Tiotropium HandiHaler^® and Respimat^® in COPD: a pooled safety analysis

Figures & data

Table 1 Clinical trials included in the pooled analysis

NCT trial number and/or publication	Boehringer Ingelheim trial number	Treatment duration (weeks)	Placebo (number of patients treated)	Tiotropium (number of patients treated)
HandiHaler^®			8,343	9,647
Casaburi et al^Citation3,a	205.114/117	49	191	279
Casaburi et al^Citation3,a	205.115/128	49	180	271
Calverley et al^Citation43,a	205.123	6	40	81
McNicholas et al^Citation44,a	205.124	4	30	65
Brusasco et al^Citation2,a and Donohue et al^Citation45,a	205.130	24	201	209
O’Donnell^Citation46,a	205.131	6	100	98
Brusasco et al^Citation2,a	205.137	24	199	193
NCT0274014^Citation7 a	205.214	48	510	500
Verkindre et al^Citation47,a	205.215	12	54	46
Celli et al^Citation48,a	205.218	4	41	40
NCT0274508^Citation49,a	205.223	6	130	131
NCT0274521^Citation50,a	205.230	25	53	55
NCT0144339^Citation5,a	205.235	206	3,006	2,986
NCT0157235^Citation51,a	205.247	25	117	117
NCT0274053^Citation52,a	205.256	38	288	266
NCT0274573^Citation53,a	205.257	12	403	1,236
NCT0277264^Citation54,a	205.259	48	305	608
NCT0274547^Citation9,a	205.266	26	915	914
NCT0144326^Citation55,a	205.269	12	127	123
NCT0405236^Citation55,a	205.270	52	73	69
NCT0274079^Citation56,a	205.276	12	195	200
NCT0144196^Citation57,a	205.281	12	117	107
NCT0239408^Citation58,a	205.282	12	164	147
NCT0239460^Citation59,a	205.284	12	96	100
NCT0106821^Citation60,a	205.294	8	86	80
NCT0152984^Citation61,a	205.301	12	244	228
NCT0523991^Citation62	205.365	24	219	238
NCT0525512^Citation63	205.368	96	259	260
Respimat^®			3,283	3,282
NCT0239473^Citation35	205.251	12	91	88
NCT0240435^Citation35	205.252	12	90	92
NCT0168844^Citation36	205.254	48	319	332
NCT0168831^Citation36	205.255	48	334	338
NCT0387088^Citation12	205.372	48	1,965	1,952
NCT0122434^Citation64	1,205.4	4	55	53
NCT0528996^Citation65	1,205.14	24	429	427
Total			11,626	12,929

Note:

a Studies included in Kesten et al²⁶ meta-analysis.

Abbreviations: BI, Boehringer Ingelheim; NCT, National Clinical Trials (clinicaltrials.gov) identifier number.

Table 2 Patient baseline characteristics

Characteristics	HandiHaler^®		Respimat^®		Total
	Placebo n=8,343	Tiotropium n=9,647	Placebo n=3,283	Tiotropium n=3,282	Placebo n=11,626	Tiotropium n=12,929
Age, mean (SD), years	64.63 (8.90)	64.38 (8.76)	64.73 (8.85)	64.64 (8.94)	64.66 (8.89)	64.45 (8.80)
Male, n (%)	6,327 (75.8)	7,315 (75.8)	2,429 (74.0)	2,451 (74.7)	8,756 (75.3)	9,766 (75.5)
Current smoker, n (%)	2,809 (33.7)	3,329 (34.5)	1,238 (37.7)	1,233 (37.6)	4,047 (34.8)	4,562 (35.3)
Baseline spirometry, mean prebronchodilator (SD)
FEV1, L	1.17 (0.46)	1.18 (0.47)	1.11 (0.41)	1.11 (0.41)	1.15 (0.45)	1.16 (0.46)
FEV1, % predicted	41.22 (14.20)	41.66 (14.43)	40.30 (12.45)	40.11 (12.32)	40.96 (13.73)	41.27 (13.94)
FVC, L	2.51 (0.82)	2.49 (0.82)	2.45 (0.79)	2.45 (0.78)	2.49 (0.81)	2.48 (0.81)
FEV1/FVC	0.47 (0.12)	0.48 (0.13)	0.46 (0.11)	0.46 (0.11)	0.47 (0.12)	0.48 (0.12)
Baseline concomitant medicationa, n (%)
Any respiratory medication	7,057 (84.6)	8,021 (83.1)	2,767 (84.3)	2,784 (84.8)	9,824 (84.5)	10,805 (83.6)
SAMA	3,295 (39.5)	3,709 (38.4)	982 (29.9)	1,040 (31.7)	4,277 (36.8)	4,749 (36.7)
LAMA	150 (1.8)	150 (1.6)	325 (9.9)	313 (9.5)	475 (4.1)	463 (3.6)
β2 agonists	6,199 (74.3)	6,789 (70.4)	2,440 (74.3)	2,469 (75.2)	8,639 (74.3)	9,258 (71.6)
Short acting	5,044 (60.5)	5,630 (58.4)	1,816 (55.3)	1,815 (55.3)	6,860 (59.0)	7,445 (57.6)
Long acting	3,340 (40.0)	3,520 (36.5)	1,538 (46.8)	1,597 (48.7)	4,878 (42.0)	5,117 (39.6)
Steroids	4,731 (56.7)	5,379 (55.8)	1,844 (56.2)	1,821 (55.5)	6,575 (56.6)	7,200 (55.7)
ICS	4,564 (54.7)	5,184 (53.7)	1,807 (55.0)	1,785 (54.4)	6,371 (54.8)	6,969 (53.9)
OCS	547 (6.6)	635 (6.6)	100 (3.0)	100 (3.0)	647 (5.6)	735 (5.7)
ICS+LABA	2,687 (32.2)	2,904 (30.1)	1,358 (41.4)	1,395 (42.5)	4,045 (34.8)	4,299 (33.3)
Xanthines	1,705 (20.4)	2,103 (21.8)	638 (19.4)	667 (20.3)	2,343 (20.2)	2,770 (21.4)
Oxygen	399 (4.8)	414 (4.3)	63 (1.9)	54 (1.6)	462 (4.0)	468 (3.6)
Mucolytics	411 (4.9)	473 (4.9)	228 (6.9)	237 (7.2)	639 (5.5)	710 (5.5)
Other respiratory medication	178 (2.1)	196 (2.0)	35 (1.1)	46 (1.4)	213 (1.8)	242 (1.9)
Any CV medication	4,599 (55.1)	5,283 (54.8)	1,690 (51.5)	1,723 (52.5)	6,289 (54.1)	7,006 (54.2)
Cardiac disorder presentb, n (%)	2,048 (25.8)	2,257 (26.8)	852 (26.0)	891 (27.1)	2,900 (25.8)	3,148 (26.9)
Cardiac arrhythmia presentb, n (%)	611 (7.7)	719 (8.5)	350 (10.7)	428 (13.0)	961 (8.6)	1,147 (9.8)
Renal disorder presentb,c, n (%)	127 (1.6)	151 (1.8)	54 (1.6)	68 (2.1)	181 (1.6)	219 (1.9)

Notes:

a Includes patients with combination therapy.

b Excluded study 205.257, for which diagnoses could not be mapped.

c Listed as concomitant disease (any comorbidity at baseline coded to renal and/or urinary disorders).

Abbreviations: CV, cardiovascular; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity, ICS, inhaled corticosteroid; LABA, long-acting β₂ agonist; LAMA, long-acting muscarinic antagonist; OCS, oral corticosteroid; SAMA, short-acting muscarinic antagonist; SD, standard deviation.

