1. Am J Respir Crit Care Med. 2018 Feb 15;197(4):502-508. doi:
10.1164/rccm.201704-0809OC.

Randomized Controlled Trial of Urokinase versus Placebo for Nondraining Malignant
Pleural Effusion.

Mishra EK(1), Clive AO(2), Wills GH(3), Davies HE(4), Stanton AE(5), Al-Aloul
M(6), Hart-Thomas A(7), Pepperell J(8), Evison M(6), Saba T(9), Harrison RN(10), 
Guhan A(11), Callister ME(12), Sathyamurthy R(13), Rehal S(3), Corcoran JP(14),
Hallifax R(14), Psallidas I(14), Russell N(14), Shaw R(14), Dobson M(14),
Wrightson JM(14), West A(15), Lee YCG(16), Nunn AJ(3), Miller RF(17), Maskell
NA(2), Rahman NM(14)(18).

Author information: 
(1)1 Norfolk and Norwich Pleural Unit, Norfolk and Norwich University Hospital
NHS Foundation Trust, Norfolk, United Kingdom.
(2)2 Academic Respiratory Unit, School of Clinical Sciences, Southmead Hospital, 
University of Bristol, Bristol, United Kingdom.
(3)3 Medical Research Council Clinical Trials Unit and.
(4)4 Cardiff and Vale University Health Board, Cardiff, United Kingdom.
(5)5 Great Western Hospital, Swindon, United Kingdom.
(6)6 University Hospital of South Manchester NHS Foundation Trust, Manchester,
United Kingdom.
(7)7 Calderdale and Huddersfield NHS Foundation Trust, Huddersfield, United
Kingdom.
(8)8 Somerset Lung Centre, Musgrove Park Hospital, Taunton, United Kingdom.
(9)9 Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, United
Kingdom.
(10)10 North Tees and Hartlepool Hospitals NHS Foundation Trust, North Tees,
United Kingdom.
(11)11 University Hospital Ayr, Ayr, United Kingdom.
(12)12 Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
(13)13 James Cook University Hospital, South Tees, United Kingdom.
(14)14 Oxford Respiratory Trials Unit and Oxford Pleural Diseases Unit, Churchill
Hospital, Oxford, United Kingdom.
(15)15 Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
(16)16 School of Medicine and Pharmacology, University of Western Australia,
Perth, Australia; and.
(17)17 Research Department of Infection and Population Health, Institute of
Epidemiology and Healthcare, University College London, London, United Kingdom.
(18)18 National Institute for Health Research Oxford Biomedical Research Centre, 
University of Oxford, Oxford, United Kingdom.

RATIONALE: Patients with malignant pleural effusion experience breathlessness,
which is treated by drainage and pleurodesis. Incomplete drainage results in
residual dyspnea and pleurodesis failure. Intrapleural fibrinolytics lyse
septations within pleural fluid, improving drainage.
OBJECTIVES: To assess the effects of intrapleural urokinase on dyspnea and
pleurodesis success in patients with nondraining malignant effusion.
METHODS: We conducted a prospective, double-blind, randomized trial. Patients
with nondraining effusion were randomly allocated in a 1:1 ratio to intrapleural 
urokinase (100,000 IU, three doses, 12-hourly) or matched placebo.
MEASUREMENTS AND MAIN RESULTS: Co-primary outcome measures were dyspnea (average 
daily 100-mm visual analog scale scores over 28 d) and time to pleurodesis
failure to 12 months. Secondary outcomes were survival, hospital length of stay, 
and radiographic change. A total of 71 subjects were randomized (36 received
urokinase, 35 placebo) from 12 U.K. centers. The baseline characteristics were
similar between the groups. There was no difference in mean dyspnea between
groups (mean difference, 3.8 mm; 95% confidence interval [CI], -12 to 4.4 mm;
P = 0.36). Pleurodesis failure rates were similar (urokinase, 13 of 35 [37%];
placebo, 11 of 34 [32%]; adjusted hazard ratio, 1.2; P = 0.65). Urokinase was
associated with decreased effusion size visualized by chest radiography (adjusted
relative improvement, -19%; 95% CI, -28 to -11%; P < 0.001), reduced hospital
stay (1.6 d; 95% CI, 1.0 to 2.6; P = 0.049), and improved survival (69 vs. 48 d; 
P = 0.026).
CONCLUSIONS: Use of intrapleural urokinase does not reduce dyspnea or improve
pleurodesis success compared with placebo and cannot be recommended as an adjunct
to pleurodesis. Other palliative treatments should be used. Improvements in
hospital stay, radiographic appearance, and survival associated with urokinase
require further evaluation. Clinical trial registered with ISRCTN (12852177) and 
EudraCT (2008-000586-26).

DOI: 10.1164/rccm.201704-0809OC 
PMID: 28926296