Table 23, Study characteristics table for KQ 3 (RCTs) - Pulmonary Arterial Hypertension: Screening, Management, and Treatment

Study Population (N) Quality	Study Arms (N)	Trial Duration (Weeks)	Followup Assessments (Weeks)	Outcome Measures
AMBRISENTAN
Individual Drug Studies
Galie, 2008¹⁰⁶ ARIES-1 (US, Mexico, South America, Australia, and Europe) PAH (N=201) Good	Ambrisentan 5 mg daily (N=67) Ambrisentan 10 mg daily (N=67) Placebo (N=67)	12	4, 8, 12, 48	Mortality 6MWD Dyspnea Functional class Quality of life Hospitalization BNP Adverse events
Galie, 2008¹⁰⁶ ARIES-2 (Europe, Israel, and South America) PAH (N=192) Good	Ambrisentan 2.5 mg daily (N=64) Ambrisentan 5 mg daily (N=63) Placebo (N=65)	12	4, 8, 12, 48	Mortality 6MWD Dyspnea Functional class Quality of life Hospitalization BNP Adverse events
BOSENTAN
Individual Drug Studies
Barst, 2010¹⁸⁵ ASSET-1 SCD with PAH (N=14) Fair	Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=6) Placebo (N=8)	16	16	Mortality 6MWD RHC
Barst, 2010¹⁸⁵ ASSET-2 PH (N=12) Fair	Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=5) Placebo (N=7)	16	16	Mortality 6MWD RHC
Channick, 2001⁹⁴ PPH or PH due to SCD (N=32) Good	Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=21) Placebo (N=11)	12	4, 8, 12, 20, 28	6MWD Dyspnea Functional class Transplantation RHC Adverse events
Galie, 2006¹⁸³ BREATHE-5 Eisenmenger syndrome (N=54) Good	Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=37) Placebo (N=17)	4	4	6MWD Functional class RHC Adverse events
Galie, 2008¹⁸⁴ EARLY PAH (N=185) Good	Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=93) Placebo (N=92)	24	24	Mortality^a 6MWD^a Dyspnea^a Functional class^a Quality of life^a Hospitalization^a RHC^a Adverse events^a
Rubin, 2002¹⁸² BREATHE PAH (N=213) Good	Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=74) Bosentan 62.5 mg 2 times daily, then 250 mg 2 times daily (N=70) Placebo (N=69)	12	4, 8, 16	Mortality 6MWD Dyspnea Functional class Hospitalization Echocardiography Adverse events
Direct Drug Comparison Studies
Wilkins, 2005¹⁵⁶ SERAPH PAH (N=26) Good	Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=12) Sildenafil 50 mg 2 times daily, then 50 mg 3 times daily (N=14)	16	16	Mortality 6MWD Quality of life Right ventricular dysfunction Echocardiography BNP
Combination Drug Studies
Humbert, 2004¹⁸⁶ BREATHE-2 PAH (N=33) Good	Epoprostenol + bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=22) Epoprostenol + placebo (N=11)	16	16	6MWD Dyspnea Functional class Hospitalization Right heart failure RHC Adverse events
EPOPROSTENOL
Individual Drug Studies
Badesch, 2000¹⁹⁴ PH associated with SCD spectrum of disease (N=111) Fair	Epoprostenol ≤2 ng/kg, then adjusted (N=56) Conventional therapy only (N=55)	12	1, 6, 12	Mortality 6MWD Dyspnea RHC Adverse events
Barst, 1996⁸⁵ PPH (N=81) Good	Epoprostenol 4 ng/kg, then adjusted (N=41) Conventional therapy only (N=40)	12	1, 6, 12	Mortality 6MWD Quality of life Transplantation RHC Adverse events
Rubin, 1990¹⁸¹ PPH (N=23) Good	Intravenous epoprostenol 1–2 ng/kg per minute initially, then increased as tolerated (N=11) Conventional therapy (N=12)	8	8	Mortality 6MWD RHC Adverse events
ILOPROST
Individual Drug Studies
