<%BANNER%>

UFIR



Assessing the Association between Omalizumab and Arteriothrombotic Events through Spontaneous Adverse Event Reporting
http://www.dovepress.com ( Publisher's URL )
CITATION PDF VIEWER
Full Citation
STANDARD VIEW MARC VIEW
Permanent Link: http://ufdc.ufl.edu/IR00000824/00001
 Material Information
Title: Assessing the Association between Omalizumab and Arteriothrombotic Events through Spontaneous Adverse Event Reporting
Series Title: Journal of Asthma and Allergy. May 2012;5:1-9
Physical Description: Journal Article
Creator: Ayad K. Ali
Hartzema, Abraham G.
Publisher: Dove Medical Press
Place of Publication: United Kingdom
Publication Date: May 2, 2012
 Notes
Abstract: Background: Omalizumab is a monoclonal antibody, indicated for the treatment of severe allergic asthma. In Europe, there have been concerns about the cardiovascular safety of omalizumab. The objective of this study was to analyze the association between omalizumab and arterial thrombotic events in a spontaneous adverse drug reaction reporting database in the US. Methods and materials: Reports of arterial thrombotic events submitted to the US Food and Drug Administration’s Adverse Event Reporting System (AERS) between 2004 and 2011 were retrieved and analyzed by the reporting odds ratio data mining algorithm. The reporting odds ratio of arterial thrombotic events for omalizumab was compared with specific asthma medications and all drugs in the AERS. Values $2 were considered significant safety signals. The Medical Dictionary for Regulatory Activities Preferred Terms were used to identify arterial thrombotic events (eg, stroke, myocardial infarction). Results: In total, 293,783 reports of arterial thrombotic events were retrieved (about 2% of all adverse drug reaction reports), corresponding to 2274 asthma drug-arterial thrombotic events pairs (omalizumab, 222; inhaled corticosteroids ICS, 131; long-acting beta-agonists LABA, 102; single-device combination ICS-LABA, 506; inhaled short-acting beta-agonists SABA, 475; oral SABA, 6; inhaled antimuscarinics AMC, 477; single-device combination AMC-SABA, 127; xanthines, 50; leukotriene modifiers, 174; and mast cell stabilizers, 4). Reporting odds ratio and 95% confidence interval values for omalizumab compared with other asthma drugs and all drugs in AERS were 2.75 (2.39–316) and 1.09 (0.95–1.24), respectively. Omalizumab ranked second after ICS in the risk of arterial thrombotic events, followed by AMC, AMC-SABA, and ICS-LABA. Conclusion: Omalizumab is associated with higher than expected reporting of arterial thrombotic events in asthmatic patients. This hypothesis needs further testing in robust epidemiological studies.
Acquisition: Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Ayad K Ali.
Publication Status: Published
 Record Information
Source Institution: University of Florida Institutional Repository
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution.
System ID: IR00000824:00001

Downloads

This item is only available as the following downloads:

Omalizumab & Arteriothrombotic Events ( PDF )


