Allopurinol in Patients with Pulmonary Hypertension Associated with Chronic Lung Disease

Figures & data

Box 1 Inclusion and Exclusion Criteria

Inclusion criteria Male or female participants aged 18 years or over Known diagnosis of chronic obstructive pulmonary disease or interstitial lung disease Stable lung disease medication for at least two weeks prior to consent Pulmonary acceleration time < 110 ms and/or right ventricular systolic pressure > 25 mm Hg and/or right ventricular free wall thickness ≥ 5.5 mm (on screening echocardiography) Exclusion criteria Documented allergy or intolerance to allopurinol Active gout (i.e flare up < 2 years) or currently taking allopurinol Left ventricular ejection fraction < 45% on echocardiography Severe aortic stenosis on echocardiography Severe hepatic disease Chronic kidney disease class 3B or greater Patients taking azathioprine, 6-mercaptopurine, or theophylline Malignancy (receiving active treatment) or other life threatening diseases Any contraindication to MRI (claustrophobia, metal implants)

Figure 1 CONSORT diagram showing participant flow through the study.

Table 1 Baseline Characteristics of Study Participants

	Allopurinol (n = 36)	Placebo (n = 35)	p
Age (years)	70 (5)	71 (6)	0.45
Male sex (%)	22 (61)	22 (63)
Height (m)	1.65 (0.11)	1.68 (0.09)	0.29
Weight (kg)	80.2 (16.6)	82.7 (17.0)	0.54
BMI (kg/m^2)	29 (5)	29 (5)	0.98
Heart rate (bpm)	79 (14)	78 (13)	0.99
Systolic BP (mm Hg)	138 (16)	140 (19)	0.67
Diastolic BP (mm Hg)	76 (9)	75 (14)	0.93
mMRC dyspnoea scale	2.8 (1.3)	2.7 (1.2)	0.14
WHO Functional class	2.3 (0.8)	2.4 (0.7)	0.48
Smoking status Current smoker Ex-/non-smoker	9 (25) 27 (75)	8 (23) 27 (77)
Pack-year history	46.9 (27.4)	50.3 (28.6)	0.61
Long-term oxygen	3 (8)	2 (6)
SaO2 (%)	96 (3)	96 (3)	0.67
PAT (ms)	94.9 (9.6)	97.1 (12.1)	0.38
COPD FEV1 (% predicted)	34 (94) 60 (21)	32 (91) 58 (20)	0.64
ILD	2 (6)	3 (9)

Notes: Data are mean (SD), n (%) or median (IQR): Independent samples t-test for normally-distributed continuous variables and Mann–Whitney U-test for non-parametric data.

Abbreviations: BMI, body mass index; mMRC, modified medical research council; FEV_1, forced expiratory volume in 1 sec; SaO_2, blood oxygen saturation; PAT, pulmonary acceleration time; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 sec; ILD, interstitial lung disease.

Table 2 Baseline Cardiac MRI Measurements

	Allopurinol (n = 36)	Placebo (n = 35)	p
RVM (g)	40.27 (1.62)	41.19 (2.06)	0.73
RVMI (g/m^2)	21.02 (0.68)	20.88 (0.83)	0.90
RVESV (mL)	49.7 (2.9)	55.8 (3.6)	0.19
RVESVI (mL/m^2)	26.1 (1.6)	28.3 (1.7)	0.33
RVEDV (mL)	118.6 (5.2)	129.1 (5.8)	0.17
RVEDVI (mL/m^2)	62.2 (2.5)	65.5 (2.3)	0.34
RVSV (mL)	68.8 (3.3)	73.4 (3.8)	0.35
RVEF (%)	57.0 (2.0)	56.5 (1.7)	0.85
RA area (cm^2)	20.8 (0.9)	21.9 (1.2)	0.45
LVM (g)	106.8 (4.8)	105.9 (4.9)	0.89
LVMI (g/m^2)	55.5 (1.8)	53.7 (2.0)	0.52
LVSV (mL)	70.9 (3.4)	76.3 (3.3)	0.25
LVEF (%)	52.9 (1.9)	56.8 (1.5)	0.10
LA area (cm^2)	21.1 (1.1)	22.8 (1.3)	0.35
VMI	0.39 (0.01)	0.39 (0.01)	0.69

Notes: Data are mean (SEM): Independent samples t-test for normally-distributed continuous variables and Mann–Whitney U-test for non-parametric data.