Olschewski, 2002¹⁹⁰ Severe PAH or chronic thromboembolic PH (N=203) Good	Aerosolized iloprost (N=101) Placebo (N=102)	12	4, 8, 12	Mortality 6MWD Dyspnea Functional class Quality of life Transplantation Right ventricular dysfunction RHC Adverse events
Olschewski, 2010¹⁹¹ AIR IPAH or other PH (N=63) Fair	Aerosolized iloprost (N=30) Conventional therapy only (N=33)	12	12, 104	Mortality 6MWD Dyspnea Functional class Quality of life Right heart failure RHC Adverse events
Combination Drug Studies
Hoeper, 2006¹⁹² COMBI IPAH (N=40) Fair	Bosentan 125 mg 2 times daily + aerosolized iloprost (N=19) Bosentan 125 mg (N=21)	12	6, 12	6MWD Adverse events
McLaughlin, 2006¹⁹³ PAH (N=67) Good	Bosentan + aerosolized iloprost (N=34) Bosentan + placebo (N=33)	12	4, 8, 12	6MWD Dyspnea Functional class Hospitalization RHC Adverse events
SILDENAFIL
Individual Drug Studies
Barst, 2011¹⁸⁸ STARTS-1 PAH (N=234) Fair	Low-dose sildenafil (N=42) Medium-dose sildenafil (N=55) High-dose sildenafil (N=77) Placebo (N=60)	16	16, >156	Mortality Functional class Quality of life RHC Adverse events
Galie, 2005¹⁸⁷ SUPER PAH (N=277) Good	Sildenafil 20 mg 3 times daily (N=69) Sildenafil 40 mg 3 times daily (N=67) Sildenafil 80 mg 3 times daily (N=71) Placebo (N=70)	12	4, 8, 12, 52, 156	Mortality 6MWD Dyspnea Hospitalization Adverse events RHC
Combination Drug Studies
Simonneau, 2008¹⁸⁹ PACES PAH (N=267) Good	Sildenafil 20 mg 3 times daily + epoprostenol, then up to 80 mg 3 times daily + epoprostenol (N=134) Placebo + epoprostenol (N=133)	16	4, 8, 12, 16	Mortality Dyspnea Quality of life Hospitalization Transplantation Adverse events
TADALAFIL
Individual Drug Studies
Bharani, 2007⁸⁸ PAH (N=11) Fair	Tadalafil 20 mg daily (N=11) Placebo 20 mg daily (N=11)	4	4	6MWD^a Dyspnea^a Functional class^a Echocardiography^a
Galie, 2009¹⁹⁶ PHIRST PAH (N=405) Good	Tadalafil 2.5 mg daily (N=82) Tadalafil 10 mg daily (N=82) Tadalafil 20 mg daily (N=80) Tadalafil 40 mg daily (N=79) Placebo (N=82)^b	16	4, 8, 12, 16	Mortality 6MWD Functional class Hospitalization RHC Adverse events
Mukhopadhyay, 2011¹⁹⁵ Eisenmenger syndrome (N=28) Fair	Tadalafil 40 mg daily (N=28) Placebo (N=28)	6	6	6MWD^a RHC^a
TREPROSTINIL
Individual Drug Studies
Hiremath, 2010¹⁹⁹ TRUST PAH (N=44) Fair	Intravenous treprostinil 4 ng/kg/min, then adjusted (N=30) Placebo (N=14)	12	12	Mortality 6MWD Dyspnea Functional class Adverse events
McLaughlin, 2003¹⁹⁸ PPH (N=26) Poor	Subcutaneous treprostinil 2.5–5.0 ng/kg/min, then adjusted (N=17) Placebo (N=9)	8	8	6MWD^a Dyspnea^a Adverse events^a
Simonneau, 2002¹⁹⁷ PAH (N=470) Good	Subcutaneous treprostinil 1.25 ng/kg/min, then adjusted (N=233) Placebo (N=236)	12	12	Mortality 6MWD Dyspnea Quality of life Transplantation Adverse events
Combination Drug Studies
McLaughlin, 2010¹³¹ TRIUMPH 1 Severe PAH (N=235) Good	Aerosolized treprostinil 18 mcg 4 times daily, gradually increased to 54 mcg+ bosentan/ sildenafil (N=115) Placebo + bosentan/sildenafil (N=120)	12	6, 12	Mortality 6MWD Dyspnea Functional class Quality of life Hospitalization Transplantation BNP Adverse events
VARDENAFIL
Individual Drug Studies
Jing, 2011²⁰⁰ EVALUATION PAH (N=66) Good	Vardenafil 5 mg daily, then 5 mg 2 times daily (N=44) Placebo (N=22)	12	12, 24	Mortality 6MWD Dyspnea Functional class Hospitalization RHC Adverse events