Full Text

PAGE 1

2012 Ali and Hartzema, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Journal of Asthma and Allergy 2012:5 1Journal of Asthma and AllergyAssessing the association between omalizumab and arteriothrombotic events through spontaneous adverse event reportingAyad K Ali Abraham G HartzemaDepartment of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA Correspondence: Ayad K Ali 101 S Newell Drive, PO Box 100496, Gainesville, FL 32610, USA Tel 1 352 273 6629 Fax 1 352 273 6270 Email u Background: Omalizumab is a monoclonal antibody, indicated for the treatment of severe allergic asthma. In Europe, there have been concerns about the cardiovascular safety of omalizumab. The objective of this study was to analyze the association between omalizumab and arterial thrombotic events in a spontaneous adverse drug reaction reporting database in the US. Methods and materials: Reports of arterial thrombotic events submitted to the US Food and Drug Administrations Adverse Event Reporting System (AERS) between 2004 and 2011 were retrieved and analyzed by the reporting odds ratio data mining algorithm. The reporting odds ratio of arterial thrombotic events for omalizumab was compared with specic asthma medications and all drugs in the AERS. Values 2 were considered signicant safety signals. The Medical Dictionary for Regulatory Activities Preferred Terms were used to identify arterial thrombotic events (eg, stroke, myocardial infarction). Results: In total, 293,783 reports of arterial thrombotic events were retrieved (about 2% of all adverse drug reaction reports), corresponding to 2274 asthma drug-arterial thrombotic events pairs (omalizumab, 222; inhaled corticosteroids [ICS], 131; long-acting beta-agonists [LABA], 102; single-device combination ICS-LABA, 506; inhaled short-acting beta-agonists [SABA], 475; oral SABA, 6; inhaled antimuscarinics [AMC], 477; single-device combination AMC-SABA, 127; xanthines, 50; leukotriene modiers, 174; and mast cell stabilizers, 4). Reporting odds ratio and 95% condence interval values for omalizumab compared with other asthma drugs and all drugs in AERS were 2.75 (2.39) and 1.09 (0.95.24), respectively. Omalizumab ranked second after ICS in the risk of arterial thrombotic events, followed by AMC, AMC-SABA, and ICS-LABA. Conclusion: Omalizumab is associated with higher than expected reporting of arterial thrombotic events in asthmatic patients. This hypothesis needs further testing in robust epidemiological studies. Keywords: omalizumab, postmarketing safety surveillance, adverse event reporting system, arterial thrombotic eventsIntroductionOmalizumab is a monoclonal antibody that blocks immunoglobulin E, thereby inhibiting the early and late inammatory reactions of asthma.1 On June 20, 2003, omalizumab (Xolair; Genentech Inc, San Francisco, CA) was approved by the US Food and Drug Administration (FDA) for the treatment of severe persistent allergic asthma refractory to standard treatment.2 The drug is available in 75 mg and 150 mg powder and a solvent for injection, which is administered subcutaneously to patients aged 6 years or older, and the dose can be repeated every 2 weeks.3Dovepresssubmit your manuscript | www.dovepress.co mDovepress 1 ORIG INAL RESEARCHopen access to scientic and medical research Open Access Full Text Article http: //dx.doi.org/10.2147/JAA.S2981 1

PAGE 2

Journal of Asthma and Allergy 2012:5 In February 2011, the UK Medicines and Healthcare Products Regulatory Agency advised prescribers to be vigilant about the possible occurrence of arterial thrombotic events in patients exposed to omalizumab, and to report suspected relevant adverse reactions to the UK spontaneous adverse event reporting system (ie, the Yellow Card Scheme).4,5 These recommendations were based on interim analyses of randomized clinical trials and an unpublished cohort study, ie, EXCELS (Evaluating Clinical Effectiveness and LongTerm Safety in patients with Moderate-to-Severe Asthma).4,6 These analyses yielded a statistically insignicant increase in the risk of arterial thrombotic events in groups exposed to omalizumab compared with their unexposed control counter parts (randomized clinical trials: hazard ratio [HR] 1.86, 95% condence interval [CI] 0.734.72); EXCELS: HR 1.11, 95% CI 0.70.76).4,6 The FDA reviewed the reported adverse events for omalizumab in July 2009, and concluded with a warning to prescribers and patients about hypersensitivity reactions, with no reference to any arteriothrombotic risks.7 This study assessed the safety prole of omalizumab with respect to arterial thrombotic events recorded in the FDA Adverse Event Reporting System (AERS) database.Methods and materials Data sourceAdverse event reports recorded in FDA AERS from January 1, 2004 to January 1, 2011 were downloaded from the FDA website (www.fda.gov) .8 The AERS contains reports of adverse drug events spontaneously submitted by physicians, pharmacists, other health care professionals, manufacturers, and consumers from the US and other countries. The Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms were used to codify the adverse events. Reports for the same patient but from different reporting sources (duplicate reports) were identied and excluded from the analysis. The structure of the AERS database is described elsewhere.9Identifying omalizumab and other asthma drugsOmalizumab and other asthma drugs were identied by their nonproprietary and brand names, which in most cases were recorded verbatim from individual adverse event reports ( Table 1). In addition to omalizumab, identied classes of asthma drugs included: inhaled corticosteroids (ICS); longacting beta-agonists (LABA); single-device combination ICSLABA; inhaled short-acting beta-agonists (SABA); orally administered SABA; inhaled antimuscarinics (AMC); singledevice combination SABA-AMC; oral xanthines; leukotriene modiers; and mast cell stabilizers. In order to maximize the accuracy of capturing all the exposures of interest, the drug variable column of the AERS dataset was manually mined to extract the exposures of interest. The Clinical Pharmacology web-based reference tool (www.clinicalpharmacology.com )10 is used to verify the names of the reported products in the drug variable whenever the recorded names are confusing or unclear, which was the case for a few reports (3.2%). Similarly, the drug name was crossreferenced with the corresponding indication variable column for the relevant report to look for asthma, chronic obstructive pulmonary disease, or respiratoryrelated clinical indications, whenever reported. Reports for drugs with other indications, unspecied or missing drug names, intravenously administered xanthines, and intranasally and ophthalmic administered corticosteroids and mast cell stabilizers, are excluded from the analysis.Identifying arterial thrombotic eventsClinical judgment was applied to identify arterial thrombotic events, which were dened by the MedDRA Preferred Terms codes classied under the terms listed in Table 2. Table 1 Drug class Individual agent Product example* Monoclonal immunoglobulin E antibody Omalizumab Xolair ICS Beclomethasone Budesonide Fluticasone Mometasone Beclovent Pulmicort Flovent Asmanex Inhaled LABA Formoterol Salmeterol Foradil Serevent Single-device ICS-LABA Budesonide-formoterol Fluticasone-salmeterol Mometasone-formoterol Symbicort Advair Dulera Inhaled SABA Salbutamol (albuterol) Ventolin Oral SABA Salbutamol (albuterol) Proventil Inhaled AMC Ipratropium Oxitropium Tiotropium Atrovent Oxivent Spiriva Single-device SABA-AMC Salbutamol-ipratropium Combivent Oral xanthines Theophylline Aminophylline Theovent Phyllocontin Leukotriene Montelukast Zileuton Singulair Accolate Mast cell stabilizers Nedocromil Cromolyn sodium Tilade IntalNote: *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. submit your manuscript | www.dovepress.co mDovepress Dovepress 2 Ali and Hartzema

