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2015-0691

Research Proposal

Project Title: 
Impact of Biologic Therapy on the Risk of Arterial and Venous Thromboembolic Events in Chronic Autoimmune Diseases: A Post-Hoc Analysis of RCTs
Scientific Abstract: 

Background: Patients with autoimmune diseases, like rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), psoriatic arthritis (PsA), and ankylosing spondylitis (SpA) are at increased risk of cardiovascular events and venous thromboembolism (VTE), particularly during periods of high disease activity. It is unclear whether biologic therapy modifies this risk.
Objective: To evaluate the association between biologic therapy and risk of major adverse cardiovascular events and VTE in autoimmune diseases.
Study Design: Individual participant-level pooled analysis of RCTs
Participants: Patients in phase III RCTs of infliximab and golimumab in RA, IBD, PsA, or SpA, receiving either placebo or active agent.
Main Outcome Measures: Risk of cardiovascular events and VTE in (a) patients treated with biologics (vs. placebo), and (b) in patients with response to therapy (vs. non-responders).
Statistical Analysis: We will perform 2 separate Cox proportional hazard analyses to evaluate the association between (a) receipt of biologics (vs. placebo), and (b) response to therapy (vs. non-response) on cardiovascular and VTE risk, after pooling data from included RCTs. All analyses will be adjusted for confounders – baseline disease activity, traditional cardiovascular (age, sex, smoking, diabetes, hypertension, hyperlipidemia, obesity, personal or family history of cardiovascular disease, use of aspirin/statins) and VTE risk factors (age, sex, immobility, hospitalization, obesity, smoking, drugs), and co-interventions. Analyses will be stratified by type of autoimmune disease.

Brief Project Background and Statement of Project Significance: 

Autoimmune diseases, including RA, IBD, PsA and SpA have been associated with an increased risk of cardiovascular events and venous thromboembolism.1-7 While traditional cardiovascular risk factors are not over-represented in these patients, chronic inflammation-driven accelerated atherosclerosis and prothrombotic state contribute to this increased risk.2,8 Atherosclerosis is a chronic inflammatory process in which immune cells infiltrate the arterial wall in response to chemotactic signals generated by activated endothelial cells.9,10,11 This association between autoimmune diseases and risk of cardiovascular and VTE events is particularly strong during periods of active disease as compared to periods of remission, consistent with the effect of high inflammatory burden.12,13
Few studies have investigated therapeutic strategies to reduce this risk.14-16 Aggressive treatment of autoimmune diseases with biologic agents may conceivably decrease cardiovascular (and VTE) risk by decreasing inflammatory burden.2, 8 However, observational studies are limited in their ability to infer the effect of disease-modifying therapy on cardiovascular risk due to confounding by severity (i.e., patients with high disease activity, inherently at high cardiovascular risk, are likely to be treated with more potent biologic therapy), so the benefit of therapy may not be apparent.17 Additionally, most observational studies are also at risk of immortal-time bias.18 It is unclear whether any impact of therapy on reducing cardiovascular risk is an independent effect of the treatment or an indirect effect by reducing inflammation.
In this proposal, our objective is to study the impact of biologic therapy both directly (vs. placebo) and indirectly (by comparing responders vs. non-responders) on cardiovascular and VTE risk, within an enriched high-risk population of patients with severe active autoimmune diseases participating in well-designed clinical trials of biologic therapy. Our central hypothesis is that response to treatment (vs. non-response), and not mere receipt of biologics (vs. placebo), is associated with reduced risk of cardiovascular and VTE events in patients with autoimmune diseases.
The significance of this work lies in comprehensively assessing how receipt and response to biologic therapy modifies the risk of thromboembolism in patients with autoimmune diseases, using a novel, innovative approach through post-hoc analyses of robust, late-stage clinical trials, avoiding biases of observational studies. By combining all autoimmune diseases, we anticipate sufficient number of events in trials for a well-powered analysis. From a scientific perspective, the information generated will advance understanding of atherosclerosis and thrombosis in chronic inflammatory diseases. From a clinical perspective, information generated from this study will be directly applicable to patient care offering a personalized therapeutic approach to cardiovascular risk in autoimmune diseases.

Specific Aims of the Project: 

Specific aim #1: To compare risk of cardiovascular events (myocardial infarction, angina, stroke, transient ischemic attacks) and VTE in biologic vs. placebo-treated patients with autoimmune diseases, including RA, IBD, PsA and SpA, in post-hoc analysis of phase III RCTs of biologic therapy, after adjusting for baseline disease activity and traditional risk factors for cardiovascular disease and VTE.
Hypothesis: Biologic-treated patients will have marginally lower risk of cardiovascular events and VTE as compared to placebo-treated patients

Specific aim #2: To compare the risk of cardiovascular events (myocardial infarction, angina, stroke, transient ischemic attacks) and venous thromboembolism (VTE) in patients with study-defined response to therapy (regardless of intervention) against non-responders, in patients with autoimmune diseases in post-hoc analysis of phase III RCTs of biologic therapy, after adjusting for baseline disease activity and traditional cardiovascular and VTE risk factors.
Hypothesis: Patients with response to therapy (regardless of intervention) will have a significantly lower risk of cardiovascular events and VTE, as compared to patients who fail to respond to therapy.

