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. 2019 Jan 31;2019(1):CD012621. doi: 10.1002/14651858.CD012621.pub2

Zhuang 2014.

Methods Randomised placebo‐controlled trial
16 weeks duration
Participants Inclusion criteria:
  • Adults aged 18 to 70 years

  • Symptomatic PAH

  • Received ambrisentan for 4 months or more

  • All diagnoses were confirmed as either idiopathic/familial PAH or PAH‐related to anorexigen use, connective tissue disease or repaired congenital heart disease. (WHO Group 1)

  • Resting mPAP ≥ 25 mmHg, pulmonary wedge pressure < 15 mmHg and PVR > 3 Wood units

  • 6MWD between 150 and 400 metres (6MWD stable for at least 1 month)

  • Stable World Health Organization (WHO) functional class (FC) for at least 1 month before stud


Exclusion criteria:
  • Thromboembolic disease

  • Untreated obstructive sleep apnoea

  • Portal hypertension

  • Chronic liver disease

  • Renal insufficiency

  • Left‐sided or unrepaired congenital heart disease

  • Substantial obstructive (FEV1/FVC ratio of 50% predicted) or restrictive (total lung capacity of 60% predicted) lung disease

  • People taking prostanoids or other PDE inhibitors


WHO FC II/III
n = 124
Interventions Tadalafil (40 mg a day) (N=60) or placebo to existing therapy with oral ambrisentan (10 mg a day) (n=64)
Outcomes 6MWD
Improvement in WHO functional class
Clinical worsening was defined as the occurrence of the following events: death, transplantation, arterial septostomy, hospitalisation due to worsening PAH, initiation of new therapy or worsening FC by week 16
Haemodynamic parameters were measured by right‐heart catheterisation
Notes Funding source not stated
Trial was conducted at Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China, between September 2011 and March 2013
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Type of randomisation is not clear
The randomisation was stratified for baseline walking distance and type of PAH (idiopathic/familial and anorexigen use vs. other types)
Allocation concealment (selection bias) Low risk Placebo‐controlled
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk Placebo‐controlled
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Unclear if outcome assessors were blinded
Incomplete outcome data (attrition bias) 
 All outcomes Low risk Withdrawals were accounted for:
In the tadalafil group: 6 participants discontinued: 3 for toxicity, 1 for worsening PAH, 2 for non‐compliance
In the placebo group: 5 participants discontinued: 4 for worsening PAH; 1 for irrelevant accidental death
Selective reporting (reporting bias) Low risk Prespecified outcomes were reported
Other bias Low risk Other risk of bias is unlikely

6MWD: six‐minute walk distance; BNP: brain nutrietic peptide; BODE: Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity; CHF: congenital heart failure; CI: cardiac index; COPD: chronic obstructive pulmonary disease; CTEPH: chronic thromboembolic pulmonary hypertension; DCMP: dilated cardiomyopathy; DLCO: diffusing capacity for carbon monoxide; EF: ejection fraction; EPBF: effective pulmonary blood flow; ERA: endothelin receptor antagonist; FEV1: forced expiratory volume in one second; HFpEF: heart failure with preserved ejection fraction; HIV: human immunodeficiency virus; IV: intravenous; LV: left ventricle; LVEF: left ventricular ejection fraction; LVSD: left ventricular systolic dysfunction; m: metres; n: number; NT‐Pro BNP: N‐terminal prohormone of brain natriuretic peptide; NYHA: New York Heart Association; PAH: pulmonary arterial hypertension; PAP: pulmonary artery pressure; PASP: pulmonary artery systolic pressure; PAWP: pulmonary artery wedge pressure; PCWP: pulmonary capillary wedge pressure; PDA: patent ductus arteriosus; PDE5: phosphodiesterase 5; PEA: pulmonary endarterectomy; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; PVRI: pulmonary vascular resistance index; QOL: quality of life; RAP: right atrial pressure; RHC: right heart catheterisation; SF‐36: short form 36; SGRQ: St George's Respiratory Questionnaire; SO2: saturation of oxygen; SVR: systemic vascular resistance; TAPSE: tricuspid annular plane systolic excursion; TLC: total lung capacity; TTE: transthoracic echocardiogram; TRV: tricuspid regurgitation velocity; VO2: volume of oxygen; WHO: World Health Organization