Table 3 IRs (per 100 patient-years) and RRs for all AEs, by subgroup

	HandiHaler^®					Respimat^®					Total
	Placebo		Tiotropium		RR (95% CI)	Placebo		Tiotropium		RR (95% CI)	Placebo		Tiotropium		RR (95% CI)
	n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR
Total	n=8,343		n=9,647			n=3,283		n=3,282			n=11,626		n=12,929
AEs	5,362 (64.3)	143.76	5,850 (60.6)	131.53	0.88 (0.85, 0.91)a	2,257 (68.7)	179.86	2,243 (68.3)	170.10	0.94 (0.89, 0.99)a	7,619 (65.5)	152.85	8,093 (62.6)	140.35	0.90 (0.87, 0.93)a
SAEs	2,158 (25.9)	23.67	2,311 (24.0)	22.28	0.94 (0.89, 1.00)a	496 (15.1)	20.81	491 (15.0)	19.48	0.94 (0.83, 1.06)	2,654 (22.8)	23.08	2,802 (21.7)	21.73	0.94 (0.89, 0.99)a
FAEs	478 (5.7)	4.15	451 (4.7)	3.46	0.85 (0.75, 0.97)a	45 (1.4)	1.75	64 (2.0)	2.37	1.37 (0.93, 2.00)	523 (4.5)	3.71	515 (4.0)	3.27	0.90 (0.79, 1.01)
Cardiac disorder presentb	n=2,048		n=2,257			n=852		n=891			n=2,900		n=3,148
AEs	1,390 (67.9)	161.25	1,547 (68.5)	152.15	0.88 (0.81, 0.94)a	607 (71.2)	196.11	649 (72.8)	202.38	1.05 (0.94, 1.17)	1,997 (68.9)	170.46	2,196 (69.8)	164.20	0.93 (0.87, 0.98)a
SAEs	715 (34.9)	35.09	755 (33.5)	31.29	0.90 (0.81, 1.00)a	164 (19.2)	27.37	184 (20.7)	27.82	1.01 (0.82, 1.25)	879 (30.3)	33.34	939 (29.8)	30.54	0.92 (0.84, 1.01)
FAEs	165 (8.1)	5.87	149 (6.6)	4.46	0.77 (0.62, 0.96)a	17 (2.0)	2.57	29 (3.3)	4.01	1.56 (0.86, 2.84)	182 (6.3)	5.24	178 (5.7)	4.38	0.84 (0.69, 1.04)
Cardiac arrhythmia presentb,c	n=611		n=719			n=350		n=428			n=961		n=1,147
AEs	406 (66.4)	182.17	497 (69.1)	177.44		256 (73.1)	212.44	320 (74.8)	211.69	1.01 (0.86, 1.19)	662 (68.9)	192.80	817 (71.2)	189.44
SAEs	199 (32.6)	38.74	219 (30.5)	31.75		69 (19.7)	28.00	94 (22.0)	29.72	1.05 (0.77, 1.44)	268 (27.9)	35.26	313 (27.3)	31.11
FAEs	49 (8.0)	6.80	49 (6.8)	5.24		5 (1.4)	1.83	21 (4.9)	6.08	3.25 (1.23, 8.60)a	54 (5.6)	5.44	70 (6.1)	5.47
Renal disorder presentb,c	n=127		n=151			n=54		n=68			n=181		n=219
AEs	92 (72.4)	198.94	111 (73.5)	191.13		41 (75.9)	229.72	51 (75.0)	284.70		133 (73.5)	207.51	162 (74.0)	213.19
SAEs	52 (40.9)	41.36	63 (41.7)	40.79		12 (22.2)	34.19	18 (26.5)	41.23		64 (35.4)	39.80	81 (37.0)	40.89
FAEs	7 (5.5)	3.35	13 (8.6)	5.79		0 (0.0)	0.00	3 (4.4)	6.10		7 (3.9)	2.81	16 (7.3)	5.85

Notes:

a Significantly different from 1.

b Excluded study 205.257, for which diagnoses could not be mapped.

c For the subgroups, there is at least one trial with patients in only one treatment group, thus no statistics are derived (no RR shown for the subgroups).

Abbreviations: AE, adverse event; CI, confidence interval; FAE, fatal adverse event; IR, incidence rate; RR, rate ratio; SAE, serious adverse event.

Table 4 IRs (per 100 patient-years) and RRs for cardiac, vascular, and respiratory AEs

	HandiHaler^®					Respimat^®					Total
	Placebo n=8,343		Tiotropium n=9,647		RR (95% CI)	Placebo n=3,283		Tiotropium n=3,282		RR (95% CI)	Placebo n=11,626		Tiotropium n=12,929		RR (95% CI)
	n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR
Cardiac disordersa	778 (9.3)	7.22	785 (8.1)	6.40	0.89 (0.80, 0.98)b	183 (5.6)	7.31	217 (6.6)	8.25	1.13 (0.93, 1.38)	961 (8.3)	7.24	1,002 (7.8)	6.73	0.93 (0.85, 1.02)
AF/flutterc	145 (1.7)	1.26	147 (1.5)	1.13	0.91 (0.72, 1.14)	24 (0.7)	0.93	22 (0.7)	0.82	0.86 (0.48, 1.54)	169 (1.5)	1.20	169 (1.3)	1.07	0.90 (0.73, 1.12)
Cardiac arrestc	31 (0.4)	0.27	23 (0.2)	0.17	0.68 (0.40, 1.17)	3 (0.1)	0.12	7 (0.2)	0.26	2.28 (0.59, 8.81)	34 (0.3)	0.24	30 (0.2)	0.19	0.82 (0.50, 1.34)
Cardiac failured	256 (3.1)	2.24	231 (2.4)	1.77	0.80 (0.67, 0.96)b	40 (1.2)	1.56	38 (1.2)	1.41	0.90 (0.58, 1.41)	296 (2.5)	2.12	269 (2.1)	1.71	0.81 (0.69, 0.96)b
Ischemic heart diseasee	215 (2.6)	1.89	225 (2.3)	1.75	0.92 (0.76, 1.11)	32 (1.0)	1.25	54 (1.6)	2.01	1.61 (1.04, 2.49)b	247 (2.1)	1.77	279 (2.2)	1.79	1.01 (0.85, 1.19)
MIf	114 (1.4)	0.99	112 (1.2)	0.85	0.87 (0.67, 1.14)	21 (0.6)	0.82	16 (0.5)	0.59	0.73 (0.38, 1.39)	135 (1.2)	0.95	128 (1.0)	0.81	0.85 (0.67, 1.09)
Palpitationsc	59 (0.7)	0.51	74 (0.8)	0.56	1.09 (0.77, 1.55)	29 (0.9)	1.13	40 (1.2)	1.49	1.33 (0.82, 2.14)	88 (0.8)	0.62	114 (0.9)	0.72	1.17 (0.88, 1.55)
Supraventricular tachycardiac	27 (0.3)	0.23	32 (0.3)	0.24	1.06 (0.64, 1.78)	21 (0.6)	0.82	16 (0.5)	0.59	0.73 (0.38, 1.39)	48 (0.4)	0.34	48 (0.4)	0.30	0.92 (0.61, 1.37)
Tachycardiac	52 (0.6)	0.45	64 (0.7)	0.49	1.05 (0.73, 1.53)	27 (0.8)	1.05	18 (0.5)	0.67	0.64 (0.35, 1.17)	79 (0.7)	0.56	82 (0.6)	0.52	0.92 (0.67, 1.25)
Ventricular tachycardia/fibrillationc	27 (0.3)	0.23	19 (0.2)	0.14	0.64 (0.35, 1.16)	2 (0.1)	0.08	3 (0.1)	0.11	1.39 (0.24, 8.26)	29 (0.2)	0.20	22 (0.2)	0.14	0.69 (0.40, 1.21)
Vascular disordersa	610 (7.3)	5.65	670 (6.9)	5.48	0.98 (0.88, 1.09)	128 (3.9)	5.09	122 (3.7)	4.60	0.90 (0.70, 1.15)	738 (6.3)	5.54	792 (6.1)	5.32	0.96 (0.87, 1.07)
Aneurysmc	41 (0.5)	0.35	53 (0.5)	0.40	1.16 (0.77, 1.75)	5 (0.2)	0.19	7 (0.2)	0.26	1.32 (0.42, 4.13)	46 (0.4)	0.32	60 (0.5)	0.38	1.18 (0.80, 1.74)
Hypertensionc	386 (4.6)	3.49	393 (4.1)	3.12	0.89 (0.77, 1.03)	81 (2.5)	3.20	97 (3.0)	3.65	1.14 (0.85, 1.53)	467 (4.0)	3.43	490 (3.8)	3.21	0.93 (0.82, 1.06)
Strokec	96 (1.2)	0.83	114 (1.2)	0.87	1.07 (0.81, 1.41)	17 (0.5)	0.66	13 (0.4)	0.48	0.73 (0.35, 1.49)	113 (1.0)	0.80	127 (1.0)	0.80	1.02 (0.79, 1.32)
Respiratory, thoracic, and mediastinal disordersa	3,676 (44.1)	60.44	3,786 (39.2)	51.15	0.81 (0.78, 0.85)b	1,490 (45.4)	83.64	1,346 (41.0)	68.38	0.82 (0.76, 0.88)b	5,166 (44.4)	65.69	5,132 (39.7)	54.77	0.81 (0.78, 0.85)b
COPD exacerbationc	2,951 (35.4)	42.70	2,907 (30.1)	34.48	0.80 (0.76, 0.84)b	1,147 (34.9)	57.82	949 (28.9)	42.84	0.74 (0.68, 0.80)b	4,098 (35.2)	46.07	3,856 (29.8)	36.22	0.78 (0.75, 0.81)b
Pneumoniac	543 (6.5)	4.92	591 (6.1)	4.74	0.95 (0.84, 1.07)	100 (3.0)	3.94	99 (3.0)	3.71	0.95 (0.72, 1.25)	643 (5.5)	4.74	690 (5.3)	4.56	0.95 (0.85, 1.06)
Respiratory failurec	215 (2.6)	1.87	189 (2.0)	1.45	0.80 (0.66, 0.97)b	28 (0.9)	1.09	26 (0.8)	0.96	0.89 (0.52, 1.52)	243 (2.1)	1.73	215 (1.7)	1.36	0.81 (0.67, 0.97)b