Abbreviations: RVM, right ventricular mass; RVMI, right ventricular mass index; RVESV, right ventricular end-systolic volume; RVEDV, right ventricular end-diastolic volume; RVSV, right ventricular stroke volume; RVEF, right ventricular ejection fraction; RA area, right atrial area; LVM, left ventricular mass; LVMI, left ventricular mass index; LVSV, left ventricular stroke volume; LVEF, left ventricular ejection fraction; LA area, left atrial area; VMI, ventricular mass index.

Table 3 CMRI Changes After Allopurinol Treatment (Intention-to-Treat Analysis)

	Allopurinol (n = 36)	Placebo (n = 35)	p
Right ventricle
Change in RVM (g)	1.85 (1.56)	0.97 (1.20)	0.66
Change in RVMI (g/m^2)	0.70 (0.75)	0.50 (0.60)	0.83
Change in RVESV (mL)	4.8 (2.5)	3.8 (2.8)	0.79
Change in RVESVI (mL/m^2)	1.9 (1.3)	1.7 (1.4)	0.92
Change in RVEDV (mL)	8.8 (4.2)	5.6 (4.2)	0.59
Change in RVEDVI (mL/m^2)	4.0 (2.2)	3.1 (2.2)	0.75
Change in RVSV (mL)	3.0 (3.1)	1.6 (2.7)	0.73
Change in RVSVI (mL/m^2)	1.4 (1.7)	1.1 (1.3)	0.88
Change in RVEF (%)	1.3 (2.4)	1.7 (1.7)	0.91
Change in RA area (cm^2)	−2.2 (1.5)	−0.6 (1.5)	0.45
Left ventricle
Change in LVM (g)	0.8 (3.2)	−1.9 (2.8)	0.52
Change in LVMI (g/m^2)	0.1 (1.5)	−1.1 (1.2)	0.53
Change in LVSV (mL)	5.8 (3.3)	0.4 (2.6)	0.20
Change in LVEF (%)	3.0 (2.0)	0.0 (1.3)	0.20
Change in LA area (cm^2)	0.6 (0.1)	−0.3 (0.8)	0.49

Note: Data are mean (SEM).

Abbreviations: RV, right ventricular; LV, left ventricular; MI, mass index; ESV, end systolic volume; EDV, end diastolic volume; SV, stroke volume; EF, ejection fraction.

Table 4 CMRI Changes for RV After Allopurinol Treatment in Subgroup GOLD 3 and 4

	Allopurinol (n = 7)	Placebo (n = 13)	p
Change in RVM (g)	−6.16 (1.97)	0.75 (1.71)	0.02
Change in RVMI (g/m^2)	−3.13 (1.00)	0.54 (0.85)	0.02
Change in RVESV (mL)	−1.4 (6.6)	2.5 (5.8)	0.68
Change in RVESVI (mL/m^2)	−1.4 (4.1)	1.5 (3.0)	0.59
Change in RVEDV (mL)	4.9 (6.2)	4.7 (6.7)	0.98
Change in RVEDVI (mL/m^2)	3.7 (3.4)	3.1 (3.6)	0.91
Change in RVSV (mL)	1.0 (9.3)	1.9 (2.8)	0.92
Change in RVSVI (mL/m^2)	1.9 (5.8)	1.4 (1.6)	0.92
Change in RVEF (%)	2.0 (7.7)	0.4 (2.4)	0.81

Note: Data are mean (SEM).

