Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD

Figures & data

Figure 1 Flowchart of selection of study subjects.

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.

Table 1 Demographic characteristics of the study subjects

Variables	Before matching					After matching
	ACEi cohort		ARB cohort		P-value	ACEi cohort		ARB cohort		P-value
Number of patients	15,196		7,283			6,226		6,226
Index year
2000	3,763	24.76%	768	10.55%	<0.0001	736	11.82%	768	12.34%	0.9693
2001	2,985	19.64%	884	12.14%		883	14.18%	880	14.13%
2002	2,552	16.79%	1,109	15.23%		1,068	17.15%	1,047	16.82%
2003	2,017	13.27%	1,336	18.34%		1,132	18.18%	1,130	18.15%
2004	2,002	13.17%	1,695	23.27%		1,264	20.30%	1,264	20.30%
2005	1,877	12.35%	1,491	20.47%		1,143	18.36%	1,137	18.26%
Age (years, SD)	68.15±9.77		66.75±9.95		<0.0001	67.43±10.01		67.24±9.82		0.2919
Male gender	11,071	72.85%	4,983	68.42%	<0.0001	4,405	70.75%	4,359	70.01%	0.3666
Monthly income NT$, n (%)
<19,100	6,597	43.41%	2,973	40.82%	<0.0001	2,658	42.69%	2,625	42.16%	0.8336
19,100–41,999	7,050	46.39%	3,262	44.79%		2,784	44.72%	2,807	45.09%
≥42,000	1,549	10.19%	1,048	14.39%		784	12.59%	794	12.75%
Hospital level, n (%)
Level 1	3,360	22.11%	3,095	42.50%	<0.0001	2,374	38.13%	2,366	38.00%	0.593
Level 2	3,625	23.85%	2,254	30.95%		1,959	31.46%	1,994	32.03%
Level 3	3,088	20.32%	1,335	18.33%		1,319	21.19%	1,267	20.35%
Level 4	5,123	33.71%	599	8.22%		574	9.22%	599	9.62%
Severe AE (count 1 year before index date)
0	10,277	67.63%	5,354	73.51%	<0.0001	4,466	71.73%	4,446	71.41%	0.9181
1	2,190	14.41%	918	12.60%		827	13.28%	833	13.38%
2+	2,729	17.96%	1,011	13.88%		933	14.99%	947	15.21%
Baseline comorbidities
Charlson score	1.82±1.06		1.80±1.05		0.4771	1.84±1.07		1.82±1.05		0.3405
Myocardial infarction	391	2.57%	131	1.80%	0.0003	142	2.28%	128	2.06%	0.389
Congestive heart failure	2,164	14.24%	849	11.66%	<0.0001	824	13.23%	796	12.79%	0.4557
Peripheral vascular disease	156	1.03%	71	0.97%	0.7167	70	1.12%	59	0.95%	0.3303
Cerebrovascular disease	1,675	11.02%	786	10.79%	0.6047	687	11.03%	679	10.91%	0.8186
Dementia	181	1.19%	87	1.19%	0.9822	81	1.30%	75	1.20%	0.6288
Rheumatologic disease	141	0.93%	74	1.02%	0.5249	60	0.96%	66	1.06%	0.5911
Peptic ulcer disease	2,830	18.62%	1,187	16.30%	<0.0001	1,087	17.46%	1,068	17.15%	0.6526
Hemiplegia or paraplegia	23	0.15%	15	0.21%	0.3510	9	0.14%	10	0.16%	0.8184
Renal disease	458	3.01%	275	3.78%	0.0026	216	3.47%	228	3.66%	0.562
Diabetes	1,650	10.86%	933	12.81%	<0.0001	799	12.83%	787	12.64%	0.747
Moderate or severe liver disease	682	4.49%	337	4.63%	0.6387	281	4.51%	299	4.80%	0.444
Tumor	410	2.70%	223	3.06%	0.1228	202	3.24%	191	3.07%	0.5729
Medication for hypertension
Alpha-blocker	2,056	13.53%	936	12.85%	0.1613	846	13.59%	831	13.35%	0.6938
Beta-blocker	6,354	41.81%	3,156	43.33%	0.0309	2,671	42.90%	2,671	42.90%	1
Calcium channel blocker	9,748	64.15%	5,128	70.41%	<0.0001	4,299	69.05%	4,306	69.16%	0.892
Diuretic	7,825	51.49%	3,474	47.70%	<0.0001	3,095	49.71%	3,042	48.86%	0.3421
Other medication
Aspirin	2,220	14.61%	1,115	15.31%	0.1667	953	15.31%	927	14.89%	0.5152
Clopidogrel	356	2.34%	340	4.67%	<0.0001	265	4.26%	267	4.29%	0.9294
Ticlopidine	591	3.89%	237	3.25%	0.0180	219	3.52%	220	3.53%	0.9612
Dipyridamole	4,415	29.05%	1,563	21.46%	<0.0001	1,444	23.19%	1,432	23.00%	0.7986
Nitrate	46	0.30%	23	0.32%	0.8681	21	0.34%	22	0.35%	0.8786
Statin	1,167	7.68%	1,031	14.16%	<0.0001	725	11.64%	733	11.77%	0.8236
NSAID	12,905	84.92%	5,929	81.41%	<0.0001	5,073	81.48%	5,111	82.09%	0.3776
Anti-hyperglycemic drugs	2,560	16.85%	1,275	17.51%	0.2183	1,127	18.10%	1,102	17.70%	0.5589
Proton-pump inhibitor	1,211	7.97%	611	8.39%	0.2800	547	8.79%	533	8.56%	0.6558
COPD drug
Long-acting beta-agonist	670	4.41%	396	5.44%	0.0007	317	5.09%	327	5.25%	0.6857
Short-acting beta-agonist	3,171	20.87%	1,432	19.66%	0.0361	1,253	20.13%	1,236	19.85%	0.7032
Long-acting muscarinic antagonist	85	0.56%	80	1.10%	<0.0001	59	0.95%	60	0.96%	0.9266
Inhaled corticosteroid	2,323	15.29%	1,479	20.31%	<0.0001	1,147	18.42%	1,196	19.21%	0.2612

Abbreviations: AE, acute exacerbation; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; NSAID, nonsteroidal anti-inflammatory drug.

