Table 4 Studies of concomitant sildenafil and bosentan

Vizza et al. (current study)

Randomized, double-blind, placebo-controlled study

Sildenafil or placebo added to bosentan therapy

No

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

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

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

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)

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

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

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

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

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)

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

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