Abbreviations: RV, right ventricular; LV, left ventricular; MI, mass index; ESV, end systolic volume; EDV, end diastolic volume; SV, stroke volume; EF, ejection fraction.

Figure 2 Scatter plots of RVM and RVMI (mean and SEM) for overall population (allopurinol n=31, placebo n=32) and subgroup GOLD 3 and 4 (allopurinol n=7, placebo n=13). There were significant (p = 0·02) differences in RVM and RVMI in the subgroup of GOLD 3/4 patients.

Table 5 Mean Change in Quality-of-Life Scores, Spirometry and Six-Minute Walk Measurements at 52 Weeks Compared to Baseline (Intention-to-Treat Analysis)

	Allopurinol (n = 36)	Placebo (n = 35)	p
SGRQ
Total score	−0·89 (1·72)	−1·30 (1·95)	0·88
Symptom score	−2·82 (2·96)	1·55 (3·67)	0·35
Activity score	1·93 (2·31)	−1·31 (2·39)	0·84
Impact score	−1·70 (2·31)	−2·37 (2·41)	0·84
SF-36
Physical functioning	−1·06 (3·09)	2·92 (2·42)	0·31
Physical role limitations	1·66 (5·74)	8·15 (6·45)	0·45
Emotional role limitations	−5·77 (6·48)	1·45 (8·47)	0·50
Energy or fatigue	−0·81 (2·64)	4·53 (3·81)	0·25
Emotional well-being	4·65 (2·85)	0·29 (3·07)	0·30
Social functioning	−2·43 (3·63)	−1·62 (3·98)	0·88
Pain	−4·08 (3·51)	1·13 (4·67)	0·37
General health	0·12 (2·73)	−0·02 (3·33)	0·97
Health change	5·56 (4·02)	6·96 (5·29)	0·83
Spirometry
FEV1	0·02 (0·03)	−0·01 (0·03)	0·42
FEV1%	1·55 (1·31)	0·16 (1·08)	0·41
FVC	0·02 (0·05)	0·02 (0·06)	0·98
FVC%	0·97 (1·41)	1·00 (1·78)	0·99
FEV1/FVC	0·97 (1·41)	1·00 (1·78)	0·74
6MWT
Distance	8·8 (10·0)	−10·0 (12·5)	0·24
Pre-test O2	−0·4 (0·3)	−0·8 (0·4)	0·51
Post-test O2	−1·3 (0·9)	−0·5 (0·8)	0·52

Note: Data are mean (SEM).

Abbreviations: SGRQ, St George Respiratory Questionnaire; SF-36, Short Form (36); FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; 6MWT, six-minute walk test.

Table 6 Mean Change in Blood Markers at 52 Weeks Compared to Baseline (Intention-to-Treat Analysis)

	Allopurinol (n = 36)	Placebo (n = 35)	p
Baseline NT-proBNP (pg/mL)	916·81 (248·62)	949·31 (275·13)	0·93
Final NT-proBNP (pg/mL)	829·18 (233·20)	1238·68 (376·36)	0·35
Change in NT-proBNP (pg/mL)	−87·6 (127·2)	289·4 (213·3)	0·13
Baseline hs-Trop I (pg/mL)	3·22 (0·55)	3·59 (0·73)	0·69
Final hs-Trop I (pg/mL)	3·03 (0·41)	3·77 (0·79)	0·40
Change in hs-Trop I (pg/mL)	−0·20 (0·48)	0·18 (0·37)	0·53
Baseline Urate (μmol/l)	350·06 (13·54)	342·94 (15·37)	0·73
Final Urate (μmol/l)	144·12 (9·12)	338·34 (15·59)	< 0·001
Change in Urate (μmol/l)	−205·9 (14·9)	−4·6 (8·5)	< 0·001

Note: Data are mean (SEM).

Abbreviations: NT-proNBP, N-terminal prohormone brain natriuretic peptide; Hs-Trop I, high sensitive troponin I.