Cardiovascular and inflammatory effects of simvastatin therapy in patients with COPD: a randomized controlled trial

Figures & data

Table 1 Baseline demographics for all subjects

Mean (SD) Unless otherwise specified	Active treatment group n=33	Placebo group n=37
Age (years), median (range)	64 (50–79)	65 (50–79)
Male sex, n (%)	26 (79)	24 (65)
Smoking status, (current:ex) n (%)	7 (21):26 (79)	15 (41):22 (59)
Pack years, median (IQR)	41 (30–53)	45 (32–59)
FEV1 (L)	1.6 (0.6)	1.4 (0.5)
FEV1 % predicted	55 (14)	53 (15)
FEV1/FVC	46 (12)	47 (12)
GOLD stage n (II, III)	20, 13	22, 15
Total cholesterol (mmol/L)	5.3 (0.8)	5.4 (0.8)
HDL cholesterol (mmol/L)	1.7 (0.4)	1.7 (0.5)
LDL cholesterol (mmol/L)	3.0 (0.7)	3.0 (0.7)

Abbreviations: FEV₁, forced expired volume in one second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HDL, high-density lipoprotein; IQR, interquartile range; L, liter; LDL, low-density lipoprotein; SD, standard deviation.

Figure 1 CONSORT diagram of study recruitment, allocation, drop-out and completion.

Notes: *Cardiac history, alcohol excess, maintenance prednisolone/antibiotics, withdrew consent, other respiratory diagnosis, never smoker, outside age range.

Table 2 Cardiovascular measurements

Mean (SD) n=total (active treatment:placebo)	Active treatment (simvastatin) group			Placebo group			Mean difference Δ active treatment versus Δ placebo (CI)	P-value (between arm change)
	Pre-treatment	Post-treatment	Post-pre mean Δ	Pre-treatment	Post-treatment	Post-pre mean Δ
Aortic PWV (m/sec) n=63 (31:32)	9.9 (3.4)	8.9 (2.2)	−1.0	9.1 (2.3)	8.9 (3.0)	−0.3	−0.7 (−1.8, 0.5)	0.24
Total cholesterol levels (mmol/L) n=64 (31:33)	5.2 (0.8)	4.1 (0.8)	−1.2	5.4 (0.8)	5.3 (0.9)	−0.1	−1.1 (−1.3, −0.8)	<0.001
Peripheral seated n=64 (31:33)
Systolic BP (mmHg)	147 (22)	144 (18)	−3.1	151 (25)	145 (24)	−5.5	2.4 (−3.7, 8.6)	0.43
Diastolic BP (mmHg)	90 (12)	87 (11)	−3.6	88 (14)	86 (12)	−2.4	−1.3 (−4.7, 2.1)	0.45
MAP (mmHg)	109 (14)	106 (12)	−3.5	109 (16)	105 (15)	−3.4	−0.1 (−3.8, 3.6)	0.98
Central seated n=62 (30:32)
Systolic BP (mmHg)	137 (18)	135 (22)	−1.6	138 (23)	133 (23)	−4.9	3.3 (−2.5, 9.0)	0.26
Diastolic BP (mmHg)	91 (12)	86 (12)	−4.1	89 (14)	85 (14)	−2.2	−1.9 (−5.5, 1.7)	0.30
MAP (mmHg)	111 (14)	108 (12)	−3.3	110 (18)	107 (16)	−3.3	−0.1 (−4.1, 4.0)	0.98
HR (bpm)	73 (13)	73 (14)	−0.4	74 (15)	76 (17)	2.3	−2.7 (−6.1, 0.7)	0.12

Abbreviations: PWV, pulse wave velocity; BP, blood pressure; MAP, mean arterial pressure; HR, heart rate; SD, standard deviation; CI, confidence interval.

Figure 2 Change in aortic PWV for active treatment and placebo groups in (A) the total study group and (B) those with a high baseline aortic PWV. Line represents mean drop from baseline. Dotted line indicates active (simvastatin) arm. Black solid line indicates placebo. Error bars indicate the standard error.

Abbreviation: PWV, pulse wave velocity.

Table 3 Patients with a high baseline aortic PWV >10 m/sec

Mean (SD) n=total (active treatment:placebo)	Active treatment (simvastatin)		Placebo		Mean difference Δ active treatment versus Δ placebo (CI)	P-value (between arm change)
	Pre-treatment	Post-treatment	Pre-treatment	Post-treatment
Aortic PWV (m/sec) n=22 (11:11)	13.5 (2.9)	10.6 (2.1)	11.6 (1.5)	11.5 (3.0)	−2.8 (−5.2, −0.3)	0.03
Peripheral seated (mmHg) n=22 (11:11)
Systolic BP	158 (27)	152 (20)	162 (31)	159 (26)	−3.2 (−15.4, 9.0)	0.59
Diastolic BP	95 (14)	91 (13)	89 (18)	87 (13)	−1.6 (−7.7, 4.4)	0.58
MAP	116 (18)	111 (14)	113 (21)	111 (15)	−2.2 (−9.5, 5.2)	0.55
Central seated (mmHg) n=20 (10:11)
Systolic BP	147 (23)	142 (20)	145 (30)	142 (27)	−1.7 (−11.6, 8.2)	0.73
Diastolic BP	95 (16)	92 (13)	88 (19)	87 (12)	−2.0 (−9.1, 5.1)	0.56
MAP	118 (19)	114 (15)	112 (24)	112 (18)	−4.4 (−11.4, 2.7)	0.21

Abbreviations: CI, confidence interval; PWV, pulse wave velocity; BP, blood pressure; MAP, mean arterial pressure; SD, standard deviation.