Notes:

a Primary SOC.

b Significantly different from 1.

c PV endpoint (see Table S1 for details).

d SMQ cardiac failure (narrow).

e SMQ ischemic heart disease sub-SMQ other ischemic heart disease (broad).

f SMQ ischemic heart disease sub-SMQ MI (broad).

Abbreviations: AE, adverse event; AF, atrial fibrillation; CI, confidence interval; COPD, chronic obstructive pulmonary disease; IR, incidence rate; MI, myocardial infarction; PV, pharmacovigilance; RR, rate ratio; SMQ, standardized Medical Dictionary for Regulatory Activities queries; SOC, system organ class.

Table 5 IRs (per 100 patient-years) and RRs for cardiac, vascular, and respiratory SAEs

	HandiHaler^®					Respimat^®					Total
	Placebo n=8,343		Tiotropium n=9,647		RR (95% CI)	Placebo n=3,283		Tiotropium n=3,282		RR (95% CI)	Placebo n=11,626		Tiotropium n=12,929		RR (95% CI)
	n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR
Cardiac disordersa	477 (5.7)	4.25	441 (4.6)	3.45	0.81 (0.71, 0.93)b	69 (2.1)	2.70	84 (2.6)	3.13	1.16 (0.84, 1.59)	546 (4.7)	3.96	525 (4.1)	3.39	0.86 (0.76, 0.97)b
AF/flutterc	85 (1.0)	0.73	82 (0.9)	0.62	0.86 (0.64, 1.17)	6 (0.2)	0.23	8 (0.2)	0.30	1.23 (0.43, 3.57)	91 (0.8)	0.64	90 (0.7)	0.57	0.89 (0.66, 1.19)
Cardiac arrestc	30 (0.4)	0.26	23 (0.2)	0.17	0.71 (0.41, 1.22)	3 (0.1)	0.12	7 (0.2)	0.26	2.28 (0.59, 8.81)	33 (0.3)	0.23	30 (0.2)	0.19	0.85 (0.52, 1.39)
Cardiac failured	170 (2.0)	1.47	157 (1.6)	1.20	0.82 (0.66, 1.02)	28 (0.9)	1.09	28 (0.9)	1.04	0.95 (0.56, 1.61)	198 (1.7)	1.40	185 (1.4)	1.17	0.84 (0.68, 1.02)
Ischemic heart diseasee	119 (1.4)	1.03	108 (1.1)	0.83	0.80 (0.61, 1.03)	15 (0.5)	0.58	20 (0.6)	0.74	1.27 (0.65, 2.49)	134 (1.2)	0.95	128 (1.0)	0.81	0.85 (0.67, 1.08)
MIf	106 (1.3)	0.92	105 (1.1)	0.80	0.88 (0.67, 1.16)	18 (0.5)	0.70	16 (0.5)	0.59	0.84 (0.43, 1.65)	124 (1.1)	0.88	121 (0.9)	0.76	0.87 (0.68, 1.13)
Palpitationsc	5 (0.1)	0.04	7 (0.1)	0.05	1.20 (0.37, 3.89)	1 (0.0)	0.04	1 (0.0)	0.04	0.98 (0.06, 15.68)	6 (0.1)	0.04	8 (0.1)	0.05	1.16 (0.39, 3.44)
Supraventricular tachycardiac	13 (0.2)	0.11	15 (0.2)	0.11	1.05 (0.50, 2.23)	2 (0.1)	0.08	2 (0.1)	0.07	0.95 (0.14, 6.53)	15 (0.1)	0.11	17 (0.1)	0.11	1.04 (0.52, 2.09)
Tachycardiac	6 (0.1)	0.05	7 (0.1)	0.05	0.89 (0.28, 2.88)	1 (0.0)	0.04	2 (0.1)	0.07	1.96 (0.18, 21.62)	7 (0.1)	0.05	9 (0.1)	0.06	1.04 (0.37, 2.95)
Ventricular tachycardia/fibrillationc	21 (0.3)	0.18	17 (0.2)	0.13	0.73 (0.38, 1.39)	0 (0.0)	0.00	1 (0.0)	0.04		21 (0.2)	0.15	18 (0.1)	0.11	0.78 (0.41, 1.46)
Vascular disordersa	126 (1.5)	1.09	155 (1.6)	1.19	1.12 (0.88, 1.41)	17 (0.5)	0.66	10 (0.3)	0.37	0.56 (0.26, 1.23)	143 (1.2)	1.01	165 (1.3)	1.05	1.05 (0.84, 1.32)
Aneurysmc	28 (0.3)	0.24	33 (0.3)	0.25	1.07 (0.65, 1.77)	3 (0.1)	0.12	2 (0.1)	0.07	0.64 (0.11, 3.75)	31 (0.3)	0.22	35 (0.3)	0.22	1.03 (0.63, 1.67)
Hypertensionc	23 (0.3)	0.20	17 (0.2)	0.13	0.67 (0.36, 1.25)	0 (0.0)	0.00	3 (0.1)	0.11		23 (0.2)	0.16	20 (0.2)	0.13	0.79 (0.44, 1.44)
Strokec	76 (0.9)	0.66	94 (1.0)	0.72	1.12 (0.83, 1.52)	13 (0.4)	0.51	10 (0.3)	0.37	0.74 (0.33, 1.68)	89 (0.8)	0.63	104 (0.8)	0.66	1.07 (0.80, 1.42)
Respiratory, thoracic, and mediastinal disordersa	1,161 (13.9)	11.20	1,123 (11.6)	9.40	0.84 (0.77, 0.91)b	245 (7.5)	9.85	224 (6.8)	8.53	0.87 (0.73, 1.04)	1,406 (12.1)	10.94	1,347 (10.4)	9.25	0.84 (0.78, 0.91)b
COPD exacerbationc	971 (11.6)	9.22	944 (9.8)	7.81	0.84 (0.77, 0.92)b	220 (6.7)	8.82	180 (5.5)	6.83	0.78 (0.64, 0.95)b	1,191 (10.2)	9.15	1,124 (8.7)	7.63	0.83 (0.76, 0.90)b
Pneumoniac	382 (4.6)	3.38	402 (4.2)	3.15	0.92 (0.80, 1.06)	64 (1.9)	2.50	54 (1.6)	2.01	0.81 (0.56, 1.16)	446 (3.8)	3.22	456 (3.5)	2.95	0.91 (0.80, 1.03)
Respiratory failurec	192 (2.3)	1.67	162 (1.7)	1.24	0.77 (0.62, 0.95)b	23 (0.7)	0.89	19 (0.6)	0.70	0.80 (0.43, 1.46)	215 (1.8)	1.52	181 (1.4)	1.14	0.77 (0.63, 0.94)b

