Assessing the association between omalizumab and arteriothrombotic events through spontaneous adverse event reporting

Figures & data

Table 1 Identified asthma drugs

Drug class	Individual agent	Product example*
Monoclonal immunoglobulin E antibody	Omalizumab	Xolair
ICS	Beclomethasone	Beclovent
	Budesonide	Pulmicort
	Fluticasone	Flovent
	Mometasone	Asmanex
Inhaled LABA	Formoterol	Foradil
	Salmeterol	Serevent
Single-device ICS-LABA	Budesonide-formoterol	Symbicort
	Fluticasone-salmeterol	Advair
	Mometasone-formoterol	Dulera
Inhaled SABA	Salbutamol (albuterol)	Ventolin
Oral SABA	Salbutamol (albuterol)	Proventil
Inhaled AMC	Ipratropium	Atrovent
	Oxitropium	Oxivent
	Tiotropium	Spiriva
Single-device SABA-AMC	Salbutamol-ipratropium	Combivent
Oral xanthines	Theophylline	Theovent
	Aminophylline	Phyllocontin
Leukotriene modifiers	Montelukast	Singulair
	Zafirlukast	Accolate
	Zileuton	Zyflo
Mast cell stabilizers	Nedocromil	Tilade
	Cromolyn sodium	Intal

Note:

* Product brand names are the property of their respective manufacturers.

Abbreviations: AMC, antimuscarinics; ICS, inhaled corticosteroids; LABA, long-acting beta-agonists; SABA, short-acting beta-agonists.

Table 2 Selected MedDRA Preferred Terms that reflect arterial thrombotic events

MedDRA Preferred Terms category*
Acute coronary syndrome	Stroke
Angina	Thrombosis
Ischemic heart disease	Cardiovascular death
Myocardial infarction

Note:

* Each term category has multiple verbatim terms identified.

Abbreviation: MedDRA, Medical Dictionary for Regulatory Activities.

Table 3 Reporting odds ratio and 95% confidence interval data mining algorithm for omalizumab

Exposure	ATE	Other ADR	Total
Omalizumab	A	B	A+B
Other asthma drugs	C	D	C+D
Total	A+C	B+D	N
$\text{ROR}=\frac{\text{A}\times \text{D}}{\text{C}\times \text{B}}95\%\hspace{0.17em}\text{CI}={\text{e}}^{\left(\text{ln}(\text{ROR})\pm 1.96\sqrt{\frac{1}{\text{A}}+\frac{1}{\text{B}}+\frac{1}{\text{C}}+\frac{1}{\text{D}}}\right)}$

Abbreviations: ATE, arteriothrombotic events; ADR, adverse drug reactions; CI, confidence interval; ROR, reporting odds ratio.

Figure 1 Study profile.

Abbreviations: AERS, Adverse Event Reporting System; ⁸ ADR, adverse drug reactions; ATE, arteriothrombotic events; ICS, inhaled corticosteroids; LABA, long-acting beta-agonists; SABA, short-acting beta-agonists; AMC, antimuscarinics; LTRM, leukotriene modifiers; MCS, mast cell stabilizers.

Table 4 Distribution of arterial thrombotic events across exposure groups

Drug	Arterial thrombotic events, n (%)*
	Angina	MI	ACS	Stroke	IHD	THR	CV death	Total
Omalizumab	12 (5.4)	65 (29.3)	4 (1.8)	60 (27.0)	40 (18.0)	11 (5.0)	30 (13.5)	222
ICS	10 (7.6)	43 (32.8)	1 (0.7)	35 (26.7)	24 (18.3)	10 (7.6)	8 (6.10)	131
LABA	9 (8.8)	35 (34.3)	4 (3.9)	17 (16.7)	18 (17.6)	6 (5.9)	13 (12.7)	102
ICS-LABA	59 (11.6)	131 (25.9)	8 (1.6)	127 (25.1)	66 (13.0)	27 (5.3)	88 (17.4)	506
SABA	50 (10.5)	166 (35.0)	10 (2.1)	97 (20.4)	114 (24.0)	31 (6.5)	7 (1.4)	475
Oral SABA	2 (33.3)	2 (33.3)	0	0	0	2 (33.3)	0	6
AMC	48 (10.0)	160 (33.5)	3 (0.6)	104 (21.8)	65 (13.6)	20 (4.2)	77 (16.1)	477
SABA-AMC	4 (3.1)	43 (33.9)	0	39 (30.7)	27 (21.3)	7 (5.5)	7 (5.5)	127
Xanthines	3 (6.0)	15 (30.0)	2 (4.0)	13 (26.0)	9 (18.0)	5 (10.0)	3 (6.0)	50
Leukotriene modifiers	2 (1.1)	41 (23.5)	6 (3.4)	44 (25.3)	60 (34.4)	15 (8.6)	6 (3.4)	174
Mast cell stabilizers	1 (25.0)	2 (50.0)	0	0	0	1 (25.0)	0	4
Asthma drugs	200 (8.8)	703 (31.0)	38 (1.6)	536 (23.5)	423 (18.6)	135 (6.0)	239 (10.5)	2274
Other drugs	15,790 (5.4)	98,929 (10.7)	2554 (0.8)	76,594 (26.3)	51,859 (17.8)	26,027 (9.0)	19,756 (6.6)	291,509
Total	15,990	99,632	2592	77,130	52,282	26,162	19,995	293,783

Note:

* Percentage of total arterial thrombotic events for the reported drug.