Study
Population (N)
Quality

Study Arms (N)

Trial Duration (Weeks)

Followup Assessments (Weeks)

Outcome Measures

AMBRISENTAN

Individual Drug Studies

Galie, 2008¹⁰⁶
ARIES-1 (US, Mexico, South America, Australia, and Europe)

PAH (N=201)

Good

Ambrisentan 5 mg daily (N=67)
Ambrisentan 10 mg daily (N=67)
Placebo (N=67)

4, 8, 12, 48

Mortality
6MWD
Dyspnea
Functional class
Quality of life
Hospitalization
BNP
Adverse events

Galie, 2008¹⁰⁶
ARIES-2 (Europe, Israel, and South America)

PAH (N=192)

Good

Ambrisentan 2.5 mg daily (N=64)
Ambrisentan 5 mg daily (N=63)
Placebo (N=65)

4, 8, 12, 48

Mortality
6MWD
Dyspnea
Functional class
Quality of life
Hospitalization
BNP
Adverse events

BOSENTAN

Individual Drug Studies

Barst, 2010¹⁸⁵
ASSET-1

SCD with PAH (N=14)

Fair

Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=6)
Placebo (N=8)

Mortality
6MWD
RHC

Barst, 2010¹⁸⁵
ASSET-2

PH (N=12)

Fair

Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=5)
Placebo (N=7)

Mortality
6MWD
RHC

Channick, 2001⁹⁴

PPH or PH due to SCD (N=32)

Good

Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=21)
Placebo (N=11)

4, 8, 12, 20, 28

6MWD
Dyspnea
Functional class
Transplantation
RHC
Adverse events

Galie, 2006¹⁸³
BREATHE-5
Eisenmenger syndrome (N=54)
Good

Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=37)
Placebo (N=17)

6MWD
Functional class
RHC
Adverse events

Galie, 2008¹⁸⁴
EARLY
PAH (N=185)
Good

Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=93)
Placebo (N=92)

Mortality^a
6MWD^a
Dyspnea^a
Functional class^a
Quality of life^a
Hospitalization^a
RHC^a
Adverse events^a

Rubin, 2002¹⁸²
BREATHE
PAH (N=213)
Good

Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=74)
Bosentan 62.5 mg 2 times daily, then 250 mg 2 times daily (N=70)
Placebo (N=69)

4, 8, 16

Mortality
6MWD
Dyspnea
Functional class
Hospitalization
Echocardiography
Adverse events

Direct Drug Comparison Studies

Wilkins, 2005¹⁵⁶
SERAPH
PAH (N=26)
Good

Bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=12)
Sildenafil 50 mg 2 times daily, then 50 mg 3 times daily (N=14)

Mortality
6MWD
Quality of life
Right ventricular dysfunction
Echocardiography
BNP

Combination Drug Studies

Humbert, 2004¹⁸⁶
BREATHE-2
PAH (N=33)
Good

Epoprostenol + bosentan 62.5 mg 2 times daily, then 125 mg 2 times daily (N=22)
Epoprostenol + placebo (N=11)

6MWD
Dyspnea
Functional class
Hospitalization
Right heart failure
RHC
Adverse events

EPOPROSTENOL

Individual Drug Studies

Badesch, 2000¹⁹⁴
PH associated with SCD spectrum of disease (N=111)
Fair

Epoprostenol ≤2 ng/kg, then adjusted (N=56)
Conventional therapy only (N=55)

1, 6, 12

Mortality
6MWD
Dyspnea
RHC
Adverse events

Barst, 1996⁸⁵
PPH (N=81)
Good

Epoprostenol 4 ng/kg, then adjusted (N=41)
Conventional therapy only (N=40)

1, 6, 12

Mortality
6MWD
Quality of life
Transplantation
RHC
Adverse events

Rubin, 1990¹⁸¹
PPH (N=23)
Good

Intravenous epoprostenol 1–2 ng/kg per minute initially, then increased as tolerated (N=11)
Conventional therapy (N=12)

Mortality
6MWD
RHC
Adverse events

ILOPROST

Individual Drug Studies

Olschewski, 2002¹⁹⁰
Severe PAH or chronic thromboembolic PH (N=203)
Good

Aerosolized iloprost (N=101)
Placebo (N=102)

4, 8, 12

Mortality
6MWD
Dyspnea
Functional class
Quality of life
Transplantation
Right ventricular dysfunction
RHC
Adverse events

Olschewski, 2010¹⁹¹
AIR
IPAH or other PH (N=63)
Fair

Aerosolized iloprost (N=30)
Conventional therapy only (N=33)

12, 104

Mortality
6MWD
Dyspnea
Functional class
Quality of life
Right heart failure
RHC
Adverse events

Combination Drug Studies

Hoeper, 2006¹⁹²
COMBI
IPAH (N=40)
Fair

Bosentan 125 mg 2 times daily + aerosolized iloprost (N=19)
Bosentan 125 mg (N=21)