What is the purpose of the analysis being proposed? Please select all that apply.: 
New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: 

• Trials of infliximab in rheumatoid arthritis (NCT00269867, NCT00236028)
• Trials of golimumab in rheumatoid arthritis (NCT00264537, NCT00264550, NCT00299546, NCT00361335, NCT01248780)
• Trials of infliximab in Crohn’s disease (NCT00207662, NCT00207766, NCT00004941, NCT00094458)
• Trial of infliximab in ulcerative colitis (NCT00036439, NCT00096655, NCT00336492, NCT00537316)
• Trials of golimumab in ulcerative colitis (NCT00487539)
• Trials of golimumab in psoriatic arthritis (NCT00265096)
• Trials of golimumab in ankylosing spondylitis (NCT00265083, NCT01248793)
• Trial of infliximab in ankylosing spondylitis (NCT00202865)
• Trial of infliximab in juvenile idiopathic arthritis (NCT00036374)
Inclusion criteria:
• Adults with:
o Active rheumatoid arthritis (defined as either at least 4 swollen joints and at least 4 tender joints at baseline, and meet at least 2 of the following criteria at screening and/or baseline: 1) C-reactive protein (CRP) >1.5mg/dl or erythrocyte sedimentation rate (ESR) >28 mm/hour 2) morning stiffness lasting 30 minutes or longer, 3) bone erosion by radiography and/or magnetic resonance imaging prior to initiation of treatment with the study agent

Main Outcome Measure and how it will be categorized/defined for your study: 

Main outcome measure will be cardiovascular and/or VTE events any time during the trial period
• Composite endpoint of major adverse cardiovascular events including
o Acute coronary syndrome including unstable angina, myocardial infarction,
o Ischemic heart failure
o Stroke and transient ischemic attack
o Cardiovascular mortality
• Venous thromboembolism events include
o Deep venous thrombosis
o Pulmonary embolism
o VTE-related mortality

Main Predictor/Independent Variable and how it will be categorized/defined for your study: 

• For specific aim #1, predictor would be intervention (active vs. placebo)
• For specific aim #2,
o For rheumatoid arthritis trials – Clinical response (ACR20 or 50 response defined as ≥20% or 50% improvement in RA symptoms)
o For ulcerative colitis trials – Clinical response (decrease in MCS by ≥3 points and 30%, with decrease in the rectal bleeding sub-score by ≥1 point, or an absolute sub-score of 0 or 1)
o For Crohn’s disease trials – Clinical response (decrease in CDAI by 100 [CR100] or 70 points [CR70] from baseline; reduction in number of draining fistulae by 50% from baseline, for fistulizing CD)
o For psoriatic arthritis trials – Clinical response (ACR20 response defined as improvement of >= 20% from baseline)
o For ankylosing spondylitis trials – Clinical response (AS20 response defined by the number of patients who achieved a 20% improvement and at least 1 absolute improvement on a 0 to 10 cm scale from baseline in at least 3 of the 4 domains: patient global, total back pain, function or inflammation)

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: 

Key confounding variables of interest in our study are:
o Traditional cardiovascular risk factors at baseline including hypertension, hyperlipidemia/hypertriglyceridemia, obesity, diabetes mellitus, smoking status, age, sex, familial or personal history of CV disease, use of aspirin/statins
o Traditional VTE risk factors: recent major surgery, obesity, smoking, hospitalization, oral contraception, and cancer
o Biochemical measures of disease severity – baseline C-reactive protein as a categorical variable (<0.5mg/dl or ≥0.5mg/dl), fecal calprotectin for IBD (<150mcg/g vs. ≥150mcg/g)
o Co-interventions – concomitant use of immunomodulators like azathioprine, 6-mercaptopurine or methotrexate (yes vs. no), concomitant use of steroids and NSAIDs (yes vs. no)
o All analysis will be stratified by autoimmune disease types (RA, PsA, SpA, IBD); trials of induction and maintenance therapy will be analyzed separately

Statistical Analysis Plan: 

• Impact of biologics on cardiovascular and VTE risk (vs. placebo): We will compare the baseline characteristics of biologic- vs. placebo-treated patients for key variables, and evaluate the incidence of major adverse cardiovascular events and VTE events in both groups. We will then perform multivariable Cox proportional hazard analysis after adjusting for type of autoimmune disease and relevant confounders including baseline disease activity (clinical, biochemical), traditional cardiovascular (age, sex, smoking status, diabetes, hypertension, hyperlipidemia, obesity, personal or family history of cardiovascular disease, use of aspirin/statins) and VTE risk factors (age, sex, smoking, obesity, immobility, hospitalization, procoagulant or anticoagulant) and co-interventions for autoimmune disease.
• Impact of response to therapy on cardiovascular and VTE risk (vs. non-responders): We will compare baseline characteristics of responders vs. non-responders (regardless of intervention) for key confounding variables, and evaluate the incidence of major adverse cardiovascular events and VTE events in both groups. Then we will perform multivariable Cox proportional hazard analysis after adjusting for type of autoimmune disease and relevant confounders including intervention arm, baseline disease activity, traditional cardiovascular and VTE risk factors, and co-interventions for autoimmune disease.