PAGE 3

Journal of Asthma and Allergy 2012:5 A complete list of the identied codes is available upon request from the corresponding author. Reports with missing or unspecied adverse events were excluded from the study.Reporting odds ratio data mining algorithmThe association between asthma drugs, including omali zumab, and arterial thrombotic events was analyzed using the reporting odds ratio and corresponding 95% CI data mining algorithm. Reporting odds ratio values for omalizumab denote the ratio of the observed to expected number of reported arterial thrombotic events compared with other asthma drugs in the data set during the analysis period. Values 1 indicate no exposure-event associations; esti mates 1 depict exposure-event safety signals. From the regulatory science perspective, safety signals are considered signicant when the reporting odds ratio estimates and the lower limits of the corresponding 95% CI are 2.11Data analysisTable 3 depicts the data mining algorithm to calculate the point estimates and the corresponding 95% CI for omalizumab, which was applied for all other asthma drugs in the study. Data management and analyses were performed using SAS software for Windows (version 9.3; SAS Institute Inc, Cary, NC). The tables and gures were generated by Microsoft Ofce Word software (Microsoft Corporation, Redmond, WA). Statistical signicance tests were conducted at the alpha 5% level.Results Overview of reportsFrom January 2004 to January 2011, 15,519,543 adverse event reports were recorded in the AERS; about 2% involved asthma drugs (280,857), and an additional 2% involved arterial thrombotic events (293,782), corresponding to 2274 asthma drug-arterial thrombotic event pairs, with 222 (10%) reports concerning omalizumab. Omalizumab ranked fourth in the number of arterial thrombotic event reports for asthma drugs, preceded by ICS-LABA, inhaled SABA, and AMC (Figure 1). Table 4 shows the distribution of identied specic arterial thrombotic events for asthma drugs. Myocardial infarction and stroke accounted for 29% and 27% of the arterial thrombotic event reports for omalizumab, respectively. Except for orally administered SABA and leukotriene modiers, myocardial infarction contributed to the majority of the arterial thrombotic event reports for asthma drugs. The ranking distribution of the arterial thrombotic event categories was semihomogenous across the majority of asthma drug classes. Single-device combination ICS-LABA contributed to the majority of reports for angina, stroke, and cardiovascular death. Inhaled SABA contributed to the majority of reports for myocardial infarction, acute coronary syndrome, ischemic heart disease, and thrombosis. Among the exposure groups, omalizumab ranked third in cardiovascular death category; fourth in angina, myocardial infarction, acute coronary syndrome, and stroke categories; and fth in ischemic heart disease and thrombosis categories.Serious arterial thrombotic eventsA serious adverse event is any unwanted medical incident associated with exposure to a medicinal product that, at any dose: results in patient death; is life-threatening; requires inpatient hospitalization or prolongs existing hospitalization; results in persistent or signicant disability or incapacity; or is a congenital anomaly or birth defect.12 Overall, there were 1055 serious outcomes for all asthma drugs in AERS. Table 5 lists the distribution of serious arterial thrombotic event outcomes for asthma drugs. Arterial thrombotic events that required hospitalization after exposure to omalizumab accounted for 42% of all the serious arterial thrombotic event outcomes. About 16% of these serious events were attributed to mortality. Except for single-device combination ICS-LABA and xanthines, hospitalization accounted for the vast majority of serious arterial thrombotic event outcomes for asthma drugs. Single-device Table 2 thrombotic eventsMedDRA Preferred Terms category* Acute coronary syndrome Stroke Angina Thrombosis Ischemic heart disease Cardiovascular death Myocardial infarctionNote: Abbreviation: MedDRA, Medical Dictionary for Regulatory Activities. Table 3 mining algorithm for omalizumabExposure ATE Other ADR Total Omalizumab A B AB Other asthma drugs C D CD Total AC BD N ROR AD CB 95% CI eln(ROR )1 .96 1 A 1 B 1 C 1 D Abbreviations: ATE, arteriothrombotic events; ADR, adverse drug reactions; CI, submit your manuscript | www.dovepress.co mDovepress Dovepress 3 Omalizumab and arteriothrombotic events