Notes:

a Primary SOC.

b Significantly different from 1.

c PV endpoint (see Table S1 for details).

d SMQ cardiac failure (narrow).

e SMQ ischemic heart disease sub-SMQ other ischemic heart disease (broad).

f SMQ ischemic heart disease sub-SMQ myocardial infarction (broad).

Abbreviations: AF, atrial fibrillation; CI, confidence interval; COPD, chronic obstructive pulmonary disease; IR, incidence rate; MI, myocardial infarction; PV, pharmacovigilance; RR, rate ratio; SAE, serious adverse event; SMQ, standardized Medical Dictionary for Regulatory Activities queries; SOC, system organ class.

Table 6 IRs (per 100 patient-years) and RRs for MACE, by inhaler type

	HandiHaler^®					Respimat^®					Total
	Placebo n=8,343		Tiotropium n=9,647		RR (95% CI)	Placebo n=3,283		Tiotropium n=3,282		RR (95% CI)	Placebo n=11,626		Tiotropium n=12,929		RR (95% CI)
	n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR
MACE	309 (3.7)	2.71	299 (3.1)	2.31	0.86 (0.74, 1.01)	49 (1.5)	1.91	46 (1.4)	1.71	0.90 (0.60, 1.34)	358 (3.1)	2.56	345 (2.7)	2.20	0.87 (0.75, 1.01)
Fatal MACEa	174 (2.1)	1.50	159 (1.6)	1.21	0.82 (0.66, 1.02)	18 (0.5)	0.70	31 (0.9)	1.15	1.66 (0.93, 2.96)	192 (1.7)	1.35	190 (1.5)	1.20	0.90 (0.74, 1.10)

Notes:

a Including death unknown. Fatal MACE includes the following terms: cardiac SOC (fatal) or vascular SOC (fatal) or SMQ ischemic heart disease sub-SMQ myocardial infarction (broad) (fatal) or stroke #PV (fatal) or sudden death PT or cardiac death PT or sudden cardiac death PT or death PT.

Abbreviations: CI, confidence interval; IR, incidence rate; MACE, major adverse cardiovascular event; PT, preferred term; PV, pharmacovigilance; RR, rate ratio; SMQ, standardized Medical Dictionary for Regulatory Activities queries; SOC, system organ class.

Table 7 IRs (per 100 patient-years) and RRs for potential anticholinergic AEs

	Placebo n=11,626		Tiotropium n=12,929		RR (95% CI)
	n (%)	IR	n (%)	IR
Eye disordersa	418 (3.6)	3.05	471 (3.6)	3.09	1.01 (0.88, 1.15)
Glaucomab	38 (0.3)	0.27	41 (0.3)	0.26	0.97 (0.62, 1.52)
Vision blurredc	67 (0.6)	0.47	62 (0.5)	0.39	0.80 (0.57, 1.14)
Gastrointestinal disordersa	1,569 (13.5)	12.65	2,082 (16.1)	15.58	1.20 (1.13, 1.29)d
Abdominal painc	206 (1.8)	1.47	246 (1.9)	1.57	1.04 (0.86, 1.25)
Constipationc	185 (1.6)	1.32	264 (2.0)	1.69	1.28 (1.06, 1.54)d
Dry mouthc	196 (1.7)	1.40	519 (4.0)	3.39	2.35 (1.99, 2.77)d
Dyspepsiac	376 (3.2)	2.73	515 (4.0)	3.38	1.21 (1.06, 1.38)d
Dysphagiac	24 (0.2)	0.17	33 (0.3)	0.21	1.21 (0.71, 2.08)
Gastroesophageal reflux diseasec	261 (2.2)	1.87	374 (2.9)	2.42	1.25 (1.06, 1.46)d
Gastrointestinal obstructione	33 (0.3)	0.23	64 (0.5)	0.40	1.76 (1.16, 2.69)d
Stomatitisc	36 (0.3)	0.25	49 (0.4)	0.31	1.12 (0.73, 1.73)
Metabolism and nutrition disordersa	639 (5.5)	4.76	663 (5.1)	4.41	0.92 (0.83, 1.03)
Dehydrationc	32 (0.3)	0.22	40 (0.3)	0.25	1.14 (0.71, 1.82)
Hyperglycemia/new-onset diabetes mellitusf	212 (1.8)	1.52	225 (1.7)	1.44	0.94 (0.78, 1.13)
Nervous system disordersa	1,051 (9.0)	8.02	1,233 (9.5)	8.51	1.02 (0.94, 1.11)
Dizzinessc	280 (2.4)	2.01	333 (2.6)	2.15	1.03 (0.88, 1.21)
Headachec	398 (3.4)	2.88	475 (3.7)	3.09	1.00 (0.88, 1.14)
Sleep disturbancec	204 (1.8)	1.46	242 (1.9)	1.55	1.05 (0.87, 1.26)
Syncopec	72 (0.6)	0.51	85 (0.7)	0.54	1.06 (0.77, 1.45)
Psychiatric disordersa	533 (4.6)	3.90	615 (4.8)	4.06	1.01 (0.90, 1.14)
Anxiety symptoms/fearsc	194 (1.7)	1.38	203 (1.6)	1.29	0.89 (0.73, 1.09)
Cognitive impairmentc	2 (0.0)	0.01	1 (0.0)	0.01	0.46 (0.04, 5.09)
Confusionc	22 (0.2)	0.15	18 (0.1)	0.11	0.70 (0.37, 1.31)
Insomniac	184 (1.6)	1.31	227 (1.8)	1.45	1.10 (0.90, 1.34)
Restlessnessc	13 (0.1)	0.09	12 (0.1)	0.08	0.65 (0.29, 1.46)
Depression and self-injuryg	173 (1.5)	1.23	209 (1.6)	1.33	1.08 (0.88, 1.32)
Renal and urinary disordersa	341 (2.9)	2.46	396 (3.1)	2.56	1.04 (0.90, 1.20)
Dysuriac	23 (0.2)	0.16	52 (0.4)	0.33	2.07 (1.26, 3.39)d
Renal failurec	68 (0.6)	0.48	73 (0.6)	0.46	0.97 (0.70, 1.36)
Urinary retentionc	36 (0.3)	0.25	62 (0.5)	0.39	1.56 (1.03, 2.36)d
Urinary tract infectionc	287 (2.5)	2.06	350 (2.7)	2.26	1.08 (0.92, 1.26)

Notes:

a Primary SOC.

b SMQ glaucoma (narrow).

c PV endpoint (see Table S1 for details).

d Significantly different from 1.

e SMQ gastrointestinal perforation, ulceration, hemorrhage, or obstruction.

f SMQ hyperglycemia/new-onset diabetes mellitus (narrow).

g SMQ depression and self-injury (excluding suicide and self-injury) (narrow).

