Proton pump inhibitors use is associated with a lower risk of acute exacerbation and mortality in patients with coexistent COPD and GERD

Figures & data

Table 1 Characteristics in COPD with symptomatic GERD (COPD + GERD) cohort and COPD alone cohort

Characteristics	COPD + GERD		COPD alone		p-value
	n	%	n	%
N	3,485		13,938
Age, years (mean ± SD)	68.06±12.55		67.88±12.27		0.4162
Age
40–49	341	9.78	1,275	9.15	0.8355
50–59	690	19.80	2,855	20.48
60–69	810	23.24	3,170	22.74
70–79	981	28.15	4,199	30.13
≥80	663	19.02	2,439	17.50
Follow-up, years (mean ± SD)a	3.67±1.99		4.08±1.85		<0.0001
Sex
Female	1,230	35.29	4,920	35.30	0.9955
Male	2,255	64.71	9,018	64.70
Comorbiditiesb
Arrhythmia	386	11.08	991	7.11	<0.0001
Heart failure	322	9.24	840	6.03	<0.0001
Ischemic heart disease	812	23.30	2,247	16.12	<0.0001
Peripheral vascular disease	147	4.22	357	2.56	<0.0001
Stroke	746	21.41	1,768	12.68	<0.0001
Asthma	402	11.54	1,183	8.49	<0.0001
Psychiatric disorder	486	13.95	1,173	8.42	<0.0001
Lung cancer	65	1.87	155	1.11	0.0004
COPD severityb
COPD-related ED visit					<0.0001
0	3,311	95.01	13,631	97.80
≥1	174	4.99	307	2.20
COPD-related hospitalization					<0.0001
0	2,955	84.79	13,085	93.88
≥1	530	15.21	853	6.12
COPD medicationsc					<0.0001
0–2	2,727	78.25	12,347	88.59
≥3	758	21.75	1,591	11.41
PPIsa	3,028	86.89	2,132	15.30	<0.0001
H2RAsa	1,870	53.66	3,322	23.83	<0.0001

Notes:

a Measured from index date to the end of follow-up.

b Measured in 1 year before index date.

c Included long-acting β2-agonists, long-acting muscarinic antagonist, inhaled corticosteroid, short-acting β2-agonists, short acting muscarinic antagonist, xanthines.

Abbreviations: ED, emergency department; GERD, gastroesophageal reflux disease; H2RAs, histamine2-receptor antagonists; PPIs, proton pump inhibitors.

Table 2 Rate of COPD exacerbations in COPD + GERD cohort and COPD alone cohort

Variables	COPD + GERD		COPD alone		Relative risk (95% CI)	p-valuea
	Events	Rateb	Events	Rateb
Exacerbations of COPDc	2,284	17.83	5,698	10.03	1.78 (1.69–1.87)	<0.0001
Moderate exacerbationsc
OPD visits	1,286	10.04	3,751	6.60	1.52 (1.43–1.62)	<0.0001
ED visits	123	0.96	380	0.67	1.44 (1.16–1.76)	0.0007
Severe exacerbationsc
Hospitalizations	875	6.83	1,567	2.76	2.48 (2.28–2.69)	<0.0001
ICU admissions	150	1.17	246	0.43	2.70 (2.19–3.33)	<0.0001
Hospital stay	16,643	129.96	28,028	49.34	2.63 (2.58–2.69)	<0.0001
Medications, during exacerbationc
Average dose of steroids (mg, mean ± SD)d	280.5±524.6		217.8±324.1			<0.0001
Duration of antibiotics (days, median ± SD)e	11±15.70		9±23.53			<0.0001

Notes:

a Determined by Student’s t-test for normal distributions; Mann–Whitney U test for non-normal distributions.

b Incidence rate per 100 person-year.

c Exacerbation was measured from index date to the end of follow-up.

d Prednisolone-equivalent fillings.

e Included pneumonia-related antibiotics.

Abbreviations: ED, emergency department; GERD, gastroesophageal reflux disease; ICU, intensive care unit; OPD, outpatient department.

Figure 1 Kaplan–Meier curve for cumulative risk of AECOPD in COPD patients.

Note: There was a statistically significant difference between the COPD with symptomatic GERD and COPD alone curves (log-rank test, p<0.0001).

Abbreviations: AECOPD, acute exacerbation of COPD; GERD, gastroesophageal reflux disease.

Figure 2 Kaplan–Meier curve for survival probability in COPD patients.

Note: There was a statistically significant difference between the COPD with symptomatic GERD and COPD alone curves (log-rank test, p<0.0001).
Abbreviation: GERD, gastroesophageal reflux disease.

Table 3 Association between PPIs/H2RAs use and risk of acute exacerbation and mortality in COPD with symptomatic GERD

Variables	Acute exacerbation		Mortality
	HR (95% CI)a	p-value	HR (95% CI)a	p-value
PPIsb
<1 DDD per day	Reference		Reference
≥1 DDD per day	0.31 (0.20–0.50)	<0.0001	0.36 (0.20–0.65)	0.0007
H2RAsb
<1 DDD per day	Reference		Reference
≥1 DDD per day	0.75 (0.47–1.21)	0.2415	0.80 (0.39–1.63)	0.5375

Notes:

a Adjusted for all factors listed in Table 1; all factors with p<0.1 in univariate analyses were included in the Cox multivariate analysis.

b Medications were analyzed as time-dependent covariates (time interval: every 90 days), and were followed for a period of 1 year after the index date.

Abbreviations: DDD, defined daily dose; GERD, gastroesophageal reflux disease; H2RAs, histamine2-receptor antagonists; HR, hazard ratio; PPIs, proton pump inhibitors.

Table 4 Association between PPIs/H2RAs use and risk of acute exacerbations and mortality in patients with COPD

Variables	Acute exacerbation		Mortality
	HR (95% CI)a	p-value	HR (95% CI)a	p-value
COPD alone	Reference		Reference
COPD with symptomatic GERD, treated with
PPIs or H2RAs <1 DDD/dayb	1.75 (1.50–2.03)	<0.0001	1.97 (1.56–2.50)	<0.0001
H2RAs ≥1 DDD/dayb	1.28 (0.91–1.80)	0.1625	1.33 (0.78–2.25)	0.2965
PPIs ≥1 DDD/dayb	0.58 (0.38–0.90)	0.0156	0.95 (0.54–1.67)	0.8471

Notes:

a Adjusted for all factors listed in Table 1; all factors with p<0.1 in univariate analyses were included in the Cox multivariate analysis.

b Medications were analyzed as time-dependent covariates (time interval: every 90 days), and were followed for a period of 1 year after the index date.

Abbreviations: DDD, defined daily dose; GERD, gastroesophageal reflux disease; H2RAs, histamine2-receptor antagonists; HR, hazard ratio; PPIs, proton pump inhibitors.