PAGE 4

Journal of Asthma and Allergy 2012:5 combination ICS-LABA contributed to the majority of the mortality, life-threatening, and other unspecied serious arterial thrombotic event outcomes. Inhaled AMC contributed to the majority of serious disability and hospitalization outcomes. On the other hand, the preponderance of arterial thrombotic event outcomes that required intervention was for inhaled SABA. Compared with other asthma drugs, omalizumab ranked third in arterial thrombotic event outcomes that caused death, resulted in disability, and required hospitalization; seventh in lifethreatening arterial thrombotic events outcomes; and second in other unspecied serious arterial thrombotic events outcomes.Characteristics of arterial thrombotic event reports for omalizumabTable 6 shows the characteristics of arterial thrombotic event reports for omalizumab. The majority of omalizumab users who experienced arterial thrombotic events were females aged 45 years. About 94% of the arterial thrombotic event reports were expedited reports, ie, reports for serious and unexpected events submitted by the manufacturer to the AERS within 15 days of occurrence.13 The product manufacturer is required to submit periodic reports for all adverse events quarterly for the rst three years after product approval, and annually thereafter over multiple years.13 Periodic arterial thrombotic event reports for omalizumab accounted for 3% of the submitted arterial thrombotic event reports. Approximately 4% of the arterial thrombotic event reports were submitted directly by consumers or health care professionals. Fifty-ve percent of the reports were initially submitted to the AERS, and 45% were classied as follow-up reports. The majority of arterial thrombotic event reports were received from within the US. Of the IC S 131 (5 .7 6% ) LA BA 102 (4 .4 8% ) ICS/ LA BA 506 (2 2.2 %) Inhaled SA BA 475 (2 0.9 %) Oral SA BA 6 (0.26 %) To tal number of AD R re po rt s 15,5 19,5 43 AE RS January 1, 20 04 Januar y 1, 20 11 Omalizumab 222 (9 .7 6% ) To tal number of AT E re po rts 293,7 83 AM C 477 (2 0.9 %) SA BA /A MC 127 (5 .5 8% ) Xanthine s 50 (2.2 0% ) LT RM 174 (7 .6 5% ) MC S 4 (0.17 %) AT E repo rts for othe r drugs 291, 509 AT E repo rts for as th ma drugs 2274 Figure 1 Abbreviations: AERS, Adverse Event Reporting System;8 ADR, adverse drug reactions; ATE, arteriothrombotic events; ICS, inhaled corticosteroids; LABA, long-acting submit your manuscript | www.dovepress.co mDovepress Dovepress 4 Ali and Hartzema

