper respiratory tract infection | 3 (6) | 0 | 1 (2) | 0 |
Nausea | 4 (8) | 2 (4) | 0 | 0 |
Discussion
Study | Design | Additional PAH-specific therapy? | N | IPAH/HPAH patients % | CTD patients, % | WHO or NYHA FC II/III/IV, % of patients | Age, y, mean ± SD | Sildenafil dose | Key results |
---|---|---|---|---|---|---|---|---|---|
Vizza et al. (current study) | Randomized, double-blind, placebo-controlled study Sildenafil or placebo added to bosentan therapy | No | 103 | 65% | 35% | 34%/65%/1% | Median (range), 59 (19–83) y | 20 mg TID (bosentan 62.5 mg BID [n = 5] or 125 mg BID [n = 97]; 1 patient missing data) | No significant improvement in primary endpoint of 6MWD at week 12, nor secondary endpoints of Borg dyspnea score, clinical worsening, WHO FC, BNP/proBNP Extension study: 1-year survival of 96%; no notable improvement in 6MWD |
Hoeper et al. [29] | Open label, uncontrolled study Sildenafil added to bosentan (treat to goal: 6MWD of 380 m; PVO2 of 10.4 ml/min/kg during CPET) | 1 patient also received inhaled iloprost; 1 patient with a 2-y history of IV iloprost | 9 | 100% | 0% | 0%/89%/11% | 39 ± 9 y | 25 mg TID, then 50 mg TID after 4–12 wk. if not reaching goal (standard bosentan†) |
a3 patients improved FC at 3 mo after combination therapy; 2 others improved after 6–12 mo
a6MWD improved after 3 mo of combination therapy, remained stable throughout 6–12 mo follow-up
aPVO2 improved after 3 mo of combination therapy (n = 6 patients with CPET data) |
Lunze et al. [30] | Open-label, uncontrolled study Upfront combination or sildenafil added to bosentan | No | 11 | 36% | 0% (CHD, 45%; CTEPH, 9%; radiogenic, 9%) | 18%/82%/0% | Median (range), 12.9 (5.5–54.7) | Mean, 2.1± 0·9 mg/kg (bosentan, 2.3 ± 0·6 mg/kg) | After median (range) follow-up of 1.1 (0.5–2.5) y,
a~1-FC (NYHA) improvement
aIncreased transcutaneous O2 saturation and PVO2 (n = 10)
aImproved 6MWD (n = 8)
aDecreased mPAP (n = 9), resting heart rate Right ventricular systolic pressure |
van Wolferen et al. [31] | Open-label, uncontrolled study Sildenafil added to bosentan (which patients were receiving for prior 1 y) for 3 mo | NS | 15 | 60% | 20% (HIV, 7%; CHD, 13%) | 13%/87%/0% | 45 ± 15 | 50 mg BID for 4 wk., 50 mg TID until 3 mo (bosentan dose NS) |
aDecreased NT-proBNP
aIncreased 6MWD
aImproved cardiac index, right ventricular ejection fraction, right ventricular mass, RVEDV:LVEDV ratio No significant improvement: stroke volume index, left ventricular ejection fraction, left ventricular mass, RVEDV, LVEDV |
Mathai et al. [32] | Open-label, uncontrolled study Sildenafil added to bosentan monotherapy in ‘failing’ patients | 1/13 IPAH & 5/12 CTD patients required additional therapy during study (prostacyclins) | 25 | 52% (included anorexigen-associated) | 48% (all scleroderma-associated) | I/II = 20% III/IV = 80% | IPAH, 60 ± 8 CTD, 52 ± 13 | Pre-July 2005, 25 mg TID, increased to 50 mg TID after 2–3 wk.; increased to 100 mg TID if no improvement; after, 20 mg TID (patients already on higher dose continued that dose) (bosentan†) | 1-class NYHA FC improvement in 7 of 25 pts. (IPAH, n = 5; CTD, n = 2)
a6MWD improvement in IPAH pts. No 6MWD improvement in CTD pts. (Note: average daily sildenafil dose higher in CTD [168 ± 82 mg/d] vs IPAH [98 ± 65 mg/d]) |
