major cardiovascular events associated with anti-il 12/23 agents: a tale of two meta-analyses

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Major cardiovascular events associated with anti-IL 12/23 agents: A tale of two meta-analyses Erica D. Dommasch, MD, a Andrea B. Troxel, ScD, b,c and Joel M. Gelfand, MD, MSCE b,c,d Boston, Massachusetts, and Philadelphia, Pennsylvania B iologics targeting the interleukin (IL)-12/23 pathway for psoriasis have proven highly efficacious in randomized controlled trials (RCTs). However, these trials had an imbalance of major cardiovascular events in the treatment group, leading to controversy as to the cardiovascular safety of these novel drugs. Briakinumab was withdrawn from further development in part because of this controversy, in addition to possible excess risk of malignancy and serious infection. 1 Increasingly, there have been similar concerns over the cardio- vascular safety of ustekinumab. Since then, two studies have sought to evaluate an association between the two anti-IL 12/23 agents and major adverse cardiovascular events (MACEs) via meta-analysis of RCTs. 2 However, despite inclusion of the same trials and the same number of MACEs, these studies came to different conclusions regarding the risk of MACEs with the use of anti-IL 12/23 agents for psoriasis. A meta-analysis by Ryan et al 3 found no statistically significant increased risk of MACEs with the use of anti-IL 12/23 agents, with a Mantel-Haenszel risk difference of 0.012 events/person-year (95% confi- dence interval [CI], 0.001 to 0.026; P = .12), 3 while a separate meta-analysis by Tzellos et al, 2 which used the Peto One-Step OR method, found a statistically signif- icant increased OR of 4.23 (95% CI: 1.07-16.75; P = .04). Below we describe some of the statistical methods that led to these different conclusions, as well as several important factors for clinicians to consider when interpreting meta-analyses of rare adverse events. STATISTICAL METHODOLOGY LEADING TO BIAS When dealing with sparse data, such as in meta- analyses of rare events, confidence intervals tend to be wide, and small changes in the data and different statistical techniques can lead to different conclu- sions. The correct method with which to analyze this type of data has been a subject of significant de- bate. 4,5 In meta-analyses of rare events, there are often several RCTs with zero events in both arms. Additionally, in RCTs designed primarily to examine drug efficacy, there is often a substantial imbalance in number of subjects between the treatment and control populations. The Peto OR method, used in the meta-analysis by Tzellos et al, 2 effectively ex- cludes trials with zero events from the analysis; this can lead to an overestimation of true relative risk because such trials show that the event rate for both treatment and control groups is relatively low and equal. Specifically, 5 of the 9 anti-IL-12/23 RCTs meeting inclusion criteria were excluded from the analysis. In addition, the Peto method used by Tzellos et al has been shown to inflate estimates of risk when groups are unbalanced. 4-7 In reanalyzing the data set from a prominent meta-analysis by Nissen and Wolski 7 on the risk of myocardial infarc- tion with the use of rosiglitazone, Diamond, Bax, and Kaul 4 commented that the Peto OR method tended to inflate estimates of risk because of the reasons listed above. The Mantel-Haenszel method with continuity correction, as used by Ryan et al, 3 is likely Abbreviations used: CI: confidence interval FDA: Food and Drug Administration IL: interleukin MACE: major adverse cardiovascular event OR: odds ratio RCT: randomized controlled trial From the Department of Dermatology, Boston University, Boston, a and Center for Clinical Epidemiology and Biostatistics, b Depart- ment of Biostatistics and Epidemiology, c and Department of Dermatology, d University of Pennsylvania, Philadelphia. Supported by National Institute of Health/National Heart, Lung, and Blood Institute grant R01-HL089744 (Drs Gelfand and Troxel). Drs Dommasch and Troxel have no relevant financial relationships to declare. Dr Gelfand has received grants from Amgen, Pfizer, Novartis, Genentech, and Abbott, and is a consultant for Amgen, Abbott, Pfizer, Novartis, Celgene, Merck, and Janssen. Reprint requests: Erica D. Dommasch, MD, 609 Albany St, J-200, Boston, MA 02118. E-mail: [email protected]. J Am Acad Dermatol 2013;68:863-5. 0190-9622/$36.00 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.01.011 863