PAGE 5

Journal of Asthma and Allergy 2012:5 eight cases reporting dechallenge information, four reported that arterial thrombotic events did abate when omalizumab was stopped. Only one case reported rechallenge information, which indicated that arterial thrombotic events did not relapse after reinstating omalizumab. The other reports stated that experimental information did not apply or was unknown if arterial thrombotic events terminated when dechallenge ensued, or recurred when rechallenge was car ried out. About 97% of the reports classied omalizumab as the primary suspect in arterial thrombotic event occurrence. The majority of the arterial thrombotic event reports for omalizumab were submitted by physicians (52%), followed by omalizumab users (28%). Pharmacists accounted for 2% of these reports, whereas 19% of the reports were submitted by other health care professionals such as nurses. About 80% of the arterial thrombotic event reports were electronically submitted though the MedWatch online reporting portal;14 the remaining reports were sent via postal mail. About 94% of the cases reported that the patients experienced arterial thrombotic events more than two weeks after omalizumab use; only 6% of the reports stated that arterial thrombotic events occurred within two weeks of exposure. Although the majority of arterial thrombotic event reports were classied as expedited, 95% of the cases were reported more than two weeks after onset of the arterial thrombotic event. There was a trend of reporting arterial thrombotic event episodes for Table 4 Distribution of arterial thrombotic events across exposure groupsDrug 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 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 19,995 293,783Note: *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 groupsDrug Serious arterial thrombotic events, n (%)* Death Disability Hospital stay Life-threatening Required intervention OtherTotal 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 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 46,679 130,579Notes: *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 Abbreviations: AMC, antimuscarinics; ICS, inhaled corticosteroids; LABA, long-acting beta-agonists; SABA, short-acting beta-agonists. submit your manuscript | www.dovepress.co mDovepress Dovepress 5 Omalizumab and arteriothrombotic events

PAGE 6

Journal of Asthma and Allergy 2012:5 Table 6 Characteristics of arterial thrombotic event reports for omalizumabCharacteristic n (%) Sex Female 104 (52) Male 96 (48) Age (years) 13 26 (18.8) 45 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 7 (6.1) 14 107 (93.9) Time to report ATE since onset (days) 0 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.omalizumab, which was steadily increasing, especially for 2004 and 2008.Reporting odds ratio data mining algorithm resultsFigure 2 depicts the reporting odds ratio and corresponding 95% CI for omalizumab and other asthma drugs. Compared with other asthma drugs, omalizumab ranked second after ICS in showing a statistically signicant safety signal in relation to arterial thrombotic events. Exposure to omalizumab was associated with higher than expected reporting of arterial thrombotic events (reporting odds ratio 2.75, 95% CI 2.39.16). A similar analysis was conducted using all the drugs in the dataset as a comparison group, including other asthma drugs, which yielded more conservative estimates for omalizumab, albeit not statistically signicant (reporting odds ratio 1.09, 95% CI 0.951.24). Signal dilution was ensued when all the drugs in the database were used as a comparator. Figure 3 illustrates the data mining estimates for selected arterial thrombotic events for omalizumab, which are calculated in comparison with other asthma drugs in the AERS. Cardiovascular death and stroke ranked rst on the arterial thrombotic events list in detection of statistically signicant safety signals (reporting odds ratio 3.14, 95% CI 2.144.56; reporting odds ratio 3.14, 95% CI 2.414.05, respectively). Although the reporting odds ratio values for ischemic heart disease, myocardial infarction, and thrombosis risk exceeded 2.0, the lower limit of the 95% CI failed to reach that threshold, making the estimates less signicant as safety signals (reporting odds ratio 2.63, 95% CI 1.923.63; reporting odds ratio 2.55, 95% CI 1.983.29; reporting odds ratio 2.19, 95% CI 1.184.01, respectively). The data mining algorithm did not show a statistically signicant result for angina (reporting odds ratio 1.60, 95% CI 0.89.86). Albeit not statistically signicant, the analysis showed that omalizumab was associated with less than expected reporting of acute coronary syndrome compared with other asthma drugs (reporting odds ratio 0.53, 95% CI 0.20.42).DiscussionAdverse event reports submitted to the FDA AERS database from January 1, 2004 to January 1, 2011 were used to conduct a retrospective pharmacovigilance analysis aimed at evaluating the association of omalizumab with arterial thrombotic events, which yielded a statistically signicant safety signal for the association of omalizumab with arterial thrombotic events relative to other asthma drugs. Myocardial infarction (n 65) and stroke (n 60) accounted for the majority of the omalizumab arterial thrombotic event reports. However, cardiovascular death and stroke events were associated with the strongest safety signals for omalizumab (Figure 3). These ndings are consistent with the results from clinical trials and EXCELS cohort study.4,6 However, risk estimates from these studies were not statistically signicant despite the large sample sizes; this could be attributed to the fact that these studies were not powered to detect arterial thrombotic events submit your manuscript | www.dovepress.co mDovepress Dovepress 6 Ali and Hartzema