Abbreviations: AE, adverse event; CI, confidence interval; IR, incidence rate; PV, pharmacovigilance; RR, rate ratio; SMQ, standardized Medical Dictionary for Regulatory Activities queries; SOC, system organ class.

Table 8 IRs (per 100 patient-years) and RRs for potential anticholinergic SAEs

	Placebo n=11,626		Tiotropium n=12,929		RR (95% CI)
	n (%)	IR	n (%)	IR
Eye disordersa	33 (0.3)	0.23	38 (0.3)	0.24	1.07 (0.67, 1.71)
Glaucomab	1 (0.0)	0.01	2 (0.0)	0.01	1.85 (0.17, 20.37)
Vision blurredc	1 (0.0)	0.01	1 (0.0)	0.01	0.92 (0.06, 14.77)
Gastrointestinal disordersa	266 (2.3)	1.90	284 (2.2)	1.82	0.96 (0.81, 1.14)
Abdominal painc	28 (0.2)	0.20	30 (0.2)	0.19	0.94 (0.56, 1.57)
Constipationc	5 (0.0)	0.04	7 (0.1)	0.04	1.28 (0.40, 4.08)
Dyspepsiac	28 (0.2)	0.20	26 (0.2)	0.16	0.86 (0.50, 1.47)
Dysphagiac	4 (0.0)	0.03	5 (0.0)	0.03	1.12 (0.30, 4.24)
Gastroesophageal reflux diseasec	14 (0.1)	0.10	16 (0.1)	0.10	1.06 (0.51, 2.19)
Gastrointestinal obstructiond	27 (0.2)	0.19	45 (0.3)	0.28	1.51 (0.93, 2.44)
Stomatitisc	0 (0.0)	0.00	2 (0.0)	0.01
Metabolism and nutrition disordersa	77 (0.7)	0.54	71 (0.5)	0.45	0.82 (0.59, 1.13)
Dehydrationc	12 (0.1)	0.08	20 (0.2)	0.13	1.47 (0.71, 3.07)
Hyperglycemia/new-onset diabetes mellituse	22 (0.2)	0.15	29 (0.2)	0.18	1.14 (0.65, 2.00)
Nervous system disordersa	205 (1.8)	1.46	222 (1.7)	1.41	0.98 (0.81, 1.19)
Dizzinessc	26 (0.2)	0.18	23 (0.2)	0.14	0.82 (0.47, 1.43)
Headachec	5 (0.0)	0.04	5 (0.0)	0.03	0.93 (0.27, 3.20)
Sleep disturbancec	5 (0.0)	0.04	0 (0.0)	0.00	0.00
Syncopec	23 (0.2)	0.16	40 (0.3)	0.25	1.57 (0.94, 2.64)
Psychiatric disordersa	58 (0.5)	0.41	46 (0.4)	0.29	0.71 (0.48, 1.04)
Anxiety symptoms/fearsc	10 (0.1)	0.07	7 (0.1)	0.04	0.62 (0.23, 1.63)
Confusionc	5 (0.0)	0.04	5 (0.0)	0.03	0.93 (0.27, 3.27)
Insomniac	1 (0.0)	0.01	0 (0.0)	0.00	0.00
Restlessnessc	2 (0.0)	0.01	0 (0.0)	0.00	0.00
Depression and self-injuryf	20 (0.2)	0.14	15 (0.1)	0.09	0.68 (0.35, 1.31)
Renal and urinary disordersa	84 (0.7)	0.59	108 (0.8)	0.68	1.16 (0.87, 1.55)
Dysuriac	0 (0.0)	0.00	3 (0.0)	0.02
Renal failurec	32 (0.3)	0.22	46 (0.4)	0.29	1.31 (0.83, 2.06)
Urinary retentionc	12 (0.1)	0.08	24 (0.2)	0.15	1.87 (0.93, 3.73)
Urinary tract infectionc	28 (0.2)	0.20	37 (0.3)	0.23	1.19 (0.73, 1.95)

Notes:

a Primary SOC.

b SMQ glaucoma (narrow).

c PV endpoint (see Table S1 for details).

d SMQ gastrointestinal perforation, ulceration, hemorrhage, or obstruction.

e SMQ hyperglycemia/new-onset diabetes mellitus (narrow).

f SMQ depression and self-injury (excluding suicide and self-injury) (narrow).

Abbreviations: IR, incidence rate; PV, pharmacovigilance; RR, rate ratio; SAE, serious adverse event; SMQ, standardized Medical Dictionary for Regulatory Activities queries; SOC, system organ class.

Figure 1 Number of events, time at risk, and RRs for all-cause FAEs.

Notes: *Studies included in Kesten et al²⁶ meta-analysis; **RR could not be calculated for studies where 0 events occurred in one or both treatment groups.
Abbreviations: BI, Boehringer Ingelheim; CI, confidence interval; FAE, fatal adverse event; RR, rate ratio.