Table 2 Annual incidence and RR of severe exacerbation of COPD

Variables	ACEi cohort	ARB cohort	Crude RR (95% CI)	Adjusted RRa (95% CI)
	Annual incidence (per person-year)	Annual incidence (per person-year)
Before propensity score matching
Severe exacerbation	0.6873	0.5109	1.32 (1.30–1.34)	1.19 (1.17–1.21)
Hospitalization for COPD exacerbation	0.3573	0.23579	1.49 (1.46–1.52)	1.27 (1.25–1.30)
Emergency department visits for COPD exacerbation	0.4639	0.3765	1.21 (1.19–1.23)	1.14 (1.12–1.16)
After propensity score matching
Severe exacerbation	0.6521	0.5198	1.19 (1.17–1.21)	1.19 (1.16–1.21)
Hospitalization for COPD exacerbation	0.3213	0.2438	1.25 (1.21–1.28)	1.24 (1.21–1.28)
Emergency department visits for COPD exacerbation	0.4620	0.3778	1.16 (1.13–1.18)	1.16 (1.13–1.18)

Note:

a Adjusted for propensity score.

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; RR, rate ratio.

Table 3 Annual IR and risk of pneumonia among COPD patients

Variables	ACEi cohort			ARB cohort			Crude	Adjustedb	Competing risk
	Event	Person-year	IRa	Event	Person-year	IRa	HR (95% CI)	HR (95% CI)	subHR (95% CI)
Before propensity score matching
Mortality	6,277	107,841.55	5.82	2,057	52,759.75	3.90	1.50 (1.42–1.57)	1.29 (1.22–1.37)	–
Pneumonia	6,516	88,135.31	7.39	2,564	45,316.88	5.66	1.30 (1.24–1.36)	1.20 (1.14–1.26)	1.15 (1.09–1.20)
Pneumonia requiring MV	3,005	103,492.68	2.90	1,010	51,298.54	1.97	1.47 (1.37–1.58)	1.34 (1.24–1.45)	1.15 (1.09–1.20)
After propensity score matching
Mortality	2,326	42,503.29	5.47	1,864	45,472.26	4.10	1.33 (1.25–1.42)	1.33 (1.26–1.42)	–
Pneumonia	2,536	35,204.12	7.20	2,281	38,750.59	5.89	1.22 (1.15–1.29)	1.22 (1.15–1.29)	1.19 (1.13–1.26)
Pneumonia requiring MV	1,122	40,864.53	2.75	899	44,158.63	2.04	1.35 (1.23–1.47)	1.35 (1.24–1.47)	1.19 (1.13–1.25)

Notes:

a Per 100 person-years.

b Adjusted for propensity score.

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; HR, hazard ratio; IR, incidence rate; MV, mechanical ventilation; subHR, subdistribution hazard ratio.

Table 4 Sensitivity analysis

Variables	Before matching		After matching
	Crude	Adjusteda	Crude	Adjusteda
	HR (95% CI)	HR (95% CI)	HR (95% CI)	HR (95% CI)
Primary analysis
Mortality	1.5 (1.42–1.57)	1.29 (1.22–1.37)	1.33 (1.25–1.42)	1.33 (1.26–1.42)
Pneumonia	1.3 (1.24–1.36)	1.2 (1.14–1.26)	1.22 (1.15–1.29)	1.22 (1.15–1.29)
Pneumonia requiring MV	1.47 (1.37–1.58)	1.34 (1.24–1.45)	1.35 (1.23–1.47)	1.35 (1.24–1.47)
ITT analysis + competing risk
Mortality
Pneumonia	1.04 (1–1.09)	1.15 (1.09–1.2)	1.19 (1.13–1.26)	1.19 (1.13–1.26)
Pneumonia requiring MV	0.96 (0.92–1)	1.15 (1.09–1.2)	1.19 (1.12–1.25)	1.19 (1.13–1.25)
As-treated analysis
Mortality	1.5 (1.4–1.61)	1.28 (1.19–1.38)	1.29 (1.19–1.4)	1.3 (1.2–1.41)
Pneumonia	1.28 (1.21–1.36)	1.17 (1.1–1.26)	1.16 (1.08–1.25)	1.17 (1.09–1.26)
Pneumonia requiring MV	1.38 (1.25–1.52)	1.25 (1.13–1.39)	1.21 (1.07–1.36)	1.21 (1.08–1.37)
As-treated analysis + competing risk
Mortality
Pneumonia	1.07 (1.01–1.13)	1.06 (1–1.12)	1.07 (1–1.15)	1.08 (1.01–1.15)
Pneumonia requiring MV	1.01 (0.96–1.07)	1.03 (0.97–1.1)	1.04 (0.98–1.12)	1.04 (0.97–1.12)

Note:

a Adjusted for propensity score.

Abbreviations: HR, hazard ratio; ITT, intention-to-treat; MV, mechanical ventilation.