PAGE 7

Journal of Asthma and Allergy 2012:5 Reporting odds ratios (ROR) and 95% confidence intervals (CI) Omalizumab (N = 222) ICS (N = 131) LABA (N = 102) ICS/LABA (N = 506) Arterial thrombotic events 8 6 4 2 1 0.5 0.1 SABA (N = 475) Oral SABA (N = 6) AMC/SABA (N = 127) AMC (N = 477) LTRM (N = 174) Xanthines (N = 50) MCS (N = 4) Figure 2 Abbreviations: ICS, mast cell stabilizers.as an outcome of interest.4 According to our knowledge, the current pharmacovigilance analysis is the rst to detect such a safety signal in a spontaneous adverse event reporting database. However, such analysis has several limitations that are inherent in the nature of the data, which require consideration prior to drawing conclusions about such ndings. Uncertain quality of reported cases, missing information, variable reporting, and under-reporting of adverse events are common features of spontaneous reporting systems. Under-reporting in spontaneous reporting systems is attributed to reasons that range from mere ignorance of adverse event reporting requirements, the misconception that only safe products are approved for marketing, to fear of involvement in litigation.15 Furthermore, reporting rates for specic adverse events or products vary over time. This is contingent upon the length of time the product is on the market, where newer products have more frequent reports, publicity about the product or the adverse event, marketing and promotion for the product, and indication or contraindication submit your manuscript | www.dovepress.co mDovepress Dovepress 7 Omalizumab and arteriothrombotic events

PAGE 8

Journal of Asthma and Allergy 2012:5information for the product. Nevertheless, the potential for confounding and misinterpretation of signals as incidence estimates are the most common drawbacks of pharmacovigilance analyses using spontaneous reporting systems. Limited information about event temporality, concurrent morbidity, and concomitant medications introduces confounding. For example, risk factors that contribute to arterial thrombotic events occurrence are not recorded in AERS, including obesity, history of diabetes, hypertension, and hypercholesterolemia.16 Association estimates from the data mining algorithm should not be interpreted as incidence measures, rather more than expected reporting of an adverse event for a specic product. Therefore, the potential for Type I error when performing multiple statistical tests is high; the statistical signicance of these ndings is overestimated, and further studies are warranted to follow such clinically signicant associations.11ConclusionExposure to omalizumab is associated with an increased risk of arterial thrombotic events in asthmatic patients, predominantly cardiovascular death and stroke. In light of causality restraints of the current analysis, robust epidemiological studies are recommended to test this hypothesis further in order to draw conclusions that contribute to clinical practice and public health. Meanwhile, until such conclusions are made and recommendations are prepared by regulatory authorities, the ndings suggest that prescribers should cautiously prescribe omalizumab to asthmatic patients who have risk factors that contribute to arteriothrombotic events. AcknowledgmentThe authors thank Teba Mohammad for reviewing the nal draft of the manuscript. Publication of this article was funded in part by the University of Florida Open-Access Publishing Fund.DisclosureThe authors report no conicts of interest in this work.References1. Buhl R. Anti-IgE antibodies for the treatment of asthma. Curr Opin Pulm Med. 2005;11(1):27. 2. Food and Drug Administration. FDA approved drug products (Drugs @ FDA), updated August 2011. Available from: http://www. accessdata. fda.gov/scripts/cder/drugsatfda/index.cfm Accessed August 3, 2011. 3. American Society for Health-System Pharmacists. AHFS Drug Infor mation Essentials: 2004. Omalizumab. Bethesda, MD: American Society for Health-System Pharmacists; 2004. 4. Medicines and Healthcare Regulatory Agency. Omalizumab: Potential risk of arterial thrombotic events. Available from: http://www.mhra.gov. uk/home/groups/dsu/documents/publication/con108718.pdf Accessed August 3, 2011. 5. World Health Organization. Omalizumab: Potential risk of arte rial thrombotic events. 2011. Available from: http://www.who.int/ medicines/publications/Newsletter_2-2011.pdf Accessed August 3, 2011. 6. Long AA, Fish JE, Rahmaoui A, et al. Baseline characteristics of patients enrolled in EXCELS: a cohort study. Ann Allergy Asthma Immunol. 2009; 103(3):212. 7. Food and Drug Administration. Postmarket drug safety infor mation for patients and providers. Early communication about an ongoing safety review of omalizumab (marketed as Xolair). July 16, 2009. Available from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/DrugSafetyInformationforHeath careProfessionals/ucm172218.htm. Accessed August 3, 2011. 0 1 2 4 3 Reporting odds ratio (ROR), 95% confidence interval (CI) 0 RO R 1 < RO R 2 < ROR 3 < RO R Cardiovascular de at h Stroke Ischemic heart disease My ocardial infarction Th rombosis An gina A cu te coro na ry sy ndrome Ar terial th rombotic events for omalizumab 5 n = 4 n = 12 n = 11 n = 65 n = 40 n = 60 n = 30 Figure 3 submit your manuscript | www.dovepress.co mDovepress Dovepress8 Ali and Hartzema