Table 9 IRs (per 100 patient-years) and RRs for FAEs according to SOC and PTa

	HandiHaler^®					Respimat^®					Total
	Placebo n=8,343		Tiotropium n=9,647		RR (95% CI)	Placebo n=3,283		Tiotropium n=3,282		RR (95% CI)	Placebo n=11,626		Tiotropium n=12,929		RR (95% CI)
	n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR		n (%)	IR	n (%)	IR
Respiratory, thoracic, and mediastinal disorders	143 (1.7)	1.23	118 (1.2)	0.90	0.74 (0.58, 0.95)b	16 (0.5)	0.62	16 (0.5)	0.59	0.96 (0.48, 1.92)	159 (1.4)	1.12	134 (1.0)	0.84	0.76 (0.61, 0.96)b
COPD	67 (0.8)	0.57	61 (0.6)	0.46	0.82 (0.58, 1.16)	4 (0.1)	0.16	8 (0.2)	0.30	1.88 (0.56, 6.28)	71 (0.6)	0.50	69 (0.5)	0.43	0.88 (0.63, 1.22)
Respiratory failure	51 (0.6)	0.44	33 (0.3)	0.25	0.59 (0.38, 0.91)b	5 (0.2)	0.19	2 (0.1)	0.07	0.37 (0.07, 1.99)	56 (0.5)	0.39	35 (0.3)	0.22	0.57 (0.37, 0.87)b
Acute respiratory failure	8 (0.1)	0.07	8 (0.1)	0.06	0.92 (0.35, 2.46)	2 (0.1)	0.08	0 (0.0)	0.00	0	10 (0.1)	0.07	8 (0.1)	0.05	0.74 (0.29, 1.89)
Neoplasms benign, malignant, and unspecified	118 (1.4)	1.01	117 (1.2)	0.89	0.91 (0.70, 1.17)	5 (0.2)	0.19	8 (0.2)	0.30	1.53 (0.50, 4.68)	123 (1.1)	0.87	125 (1.0)	0.79	0.93 (0.73, 1.20)
Lung neoplasm malignant	19 (0.2)	0.16	21 (0.2)	0.16	1.00 (0.54, 1.85)	2 (0.1)	0.08	4 (0.1)	0.15	1.92 (0.35, 10.59)	21 (0.2)	0.15	25 (0.2)	0.16	1.09 (0.61, 1.93)
Cardiac disorders	106 (1.3)	0.91	89 (0.9)	0.67	0.75 (0.56, 0.99)b	12 (0.4)	0.47	23 (0.7)	0.85	1.86 (0.92, 3.75)	118 (1.0)	0.83	112 (0.9)	0.70	0.80 (0.66, 1.11)
Cardiac failure	10 (0.1)	0.09	14 (0.1)	0.11	1.25 (0.55, 2.83)	4 (0.1)	0.16	2 (0.1)	0.07	0.47 (0.08, 2.66)	14 (0.1)	0.10	16 (0.1)	0.10	1.04 (0.50, 2.14)
MI and acute MI	25 (0.3)	0.21	20 (0.2)	0.15	0.71 (0.39,1.30)	3 (0.1)	0.12	6 (0.2)	0.22	1.94 (0.48, 7.81)	28 (0.2)	0.20	26 (0.2)	0.16	0.84 (0.49, 1.45)
Cardiac arrest	17 (0.2)	0.15	10 (0.1)	0.08	0.53 (0.24,1.17)	2 (0.1)	0.08	2 (0.1)	0.07	0.98 (0.14, 6.90)	19 (0.2)	0.13	12 (0.1)	0.08	0.58 (0.28, 1.20)
Cardiopulmonary failure	8 (0.1)	0.07	9 (0.1)	0.07	1.00 (0.38, 2.63)	2 (0.1)	0.08	1 (0.0)	0.04	0.49 (0.04, 5.36)	10 (0.1)	0.07	10 (0.1)	0.06	0.90 (0.37, 2.19)
Cardiorespiratory arrest	6 (0.1)	0.05	7 (0.1)	0.05	1.09 (0.37, 3.23)	1 (0.0)	0.04	4 (0.1)	0.15	3.92 (0.44, 35.09)	7 (0.1)	0.05	11 (0.1)	0.07	1.49 (0.58, 3.81)
Cardiac failure congestive	10 (0.1)	0.09	6 (0.1)	0.05	0.51 (0.18, 1.45)	0 (0.0)	0.00	1 (0.0)	0.04		10 (0.1)	0.07	7 (0.1)	0.04	0.60 (0.22, 1.63)
Infections and infestations	63 (0.8)	0.54	61 (0.6)	0.46	0.88 (0.62, 1.26)	9 (0.3)	0.35	7 (0.2)	0.26	0.75 (0.28, 2.04)	72 (0.6)	0.51	68 (0.5)	0.43	0.87 (0.62, 1.21)
Pneumonia	26 (0.3)	0.22	26 (0.3)	0.20	0.91 (0.53, 1.57)	3 (0.1)	0.12	2 (0.1)	0.07	0.63 (0.10, 3.90)	29 (0.2)	0.20	28 (0.2)	0.18	0.89 (0.53, 1.49)
Sepsis	17 (0.2)	0.15	8 (0.1)	0.06	0.44 (0.19, 1.01)	1 (0.0)	0.04	0 (0.0)	0.00	0	18 (0.2)	0.13	8 (0.1)	0.05	0.41 (0.18, 0.95)b
Septic shock	8 (0.1)	0.07	6 (0.1)	0.05	0.69 (0.24, 2.00)	3 (0.1)	0.12	1 (0.0)	0.04	0.33 (0.03, 3.12)	11 (0.1)	0.08	7 (0.1)	0.04	0.59 (0.23, 1.54)
General disorders and admin­istration site conditions	55 (0.7)	0.47	60 (0.6)	0.45	1.00 (0.69, 1.44)	4 (0.1)	0.16	10 (0.3)	0.37	2.38 (0.76, 7.43)	59 (0.5)	0.41	70 (0.5)	0.44	1.09 (0.77, 1.54)
Death	28 (0.3)	0.24	37 (0.4)	0.28	1.20 (0.73, 1.97)	3 (0.1)	0.12	5 (0.2)	0.18	1.57 (0.39, 6.36)	31 (0.3)	0.22	42 (0.3)	0.26	1.24 (0.78, 1.97)
Sudden death	11 (0.1)	0.09	12 (0.1)	0.09	1.00 (0.44, 2.27)	1 (0.0)	0.04	2 (0.1)	0.07	1.96 (0.18, 21.63)	12 (0.1)	0.08	14 (0.1)	0.09	1.08 (0.50, 2.33)
Nervous system disorders	16 (0.2)	0.14	18 (0.2)	0.14	1.02 (0.52, 2.01)	1 (0.0)	0.04	1 (0.0)	0.04	0.92 (0.06, 13.48)	17 (0.1)	0.12	19 (0.1)	0.12	1.02 (0.53, 1.96)
Vascular disorders	17 (0.2)	0.15	8 (0.1)	0.06	0.44 (0.19, 1.02)	1 (0.0)	0.04	0 (0.0)	0.00	0	18 (0.2)	0.13	8 (0.1)	0.05	0.42 (0.18, 0.96)b
Renal and urinary disorders	1 (0.0)	0.01	6 (0.1)	0.05	5.75 (0.67, 49.16)	0 (0.0)	0.00	2 (0.1)	0.07		1 (0.0)	0.01	8 (0.1)	0.05	7.65 (0.93, 63.05)

Notes:

a SOCs with a frequency of at least 3% of the total number of fatal events within any of the treatment arms in either study pool, ie, HandiHaler^®, Respimat^® or both combined are shown; PTs with an occurrence of at least 10 fatal events within the pooled analysis are shown.

b Significantly different from 1.

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; FAE, fatal adverse event; IR, incidence rate; MI, myocardial infarction; PT, preferred term; RR, rate ratio; SOC, system organ class.