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Page 1: Major cardiovascular events associated with anti-IL 12/23 agents: A tale of two meta-analyses

Major cardiovascular events associated with anti-IL12/23 agents: A tale of two meta-analyses

Erica D. Dommasch, MD,a Andrea B. Troxel, ScD,b,c and Joel M. Gelfand, MD, MSCEb,c,d

Boston, Massachusetts, and Philadelphia, Pennsylvania

iologics targeting the interleukin (IL)-12/23

Abbreviations used:

CI: confidence intervalFDA: Food and Drug AdministrationIL: interleukinMACE: major adverse cardiovascular eventOR: odds ratioRCT: randomized controlled trial

B pathway for psoriasis have proven highlyefficacious in randomized controlled trials

(RCTs). However, these trials had an imbalance ofmajor cardiovascular events in the treatment group,leading to controversy as to the cardiovascular safetyof these novel drugs. Briakinumab was withdrawnfrom further development in part because of thiscontroversy, in addition to possible excess risk ofmalignancy and serious infection.1 Increasingly,there have been similar concerns over the cardio-vascular safety of ustekinumab.

Since then, two studies have sought to evaluate anassociation between the two anti-IL 12/23 agents andmajor adverse cardiovascular events (MACEs) viameta-analysis of RCTs.2 However, despite inclusionof the same trials and the same number of MACEs,these studies came to different conclusions regardingthe risk of MACEs with the use of anti-IL 12/23 agentsfor psoriasis. A meta-analysis by Ryan et al3 found nostatistically significant increased risk ofMACEswith theuse of anti-IL 12/23 agents,with aMantel-Haenszel riskdifference of 0.012 events/person-year (95% confi-dence interval [CI], �0.001 to 0.026; P = .12),3 while aseparatemeta-analysis byTzellos et al,2whichused thePeto One-Step OR method, found a statistically signif-icant increasedORof 4.23 (95%CI: 1.07-16.75;P= .04).Belowwe describe some of the statistical methods thatled to these different conclusions, as well as severalimportant factors for clinicians to consider wheninterpreting meta-analyses of rare adverse events.

STATISTICAL METHODOLOGY LEADINGTO BIAS

When dealing with sparse data, such as in meta-analyses of rare events, confidence intervals tend to

From the Department of Dermatology, Boston University, Boston,a

and Center for Clinical Epidemiology and Biostatistics,b Depart-

ment of Biostatistics and Epidemiology,c and Department of

Dermatology,d University of Pennsylvania, Philadelphia.

Supported by National Institute of Health/National Heart, Lung, and

Blood Institute grant R01-HL089744 (Drs Gelfand and Troxel).

Drs Dommasch and Troxel have no relevant financial relationships

to declare. Dr Gelfand has received grants from Amgen, Pfizer,

be wide, and small changes in the data and differentstatistical techniques can lead to different conclu-sions. The correct method with which to analyze thistype of data has been a subject of significant de-bate.4,5 In meta-analyses of rare events, there areoften several RCTs with zero events in both arms.Additionally, in RCTs designed primarily to examinedrug efficacy, there is often a substantial imbalancein number of subjects between the treatment andcontrol populations. The Peto OR method, used inthe meta-analysis by Tzellos et al,2 effectively ex-cludes trials with zero events from the analysis; thiscan lead to an overestimation of true relative riskbecause such trials show that the event rate for bothtreatment and control groups is relatively low andequal. Specifically, 5 of the 9 anti-IL-12/23 RCTsmeeting inclusion criteria were excluded from theanalysis. In addition, the Peto method used byTzellos et al has been shown to inflate estimates ofrisk when groups are unbalanced.4-7 In reanalyzingthe data set from a prominent meta-analysis byNissen and Wolski7 on the risk of myocardial infarc-tionwith the use of rosiglitazone, Diamond, Bax, andKaul4 commented that the Peto OR method tendedto inflate estimates of risk because of the reasonslisted above. The Mantel-Haenszel method withcontinuity correction, as used by Ryan et al,3 is likely

Novartis, Genentech, and Abbott, and is a consultant for

Amgen, Abbott, Pfizer, Novartis, Celgene, Merck, and Janssen.