Analysis will be clustered by RCT, and stratified by type of autoimmune disease (RA, IBD, PsA, SpA). We will perform additional subgroup analysis by trial design (induction vs. maintenance), type of anti-TNF agent (infliximab vs. golimumab).

Narrative Summary: 

Chronic inflammation is an independent risk factor for cardiovascular diseases and venous thromboembolism (VTE), and hence, patients with autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel diseases, psoriatic arthritis, and ankylosing spondylitis are at increased risk. This risk is particularly increased during disease flares or prolonged activity indicating a correlation with the inflammatory burden. The aim of this study is to evaluate the effect of biologic therapy, in particular response to treatment, on the risk of cardiovascular events and VTE, and related mortality, in randomized controlled trials (RCTs) of biologic therapy in autoimmune diseases.

Project Timeline: 

Once study is approved and data access provided (assuming by February 2016), our key milestones dates are:
o Project start date: March 1, 2016
o Analysis completion date: May 1, 2016
o Manuscript drafted: July 1, 2016
o Manuscript submitted for publication: August 1, 2016
o Date results reported back to YODA: August 1, 2016

Dissemination Plan: 

We anticipate generation of at least 2 manuscripts from this project – one including data on risk modification of cardiovascular events and on risk modification of venous thromboembolism risk. The target audience would be primary care physicians, rheumatologists, gastroenterologists, cardiologists as well as physician-scientists with interest in atherosclerosis and autoimmune diseases.

Bibliography: 

1. Avina-Zubieta JA, Thomas J, Sadatsafavi M, et al. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 2012;71:1524-9.
2. Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol 2011;7:399-408.
3. Singh S, Singh H, Loftus EV, Jr., et al. Risk of cerebrovascular accidents and ischemic heart disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014;12:382-93 e1: quiz e22.
4. Fumery M, Xiaocang C, Dauchet L, et al. Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: a meta-analysis of observational studies. J Crohns Colitis 2014;8:469-79.
5. Eder L, Wu Y, Chandran V, et al. Incidence and predictors for cardiovascular events in patients with psoriatic arthritis. Ann Rheum Dis 2015.
6. Mathieu S, Pereira B, Soubrier M. Cardiovascular events in ankylosing spondylitis: an updated meta-analysis. Semin Arthritis Rheum 2015;44:551-5.
7. Kim SC, Schneeweiss S, Liu J, et al. Risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2013;65:1600-7.
8. Singh S, Kullo IJ, Pardi DS, et al. Epidemiology, risk factors and management of cardiovascular diseases in IBD. Nat Rev Gastroenterol Hepatol 2015;12:26-35.
9. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-95.
10. Hansson GK, Robertson AK, Soderberg-Naucler C. Inflammation and atherosclerosis. Annu Rev Pathol 2006;1:297-329.
11. Lusis AJ. Atherosclerosis. Nature 2000;407:233-41.
12. Kristensen SL, Ahlehoff O, Lindhardsen J, et al. Disease activity in inflammatory bowel disease is associated with increased risk of myocardial infarction, stroke and cardiovascular death - a danish nationwide cohort study. PLoS One 2013;8:e56944.
13. Myasoedova E, Chandran A, Ilhan B, et al. The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease. Ann Rheum Dis 2015.
14. Chen YJ, Chang YT, Shen JL, et al. Association between systemic antipsoriatic drugs and cardiovascular risk in patients with psoriasis with or without psoriatic arthritis: a nationwide cohort study. Arthritis Rheum 2012;64:1879-87.
15. Greenberg JD, Kremer JM, Curtis JR, et al. Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:576-82.
16. Thapa SD, Hadid H, Schairer J, et al. Effect of Inflammatory Bowel Disease-Related Characteristics and Treatment Interventions on Cardiovascular Disease Incidence. Am J Med Sci 2015;350:175-80.
17. Singh S, Loftus EV, Jr. Cardiovascular risk in inflammatory bowel disease: it's a heartache! Gastroenterology 2013;145:1484-6.
18. Targownik LE, Suissa S. Understanding and Avoiding Immortal-Time Bias in Gastrointestinal Observational Research. Am J Gastroenterol 2015;110:1647-50.

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