Table S1 PV endpoint definition

PV endpoint/SMQ	MedDRA PT
Abdominal pain	Abdominal pain; abdominal pain lower; abdominal pain upper; abdominal rebound tenderness; abdominal tenderness; epigastric discomfort; gastrointestinal pain
Aneurysm	Aneurysm; aneurysm arteriovenous; aneurysm ruptured; aortic aneurysm; aortic aneurysm rupture; aortic aneurysm syphilitic; aortic dissection; aortic dissection rupture; aortic intramural hematoma; aortic stent insertion; artery dissection; cardiac aneurysm; carotid aneurysm rupture; cerebral aneurysm ruptured syphilitic; Charcot–Bouchard microaneurysms; coronary artery aneurysm; coronary artery dissection; dissecting coronary artery aneurysm; femoral artery aneurysm; femoral artery dissection; hemorrhage coronary artery; hepatic artery aneurysm; infective aneurysm; intracranial aneurysm; mycotic aneurysm; peripheral artery aneurysm; peripheral artery dissection; pulmonary artery aneurysm; renal aneurysm; renal artery dissection; retinal aneurysm; ruptured cerebral aneurysm; splenic artery aneurysm; subclavian artery aneurysm; superior vena cava dilatation; venous aneurysm
Anxiety symptoms/fears	Acrophobia; activation syndrome; acute stress disorder; agitation; agitation neonatal; agoraphobia; animal phobia; anticipatory anxiety; anxiety; anxiety disorder; anxiety disorder due to a general medical condition; arachnophobia; autophobia; Burnout syndrome; claustrophobia; compulsions; compulsive hand washing; dysmorphophobia; emetophobia; fear; fear of animals; fear of closed spaces; fear of crowded places; fear of death; fear of disease; fear of eating; fear of falling; fear of needles; fear of open spaces; fear of pregnancy; fear of weight gain; generalized anxiety disorder; haphephobia; hydrophobia; limited symptom panic attack; nervousness; neurosis; noctiphobia; nocturnal fear; nosophobia; obsessive thoughts; obsessive-compulsive disorder; ochlophobia; osmophobia; pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection; panic attack; panic disorder; panic disorder with agoraphobia; panic disorder without agoraphobia; panic reaction; paruresis; performance fear; phagophobia; pharmacophobia; phobia; phobia of driving; phobia of exams; phobia of flying; phobic avoidance; phonophobia; photaugiaphobia; post-traumatic stress disorder; postpartum neurosis; postpartum stress disorder; social fear; social phobia; stress; tension; thanatophobia
Cardiac arrest	Atrioventricular dissociation; cardiac arrest; cardiac death; cardiac massage; cardiorespiratory arrest; cardiogenic shock; pulseless electrical activity; resuscitation
Cardiac failure (SMQ cardiac failure [narrow])	Acute left ventricular failure; acute pulmonary edema; acute right ventricular failure; cardiac asthma; cardiac failure; cardiac failure acute; cardiac failure chronic; cardiac failure congestive; cardiac failure high output; cardiogenic shock; cardiopulmonary failure; cardiorenal syndrome; chronic left ventricular failure; chronic right ventricular failure; cor pulmonale; cor pulmonale acute; cor pulmonale chronic; ejection fraction decreased; hepatic congestion; hepatojugular reflux; left ventricular failure; low cardiac output syndrome; neonatal cardiac failure; pulmonary edema; pulmonary edema neonatal; right ventricular failure; ventricular failure
Cognitive impairment	Cognitive disorder
Confusion	Confusion postoperative; confusional state; disorientation
Constipation	Colonic pseudo-obstruction; constipation; feces hard; infrequent bowel movements; postprocedural constipation
COPD exacerbation	Chronic obstructive pulmonary disease; infective exacerbation of chronic obstructive airways disease; obstructive airways disorder
Dehydration	Dehydration
Depression and self-injury (SMQ depression and self-injury (excluding suicide and self-injury) (narrow)	Activation syndrome; adjustment disorder with depressed mood; adjustment disorder with mixed anxiety and depressed mood; agitated depression; anhedonia; antidepressant therapy; childhood depression; decreased interest; depressed mood; depression; depression postoperative; depressive symptom; dysphoria; dysthymic disorder; electroconvulsive therapy; feeling guilty; feeling of despair; feelings of worthlessness; major depression; menopausal depression; postpartum depression
Dizziness	Dizziness; dizziness exertional; dizziness postural; vertigo; vertigo positional
Dry mouth	Aptyalism; dry mouth; dry throat; lip dry
Dyspepsia (including reflux)	Abdominal discomfort; dyspepsia; epigastric discomfort; esophageal pain; esophagitis; gastritis; gastroesophageal reflux disease; reflux gastritis; reflux laryngitis
Dysphagia	Dysphagia; esophageal hypomotility; malignant dysphagia
Dysuria	Dysuria; strangury
Gastroesophageal reflux disease	Dyspepsia; esophageal pain; esophagitis; reflux gastritis; gastroesophageal reflux; disease; reflux laryngitis
Gastrointestinal obstruction (SMQ gastrointestinal perforation, ulceration, hemorrhage, or obstruction)	Anal stenosis; anastomotic stenosis; anastomotic ulcer, obstructive; anorectal stenosis; barium impaction; colonic obstruction; colonic stenosis; distal ileal obstruction syndrome; distal intestinal obstruction syndrome; duodenal obstruction; duodenal scarring; duodenal stenosis; duodenal ulcer perforation, obstructive; duodenal ulcer, obstructive; esophageal obstruction; esophageal stenosis; fibrosing colonopathy; gastric stenosis; gastric ulcer hemorrhage, obstructive; gastric ulcer perforation, obstructive; gastric ulcer, obstructive; gastrointestinal anastomotic leak; gastrointestinal hypomotility; gastrointestinal motility disorder; gastrointestinal obstruction; gastrointestinal stenosis; ileal stenosis; impaired gastric emptying; intestinal obstruction; intestinal stenosis; jejuna tenosis; large intestinal obstruction; large intestinal obstruction reduction; large intestinal stricture; necrotizing colitis; necrotizing gastritis; necrotizing esophagitis; neonatal intestinal obstruction; obstruction gastric; peptic ulcer perforation, obstructive; peptic ulcer, obstructive; prepyloric stenosis; rectal obstruction; rectal stenosis; small intestinal bacterial overgrowth; small intestinal obstruction; small intestinal stenosis
Glaucoma (SMQ glaucoma) (narrow)	Angle closure glaucoma; borderline glaucoma; developmental glaucoma; diabetic glaucoma; fundoscopy abnormal; glaucoma; glaucoma drug therapy; glaucoma surgery; glaucoma traumatic; glaucomatocyclitic crises; glaucomatous optic disc atrophy; gonioscopy abnormal; halo vision; intraocular pressure; fluctuation; intraocular pressure increased; intraocular pressure test abnormal; iridotomy; loss of visual contrast sensitivity; normal tension glaucoma; ocular hypertension; open angle glaucoma; ophthalmic fluid drainage; optic discs blurred; optic nerve cup/disc ratio increased; optic nerve cupping; phacolytic glaucoma; phacotrabeculectomy; pigmentary glaucoma; pupillary light reflex tests abnormal; slit-lamp tests abnormal; trabeculectomy; trabeculoplasty; visual field tests abnormal
Headache	Basilar migraine; chronic paroxysmal hemicrania; cluster headache; complicated migraine; drug withdrawal headache; headache; migraine; migraine with aura; migraine without aura; ophthalmoplegic migraine; post-traumatic headache; postictal headache; retinal migraine; SUNCT syndrome; sinus headache; status migrainosus; temporomandibular joint syndrome; tension headache; typical aura without headache
Hyperglycemia/new-onset diabetes mellitus (SMQ Hyperglycemia/new-onset diabetes mellitus) (narrow)	Blood 1,5-anhydroglucitol decreased; blood glucose increased; diabetes complicating pregnancy; diabetes mellitus; diabetes mellitus inadequate control; diabetes with hyperosmolarity; diabetic coma; diabetic hyperglycemic coma; diabetic hyperosmolar coma; diabetic ketoacidosis; diabetic ketoacidotic hyperglycemic coma; fructosamine increased; gestational diabetes; glucose tolerance impaired; glucose tolerance impaired in pregnancy; glucose urine present; glycosuria; glycosuria during pregnancy; glycosylated hemoglobin increased; hyperglycemia; hyperglycemic hyperosmolar nonketotic syndrome; impaired fasting glucose; insulin resistance; insulin resistance syndrome; insulin-resistant diabetes; insulin-requiring Type 2 diabetes mellitus; ketoacidosis; ketonuria; ketosis; latent autoimmune diabetes in adults; metabolic syndrome; neonatal diabetes mellitus; pancreatogenous diabetes; Type 1 diabetes mellitus; Type 2 diabetes mellitus; urine ketone body present