Porhownik et al. [33] | Open-label, uncontrolled study Sildenafil added to bosentan in patients with inadequate improvement on monotherapy | No | 10 | 80% | 20% | 50%/50%/0% (before combination therapy) | 49.7 (range, 24–72) | NS |
aMean 6MWD improved at 6 mo vs baseline value before combination therapy initiation 1-class FC improvement in 3 pts. at 3 mo after combination therapy, maintained at 6 mo |
D’Alto et al. [34] | Open-label, uncontrolled study Sildenafil added to patients with clinical deterioration on bosentan monotherapy | NS | 32 | 0% | 0% (CHD, 100% [88% Eisen-menger]) | NS | 37.1 ± 13.7 | 20 mg TID (bosentan, 94% 125 mg BID, 6% 62.5 mg BID [due to edema]) |
aImproved WHO FC, 6MWD, SpO2 post-exercise, Borg dyspnea index, NT-proBNP No significant differences: resting SpO2, heart rate (resting or post-exercise), hematocrit, hemoglobin, red blood cell count, platelets, aspartate and alanine aminotransferases |
Iversen et al. [35] | Randomized, double-blind, placebo-controlled, crossover study Open-label bosentan for 9 mo, with sildenafil or placebo added at 3 mo and opposite treatment last 3 mo | No | 21 | 0% | 0% (CHD, 100% [all Eisen-menger]) | 43%/48%/5% | 42 (range, 22–68) | 25 mg TID for 2 wk., then 50 mg TID for 10 wk. (or matching placebo) (bosentan, 62.5 mg BID for 2 wk., then 125 mg BID) | Trend toward 6MWD improvement with combination therapy
aResting systemic O2 saturation No significant changes in systolic or diastolic blood pressure; systemic O2 saturation during exercise; NT-proBNP; NYHA FC; pulmonary, systemic or pulmonary/systemic blood flow (assess with catheterization or MRI); pulmonary or systemic vascular resistance (Note: only patients completing the trial [n = 19] included in analysis) |
Galie et al. [36] | Randomized, double-blind, placebo-controlled study of bosentan Subset of patients receiving open-label sildenafil | No | 28 | 61%‡
| 18%‡
(CHD, 17%; HIV, 4%; other, 1%)‡
| NS | Bosentan group, 45.2 ± 17.9‡
Placebo group, 44.2 ± 16.5‡
| NS (bosentan†; unless <40 kg, then 62.5 mg BID) |
aPVR improved vs baseline at 6 mo No significant difference in 6MWD at 6 mo |
Benza et al. [abstract] [10] | Open-label, uncontrolled study Treat to goal (6MWD ≥380 m), bosentan for 16 wk.; continue monotherapy or add sildenafil for additional 12 wk | No (patients were treatment-naïve) | 100 | NS | NS | NS/NS/79%/NS | 56 | 20 mg TID (bosentan, 125 mg BID) | 31% of patients reached 6MWD goal (bosentan, 16%; combination, 15%); mean improvement of 22 and 45 m vs baseline at wk. 16 and 28, respectively 23% of patients had ≥1-class FC improvement vs baseline at wk. 16; 34% at wk. 28 (n = 85) |
McLaughlin et al. [24] | Randomized, double-blind, placebo-controlled study Bosentan or placebo added to stable dose sildenafil (≥12 mo) until first morbidity/mortality event | NS | 334 | NS | NS | NS | NS | ≥20 mg TID (bosentan 125 mg BID) | No significant improvement in time to first morbidity/mortality event vs placebo (primary endpoint; 17% risk reduction vs placebo; P = 0.25) Placebo-corrected improvement of 21.8 m in 6MWD at wk. 16; NT-proBNP level over 20 mo was 23.5% lower with bosentan vs placebo; no treatment difference for other endpoints |