Table S1 Baseline demographics in subjects with a high baseline aortic pulse wave velocity

Mean (SD) Unless otherwise specified	Active treatment (simvastatin) group	Placebo
Total number of patients, n	12	13
Age (years), median (range)	70 (54–77)	64 (52–75)
Male sex, n (%)	9 (75)	10 (77)
Smoking status (current:ex)	4:8	5:8
Pack years, median (IQR)	41.5 (33–50)	53 (37–68)
Aortic PWV (m/sec)	13.2 (2.9)	12.0 (2.1)
Peripheral systolic BP (mmHg)	156 (27)	159 (31)
Peripheral diastolic BP (mmHg)	94 (14)	90 (18)
FEV1 (L)	1.4 (0.6)	1.6 (0.7)
FEV1 % predicted	51 (13)	55 (17)
FEV1/FVC	41 (8)	48 (10)
Total cholesterol (mmol/L)	5.3 (0.8)	5.3 (0.8)
HDL cholesterol (mmol/L)	1.7 (0.4)	1.7 (0.5)
LDL cholesterol (mmol/L)	3.0 (0.6)	2.8 (0.7)

Abbreviations: PWV, pulse wave velocity; BP, blood pressure; FEV₁, forced expired volume in one second; FVC, forced vital capacity; HDL, high-density lipoprotein; IQR, interquartile range; L, liter; LDL, low-density lipoprotein; SD, standard deviation.

Table S2 Physiological and inflammatory measures

Mean (SD) unless otherwise specified n=active treatment: placebo	Active treatment (simvastatin) group			Placebo group			Mean difference Δ active treatment versus Δ placebo (CI)	P-value (between arm change)
	Pre-treatment	Post-treatment	Post–Pre mean Δ	Pre-treatment	Post-treatment	Post-Pre mean Δ
Circulating MMP-9 (ng/mL)	53.1 (16.3)	50.4 (16.8)	−2.9	60.4 (17.2)	56.1 (17.8)	−3.1	0.2 (–10.8, 11.2)	0.97
Circulating hs-CRP (mg/L) n=31:32*	3.5 (3.1)	2.9 (3.9)	0.8	3.0 (3.0)	3.0 (2.9)	0.2	0.5 (–3.2, 4.1)	0.79
Dominant hand grip strength (kg) n=31:33	35.3 (9.2)	35.3 (8.5)	0.1	32.2 (8.3)	33.0 (8.4)	0.9	−0.8 (–2.6, 0.9)	0.36
6MWD (m) n=30:31	343 (75)	339 (84)	−3.6	332 (76)	338 (88)	5.1	−8.7 (–23.6, 6.2)	0.25
FEV1 (L) n=31:33	1.59 (0.6)	1.59 (0.6)	0.0	1.41 (0.5)	1.43 (0.6)	0.0	0 (–0.07, 0.05)	0.77
FVC (L) n=31:33	3.40 (0.9)	3.3 (0.9)	−0.1	3.06 (1.0)	3.07 (1.0)	0.0	−0.1 (–0.2, 0.02)	0.09
Sputum neutrophils (%) n=8:12*	75.2 (1.5)	75.3 (1.4)	−1.9	77.5 (1.3)	61.4 (2.2)	−6.3	4.4 (–12.0, 20.8)	0.58
Actual sputum neutrophils n=8:12*	306 (2)	310 (1)	−2.8	314 (1.2)	246 (2)	−27.8	25.0 (–50.1, 101.0)	0.50
FeNO 50 mL (ppm) n=17:19*	23.6 (1.9)	21.8 (1.9)	−2.2	14.5 (1.9)	17.8 (2.1)	6.1	−8.2 (–19.1, 2.6)	0.13
FeNO intercept n=16:19*	34.4 (2.5)	36.9 (2.5)	−0.1	27.7 (2.1)	31.1 (2.2)	4.4	−4.5 (–25.3, 16.4)	0.67
FeNO gradient n=16:19*	8.9 (2.5)	8.1 (2.5)	−2.0	4.8 (2.1)	5.9 (3.2)	3.8	−5.9 (–13.5, 1.7)	0.13

Notes:

* Geometric mean.

Abbreviations: FEV₁, forced expired volume in one second; FVC, forced vital capacity; FeNO, fraction of expired nitric oxide; L, litre; MMP-9, matrix metalloprotease-9; hs-CRP, high sensitivity C-reactive protein; 6MWD, six-minute walking distance; SD, standard deviation; CI, confidence interval.

Table S3 Patient-reported side effects and blood tests for safety

	Active treatment (simvastatin) group	Placebo group
Adverse events/Musculoskeletal
Muscle cramps	2	0
Muscle aches	5	2
Joint aches	0	2
Respiratory	4	3
Gastrointestinal	1	1
Severe adverse events
Hospital admissions	0	0
Death	0	0
Change in LFTs
Clinically relevant increase in ALT	0	0
Clinically relevant increase in gamma GT	1	1
Clinically relevant increased CPK	0	1

Abbreviations: ALT, alanine aminotransferase; gamma GT, gamma-glutamyl transferase; CPK, creatine phosphokinase; LFTs, lung function tests.