6, 12

6MWD
Adverse events

McLaughlin, 2006¹⁹³
PAH (N=67)
Good

Bosentan + aerosolized iloprost (N=34)
Bosentan + placebo (N=33)

4, 8, 12

6MWD
Dyspnea
Functional class
Hospitalization
RHC
Adverse events

SILDENAFIL

Individual Drug Studies

Barst, 2011¹⁸⁸
STARTS-1
PAH (N=234)
Fair

Low-dose sildenafil (N=42)
Medium-dose sildenafil (N=55)
High-dose sildenafil (N=77)
Placebo (N=60)

16, >156

Mortality
Functional class
Quality of life
RHC
Adverse events

Galie, 2005¹⁸⁷
SUPER
PAH (N=277)
Good

Sildenafil 20 mg 3 times daily (N=69)
Sildenafil 40 mg 3 times daily (N=67)
Sildenafil 80 mg 3 times daily (N=71)
Placebo (N=70)

4, 8, 12, 52, 156

Mortality
6MWD
Dyspnea
Hospitalization
Adverse events
RHC

Combination Drug Studies

Simonneau, 2008¹⁸⁹
PACES
PAH (N=267)
Good

Sildenafil 20 mg 3 times daily + epoprostenol, then up to 80 mg 3 times daily + epoprostenol (N=134)
Placebo + epoprostenol (N=133)

4, 8, 12, 16

Mortality
Dyspnea
Quality of life
Hospitalization
Transplantation
Adverse events

TADALAFIL

Individual Drug Studies

Bharani, 2007⁸⁸
PAH (N=11)
Fair

Tadalafil 20 mg daily (N=11)
Placebo 20 mg daily (N=11)

6MWD^a
Dyspnea^a
Functional class^a
Echocardiography^a

Galie, 2009¹⁹⁶
PHIRST
PAH (N=405)
Good

Tadalafil 2.5 mg daily (N=82)
Tadalafil 10 mg daily (N=82)
Tadalafil 20 mg daily (N=80)
Tadalafil 40 mg daily (N=79)
Placebo (N=82)^b

4, 8, 12, 16

Mortality
6MWD
Functional class
Hospitalization
RHC
Adverse events

Mukhopadhyay, 2011¹⁹⁵
Eisenmenger syndrome (N=28)
Fair

Tadalafil 40 mg daily (N=28)
Placebo (N=28)

6MWD^a
RHC^a

TREPROSTINIL

Individual Drug Studies

Hiremath, 2010¹⁹⁹
TRUST
PAH (N=44)
Fair

Intravenous treprostinil 4 ng/kg/min, then adjusted (N=30)
Placebo (N=14)

Mortality
6MWD
Dyspnea
Functional class
Adverse events

McLaughlin, 2003¹⁹⁸
PPH (N=26)
Poor

Subcutaneous treprostinil 2.5–5.0 ng/kg/min, then adjusted (N=17)
Placebo (N=9)

6MWD^a
Dyspnea^a
Adverse events^a

Simonneau, 2002¹⁹⁷
PAH (N=470)
Good

Subcutaneous treprostinil 1.25 ng/kg/min, then adjusted (N=233)
Placebo (N=236)

Mortality
6MWD
Dyspnea
Quality of life
Transplantation
Adverse events

Combination Drug Studies

McLaughlin, 2010¹³¹
TRIUMPH 1
Severe PAH (N=235)
Good

Aerosolized treprostinil 18 mcg 4 times daily, gradually increased to 54 mcg+ bosentan/ sildenafil (N=115)
Placebo + bosentan/sildenafil (N=120)

6, 12

Mortality
6MWD
Dyspnea
Functional class
Quality of life
Hospitalization
Transplantation
BNP
Adverse events

VARDENAFIL

Individual Drug Studies

Jing, 2011²⁰⁰
EVALUATION
PAH (N=66)
Good

Vardenafil 5 mg daily, then 5 mg 2 times daily (N=44)
Placebo (N=22)

12, 24

Mortality
6MWD
Dyspnea
Functional class
Hospitalization
RHC
Adverse events

From: Results

Cover of Pulmonary Arterial Hypertension: Screening, Management, and Treatment

Pulmonary Arterial Hypertension: Screening, Management, and Treatment [Internet].

Comparative Effectiveness Reviews, No. 117.

McCrory DC, Coeytaux RR, Schmit KM, et al.

Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Apr.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Table 23Study characteristics table for KQ 3 (RCTs)