Reprint requests: Erica D. Dommasch, MD, 609 Albany St, J-200,

Boston, MA 02118. E-mail: [email protected].

J Am Acad Dermatol 2013;68:863-5.

0190-9622/$36.00

� 2013 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.01.011

863

Page 2: Major cardiovascular events associated with anti-IL 12/23 agents: A tale of two meta-analyses

J AM ACAD DERMATOL

MAY 2013864 Dommasch, Troxel, and Gelfand

more appropriate in this setting because it takes intoaccount trials with no events and is less susceptibleto bias from unbalanced arms.4

UNEQUAL FOLLOW-UP TIME INTREATMENT VERSUS CONTROL GROUPS

When adrug is effective, there is often an increaseddropout rate in the placebo group compared with thetreatment group. This can lead to significantly greaterfollow-up time in the treatment group than in theplacebo group, and consequently, more opportunityto detect adverse events in the treatment group. Boththe studies by Tzellos et al2 and Ryan et al3 did notadjust for dropouts; this likely resulted in an overes-timation of true risk. For example, we conducted ameta-analysis examining the risk of infection andmalignancywith the use of antietumor necrosis factoragents in patients with psoriatic disease, which dem-onstrated a statistically significant increased risk ofoverall infection when using only event data (OR =1.18, 95% CI: 1.05-1.33), but not when conducting aseparate meta-analysis of rates with adjustment forfollow-up time (IRR = 1.01, 95% CI: 0.92-1.11).8

Ideally, a more statistically powerful time-to-eventmeta-analysis should be performed, which wouldadjust for follow-up time and be less susceptible tobias from factors such as zero events and unbalancedtreatment groups, as discussed above.8 Therefore, it isabsolutely critical that those persons conductingmeta-analyses have access to individual patient-leveldata in order to yield accurate results. Recognizing theimportance of individual patient-level data for meta-analyses, experts have increasingly called for phar-maceutical companies to make these data available.7

BOTTOM LINE FOR CLINICIANSDespite the above limitations of both meta-

analyses, the imbalance of MACEs suggests a safetysignal, which is defined as a set of data constituting ahypothesis that is relevant to the rational and safe useof a drug in humans.9 Importantly, current evidencesuggests that patients withmore severe psoriasis havean increased risk of MACE independent of traditionalrisk factors.10-12 The finding that anti-IL-12/23 thera-pies could possibly increase cardiovascular risk whileimproving skin disease is unexpected and highlightsour still incomplete understanding of the effects ofimmunomodulatory treatments and cardiovascularoutcomes. Although the methodology of the meta-analysis by Ryan et al3 is likely more appropriate, thisrisk cannot be fully defined with meta-analyses ofexisting published data from pre-approval studiesbecause of issues of bias as discussed above.Moreover, bothmethods are subject to type I statisticalerror (ie, concluding that an association existswhen in

fact the finding is only due to chance), which can be aparticular challenge when multiple comparisons aremade, as is the case with individual safety end points.For example, a randomized controlled trial of topicaltretinoin for chemoprevention of keratinocyte carci-noma was terminated early because those subjectsrandomized to tretinoin had a higher risk of death (P=.01). Although this finding is statistically significantbased on the traditional 0.05 cut-off, the authorssuggested that the finding may be due to chance,given the issueofmultiple comparisons.13Ofnote, thehypothesis regarding an increased risk ofMACEswiththe use of ustekinumab was not supported by arecently published large 5-year post-marketing studyfor ustekinumab,14 and an imbalance of MACEs hasnot been seen in other disease indications, suchas psoriatic arthritis and inflammatory bowel dis-ease.15-18 To date, the Food and Drug Administrationhas not issued changes to the prescribing informationfor ustekinumab related to cardiovascular risk. Shouldthis potential safety signal be confirmed by otherpostmarketing studies, larger RCTs will be necessaryto definitively assess the impact of anti-IL-12/23agents on cardiovascular risk. Pending further data,dermatologists may find it prudent to discuss withpatients undergoing treatment with anti-IL-12/23agents the risks, some of which remain to be defined,aswell as benefits of therapy, and advise them to havetheirmodifiable cardiovascular risk factors optimized.

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