Abbreviations: MI, myocardial infarction; ACS, acute coronary syndrome; ICS, inhaled corticosteroids; IHD, ischemic heart disease; THR, thrombosis; CV, cardiovascular; AMC, antimuscarinics; ICS, inhaled corticosteroids; LABA, long-acting beta-agonists; SABA, short-acting beta-agonists.

Table 5 Distribution of serious arterial thrombotic events across exposure groups

Drug	Serious arterial thrombotic events, n (%)*
	Death	Disability	Hospital stay	Life-threatening	Required intervention	Other§	Total
Omalizumab	30 (16.3)	10 (5.4)	78 (42.4)	1 (0.54)	0	65 (35.3)	184
ICS	8 (29)	0	10 (35.7)	2 (7.1)	1 (3.6)	7 (25)	28
LABA	13 (27)	3 (6.3)	21 (44)	2 (4.2)	0	9 (19)	48
ICS-LABA	88 (33.5)	2 (0.76)	79 (30)	11 (4.2)	1 (0.4)	82 (31.2)	263
SABA	7 (4.5)	10 (6.5)	72 (46.5)	4 (2.6)	4 (2.6)	58 (37.4)	155
Oral SABA	0	0	3 (60)	1 (20)	0	1 (20)	5
AMC	77 (29)	22 (8.3)	119 (45)	8 (3)	1 (0.4)	38 (14.3)	265
SABA-AMC	7 (16.3)	1 (2.3)	18 (42)	3 (7)	0	14 (32.6)	43
Xanthines	3 (43)	0	2 (12)	1 (6)	0	11 (65)	17
Leukotriene modifiers	6 (13)	1 (2.2)	19 (41.3)	6 (13)	0	14 (30.4)	46
Mast cell stabilizers	0	0	0	0	0	1 (100)	1
Asthma drugs	239	49	421	39	7	300	1055
Other drugs	19,756	7984	50,275	4314	816	46,379	129,524
Total	19,995	8033	50,696	4353	823	46,679	130,579

Notes:

* Percentage of total serious events for the reported drug. Number of reports is mutually not exclusive, where one report could have more than one serious outcome classification;

§ unspecified serious outcomes are classified as “other”. There were only 73 reports for congenital anomalies, which were for nonasthma drugs.

Abbreviations: AMC, antimuscarinics; ICS, inhaled corticosteroids; LABA, long-acting beta-agonists; SABA, short-acting beta-agonists.

Table 6 Characteristics of arterial thrombotic event reports for omalizumab

Characteristic	n (%)
Sex
Female	104 (52)
Male	96 (48)
Age (years)
13–44	26 (18.8)
45–64	57 (41.3)
65+	55 (39.9)
Report type
Direct	8 (3.6)
Expedited	208 (93.7)
Periodic	6 (2.7)
Report status
Initial	122 (55)
Follow-up	100 (45)
Report source
Domestic	119 (53.6)
Foreign	103 (46.4)
Experimental dechallenge
Positive result	4 (50)
Negative result	4 (50)
Experimental rechallenge
Negative result	1 (100)
Drug role in ATE occurrence
Primary suspect	206 (97.2)
Secondary suspect	6 (2.8)
Reporter occupation
Consumer	57 (27.8)
Physician	106 (51.7)
Pharmacist	4 (2.0)
Other health care professional	38 (18.5)
Report submission mode
Electronic	177 (79.7)
Mail	45 (20.3)
Time to ATE onset (days)
0–14	7 (6.1)
>14	107 (93.9)
Time to report ATE since onset (days)
0–14	7 (5.0)
>14	134 (95)
Reporting year
2004	4 (1.8)
2005	17 (7.7)
2006	12 (5.4)
2007	22 (10)
2008	19 (8.5)
2009	74 (33.3)
2010	74 (33.3)

Abbreviation: ATE, arteriothrombotic events.

Figure 2 Reporting odds ratios and 95% confidence intervals for arterial thrombotic events by asthma medication classes.

Abbreviations: ICS, inhaled corticosteroids; LABA, long-acting beta-agonists; SABA, short-acting beta-agonists; AMC, antimuscarinics; LTRM, leukotriene modifiers; MCS, mast cell stabilizers.

Figure 3 Visual presentation of reporting odds ratios and 95% confidence intervals for selected arterial thrombotic events for omalizumab.

Food and Drug AdministrationAdverse Event Reporting System (AERS): Latest quarterly data files4182011 Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm082193.htmAccessed May 12, 2011

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