PAGE 9

Journal of Asthma and AllergyPublish your work in this journalSubmit your manuscript here: http://www.dovepress.com/journal-of-asthma-and-allergy-journalThe Journal of Asthma and Allergy is an international, peer-reviewed open-access journal publishing original research, reports, editorials and commentaries on the following topics: Asthma; Pulmonary physiology; Asthma related clinical health; Clinical immunology and the immunological basis of disease; Pharmacological interventions and new therapies. Issues of patient safety and quality of care will also be considered. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. Journal of Asthma and Allergy 2012:5 8. Food and Drug Administration. Adverse Event Reporting System (AERS): Latest quarterly data les. April 18, 2011. Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInforma tion/Surveillance/AdverseDrugEffects/ucm082193.htm Accessed May 12, 2011. 9. Ali AK. Pharmacovigilance analysis of adverse event reports for aliskiren hemifumarate, a rst-in-class direct renin inhibitor. Ther Clin Risk Manag. 2011;7:337. 10. Clinical Pharmacology [online database]. Tampa, FL: Gold Standard Inc, 2011. Available from: http://www.clinicalpharmacology.com Updated August 2011. Accessed March 29, 2012. 11. Bate A, Edwards IR. Data mining techniques in pharmacovigilance. In: Hartzema AG, Tilson HH, Chan KA, editors. Pharmacoepidemiology and Therapeutic Risk Management. 1st ed. Cincinnati, OH: Harvey Whitney Books Co; 2008. 12. Food and Drug Administration. CFR-Code of Federal Regulations Title 21. Updated April 1, 2011. Available from: http://www.accessdata. fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr 312.32 Accessed November 11, 2011. 13. Food and Drug Administration. Staff manual guide: Chapter 53; Postmarketing surveillance and epidemiology: human drugs. Adverse drug effects. Updated May 12, 2010. Available from: http://www.fda. gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ ucm129115.htm. Accessed November 11, 2011. 14. Food and Drug Administration. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. MedWatch Online Voluntary Reporting Form (3500). Updated October 5, 2011. Available from: https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online. htm. Accessed November 13, 2011. 15. Inman WHW. Detection and investigation of drug safety problems. In: Gent M, Shigamatsu I, editors. Epidemiological Issues in Reported Drug-Induced Illnesses. Ontario, Canada: McMaster University Library Press; 1978. 16. Prandoni P. Venous and arterial thrombosis: two aspects of the same disease? Clin Epidemiol. 2009;1:1. submit your manuscript | www.dovepress.co mDovepress Dovepress Dovepress 9 Omalizumab and arteriothrombotic events