Table 1.

Study design details of groups 2 and 3 pulmonary hypertension randomized clinical trials

Trial	Study Drug	Population Studied	Exclusion Criteria	Primary Endpoint	Result
Group 2 PH clinical trials
Bonderman (11) (n = 201)	Riociguat	HFrEF (EF, ≤40%)	1. Other PH causes	Mean PAP	No change
			2. Cardiac decompensation in preceding 30 d
			3. Baseline systolic blood pressure <100 mm Hg
			4. Severe renal impairment (GFR, <30 ml/min)
			5. Cardiac ischemia with planned percutaneous coronary intervention or bypass surgery
Bermejo (1) (n = 200)	Sildenafil	Corrected valvular heart disease	1. Persistent significant valvular dysfunction	Composite clinical score*	Worsening in treated group
			2. Myocardial infarction, stroke, or life-threatening arrhythmia in preceding 6 mo
			3. Baseline systolic blood pressure <90 mm Hg
			4. Severe renal impairment (GFR, <30 ml/min) or liver dysfunction
			5. Life expectancy <2 yr
Kaluski (12) (n = 87)	Bosentan	HFrEF (EF, <35%), NYHA FC IIIb–IV	1. Baseline systolic blood pressure <100 mm Hg	Systolic PAP	No change; more frequent adverse events in treated group requiring drug discontinuation
Vachiéry (13) (n = 63)	Macitentan	HFpEF (EF, ≥30%), NYHA FC II–III	1. Baseline blood pressure >180/100 mm Hg or systolic blood pressure <90 mm Hg	Composite of fluid retention or worsening NYHA FC	Increased fluid retention in treated group
			2. Uncontrolled heart rate from atrial fibrillation
			3. Severe renal impairment (GFR, <30 ml/min) or liver dysfunction
			4. Unstable coronary artery disease or myocardial infarction within 6 mo
			5. Severe obstructive or moderate to severe restrictive lung disease
			6. Oxygen saturation <90% on room air
			7. Anemia (hemoglobin <10 g/dl)
			8. Other PH causes
Hoendermis (14) (n = 52)	Sildenafil	HFpEF (EF, ≥45%), NYHA FC II–IV	1. Severe noncardiac exercise limitation	Mean PAP	No change
			2. Other PH causes
			3. Myocardial infarction or coronary ischemia in preceding 6 mo
			4. Blood pressure <90/50 mm Hg
			5. Significant mitral or aortic valvular dysfunction
			6. Severe liver dysfunction
Group 3 PH clinical trials
Nathan (2) (n = 147)	Riociguat	Idiopathic interstitial pneumonia	1. Systolic blood pressure <95 mm Hg	6MWD	Stopped early; increased harm in treated group
			2. Forced vital capacity <45%
			3. Active smoking
Goudie (15) (n = 120)	Tadalafil	COPD	1. Left ventricular systolic dysfunction (EF, <45%)	6MWD	No change
			2. Systolic blood pressure <90 mm Hg
			3. Recent stroke or unstable angina
			4. COPD exacerbation within 1 mo
Raghu (16) (n = 68)	Ambrisentan	Idiopathic pulmonary fibrosis	1. NYHA FC III–IV	Disease progression†	Unfavorable trend; more hospitalizations in treated group
			2. EF <40%
			3. Coexisting obstructive airflow or emphysema on computed tomography
			4. Hospitalization or respiratory infection within 60 d

Definition of abbreviations: 6MWD = 6-minute-walk distance; COPD = chronic obstructive pulmonary disease; EF = ejection fraction; GFR = glomerular filtration rate; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; NYHA FC = New York Heart Association functional class; PAP = pulmonary arterial pressure; PH = pulmonary hypertension.

^*Combination of death, hospitalization for heart failure, change in NYHA FC, and patient global self-assessment.

^†Composite endpoint of 1) decline in functional vital capacity and diffusing capacity of the lung for carbon monoxide, 2) respiratory hospitalization event, and 3) death of any cause.