Hypertension	Accelerated hypertension; blood pressure ambulatory increased; blood pressure diastolic increased; blood pressure inadequately controlled; blood pressure increased; blood pressure orthostatic increased; blood pressure systolic increased; diastolic hypertension; endocrine hypertension; essential hypertension; hypertension; hypertensive angiopathy; hypertensive cardiomegaly; hypertensive cardiomyopathy; hypertensive crisis; hypertensive emergency; hypertensive encephalopathy; hypertensive heart disease; hypertensive nephropathy; labile hypertension; Liddle’s syndrome; malignant hypertension; malignant hypertensive heart disease; malignant renal hypertension; mean arterial pressure increased; neurogenic hypertension; orthostatic hypertension; paradoxical pressor response; procedural hypertension; renal hypertension; renovascular hypertension; secondary hypertension; systolic hypertension
Insomnia	Initial insomnia; insomnia; middle insomnia; poor quality sleep; sleep disorder; sleep phase rhythm disturbance; somnambulism
Ischemic heart disease (SMQ ischemic heart disease sub-SMQ other ischemic heart disease) (broad)	Angina pectoris; angina unstable; arteriogram coronary abnormal; arteriosclerosis coronary artery; arteriospasm coronary; cardiac stress test abnormal; computerized tomogram; coronary artery abnormal; coronary angioplasty; coronary arterial stent insertion; coronary artery bypass; coronary artery disease; coronary artery dissection; coronary artery insufficiency; coronary artery restenosis; coronary artery stenosis; coronary endarterectomy; coronary no-reflow phenomenon; coronary ostial stenosis; coronary revascularization; dissecting coronary artery aneurysm; electrocardiogram signs of myocardial; electrocardiogram ST segment depression; electrocardiogram ST–T segment abnormal; electrocardiogram ST–T segment depression; electrocardiogram T-wave abnormal; electrocardiogram T-wave inversion; exercise electrocardiogram abnormal; exercise test abnormal; external counterpulsation; hemorrhage coronary artery; in-stent coronary artery restenosis; ischemic cardiomyopathy; microvascular angina; myocardial ischemia; other ischemic heart disease (broad) ischemia; percutaneous coronary intervention; prinzmetal angina; stress cardiomyopathy; stress echocardiogram abnormal; subclavian coronary steal; syndrome; subendocardial ischemia
MI (SMQ ischemic heart disease sub-SMQ myocardial infarction) (broad)	Acute coronary syndrome; acute myocardial infarction; blood creatine phosphokinase; MB abnormal; blood creatine phosphokinase; MB increased; blood creatine phosphokinase abnormal; blood creatine phosphokinase increased; cardiac enzymes increased; coronary artery embolism; coronary artery occlusion; coronary artery reocclusion; coronary artery thrombosis; coronary bypass thrombosis; electrocardiogram electrically inactive area; electrocardiogram Q-wave abnormal; electrocardiogram ST segment abnormal; electrocardiogram ST segment elevation; electrocardiogram ST–T segment elevation; infarction; Kounis syndrome; myocardial infarction; myocardial reperfusion injury; myocardial stunning; papillary muscle infarction; postprocedural myocardial infarction; postinfarction angina; scan myocardial perfusion abnormal; silent myocardial infarction; troponin I increased; troponin T increased; troponin increased; vascular graft occlusion
Palpitations	Extrasystoles; palpitations; supraventricular extrasystoles; ventricular extrasystoles
Pneumonia	Atypical mycobacterial pneumonia; bronchopneumonia; congenital pneumonia; embolic pneumonia; Enterobacter pneumonia; lobar pneumonia; miliary pneumonia; neonatal pneumonia; pneumonia; pneumonia adenoviral; pneumonia anthrax; pneumonia bacterial; pneumonia blastomyces; pneumonia Bordetella; pneumonia Chlamydial; pneumonia Cryptococcal; pneumonia Cytomegaloviral; pneumonia Escherichia; pneumonia fungal; pneumonia hemophilus; pneumonia helminthic; pneumonia herpes viral; pneumonia influenzal; pneumonia Klebsiella; pneumonia Legionella; pneumonia measles; pneumonia Moraxella; pneumonia mycoplasmal; pneumonia necrotizing; pneumonia parainfluenzae viral; pneumonia pneumococcal; pneumonia primary atypical; pneumonia respiratory syncytial viral; pneumonia Salmonella; pneumonia Staphylococcal; pneumonia Streptococcal; pneumonia toxoplasmal; pneumonia Tularemia; pneumonia viral; post procedural pneumonia
Renal failure	Acute prerenal failure; anuria; cardiorenal syndrome; diabetic end-stage renal disease; hepatorenal failure; postoperative renal failure; renal failure; renal failure acute; renal failure chronic
Respiratory failure	Acute respiratory failure; cardiopulmonary failure; chronic respiratory failure; hypoxia; respiratory acidosis; respiratory failure; respiratory paralysis
Restlessness	Agitation; psychomotor hyperactivity; restlessness
Sleep disturbance	Abnormal dreams; insomnia; nightmare; poor quality sleep; sedation; sleep disorder; sleep phase rhythm disturbance; sleep talking; somnambulism; somnolence
Stomatitis	Aphthous stomatitis; mouth ulceration; oral mucosal eruption; oropharyngeal blistering; stomatitis; stomatitis hemorrhagic; stomatitis necrotizing
Stroke	Amaurosis fugax; basal ganglia hemorrhage; basilar artery occlusion; basilar artery thrombosis; brachiocephalic artery occlusion; brain stem hemorrhage; brain stem infarction; brain stem ischemia; brain stem stroke; brain stem thrombosis; carotid aneurysm rupture; carotid arterial embolus; carotid artery occlusion; carotid artery thrombosis; central nervous system hemorrhage; cerebellar artery occlusion; cerebellar artery thrombosis; cerebellar embolism; cerebellar hematoma; cerebellar hemorrhage; cerebellar infarction; cerebellar ischemia; cerebral arteriovenous malformation hemorrhagic; cerebral artery embolism; cerebral artery occlusion; cerebral artery thrombosis; cerebral hematoma; cerebral hemorrhage; cerebral hemorrhage fetal; cerebral hemorrhage neonatal; cerebral infarction; cerebral infarction fetal; cerebral ischemia; cerebral thrombosis; cerebrovascular accident; embolic cerebral infarction; embolic stroke; hemorrhage intracranial; hemorrhagic cerebral infarction; hemorrhagic stroke; hemorrhagic transformation stroke; intracranial hematoma; intracranial tumor hemorrhage; intraoperative cerebral artery occlusion; intraventricular hemorrhage; intraventricular hemorrhage neonatal; ischemic cerebral infarction; ischemic stroke; lacunar infarction; lateral medullary syndrome; pituitary hemorrhage; pituitary infarction; postprocedural stroke; precerebral artery occlusion; putamen hemorrhage; reversible ischemic neurological deficit; ruptured cerebral aneurysm; stroke in evolution; subarachnoid hemorrhage; subarachnoid hemorrhage neonatal; subdural hemorrhage neonatal; thalamic infarction; thalamus hemorrhage; thrombotic cerebral infarction; thrombotic stroke; transient ischemic attack; vertebral artery dissection; vertebral artery occlusion; vertebral artery thrombosis
Supraventricular tachycardia	Atrial tachycardia; postural orthostatic tachycardia syndrome; sinus tachycardia; supraventricular tachycardia; tachycardia paroxysmal
Syncope	Loss of consciousness; presyncope; syncope
Tachycardia	Heart rate increased; sinus tachycardia; tachycardia
Urinary retention	Bladder neck obstruction; residual urine volume increased; urinary hesitation; urinary retention; urinary retention postoperative; urinary tract obstruction; urine flow decreased
Urinary tract infection	Adenoviral hemorrhagic; cystitis; asymptomatic bacteriuria; bacterial pyelonephritis; bacteriuria; bladder candidiasis; cystitis; cystitis Escherichia; cystitis glandularis; cystitis gonococcal; cystitis hemorrhagic; cystitis interstitial; cystitis Klebsiella; cystitis noninfective; cystitis pseudomonal; cystitis radiation; cystitis ulcerative; cytomegalovirus urinary tract infection; emphysematous cystitis; eosinophilic cystitis; Escherichia urinary tract infection; fungal cystitis; genitourinary tract infection; kidney infection; perinephric abscess; pyelocystitis; pyelonephritis; pyelonephritis acute; pyelonephritis chronic; pyelonephritis mycoplasmal; pyonephrosis; renal abscess; renal cyst infection; schistosomiasis bladder; Streptococcal urinary tract infection; trigonitis; tuberculosis bladder; ureter abscess; ureteritis; urethral abscess; urethral carbuncle; urethral stricture post infection; urethritis; urinary bladder abscess; urinary tract abscess; urinary tract infection; urinary tract infection bacterial; urinary tract infection enterococcal; urinary tract infection fungal; urinary tract infection neonatal; urinary tract infection pseudomonal; urinary tract infection staphylococcal; urosepsis; viral hemorrhagic cystitis
Ventricular tachycardia/fibrillation	Ventricular fibrillation; ventricular tachycardia
Vision blurred	Accommodation disorder; altered visual depth perception; diplopia; erythropsia; glare; halo vision; hypermetropia; loss of visual contrast sensitivity; malignant myopia; myopia; night blindness; oscillopsia; phosphenes; photopsia; presbyopia; refraction disorder; tunnel vision

Abbreviations: MB, creatine kinase-MB; MedDRA, Medical Dictionary for Regulatory Activities; MI, myocardial infarction; PT, preferred term; PV, pharmacovigilance; SMQ, standardized MedDRA queries.

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