Increased Risk of Venous Thromboembolic Events With Corticosteroid Versus Biologic Therapy for Inflammatory Bowel Disease

Abstract

We read with interest the article by Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar in which they studied the association between corticosteroid therapy and venous thromboembolism (VTE) in 15,100 patients with inflammatory bowel disease (IBD) using a large US Commercial Claims Database.1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar Compared with corticosteroid monotherapy, biologic monotherapy was associated with a lower odds (adjusted odds ratio, 0.21) of VTE, whereas combination therapy (corticosteroids + biologics) was associated with a similar odds (adjusted odds ratio, 1.01) of VTE over a 1-year follow-up period, after controlling for several demographic and clinical factors. VTE events were observed exclusively during the first 2 months of treatment in patients receiving biologic monotherapy, whereas they were observed throughout the follow-up period in corticosteroid-treated patients. Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar concluded that corticosteroid use is associated independently with the development of VTE in IBD patients.We praise the authors for undertaking a rigorous analysis of this important question in a large IBD cohort. However, there are several issues that limit inference of a causal association between corticosteroid use and VTE risk. First, it is impossible to separate the direct impact of IBD treatment on VTE events from its indirect impact on VTE through its effects on disease activity. Biologic therapy achieves better overall disease control than corticosteroid-based treatment in IBD,2Hanauer S.B. et al.Lancet. 2002; 359: 1541-1549Google Scholar, 3Colombel J.F. et al.Gastroenterology. 2007; 132: 52-65Google Scholar, 4D'haens G. et al.Lancet. 2008; 371: 660-667Google Scholar, 5Rutgeerts G. et al.N Engl J Med. 2005; 353: 2462-2476Google Scholar which may have largely dictated the observed associations. The observation that biologic monotherapy was associated with much faster resolution of VTE risk supports this notion because corticosteroid-treated patients are more likely to have had persistently active disease, disputing the argument by Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar that the period beyond the first few months should be less reflective of disease activity. Furthermore, because most patients likely would have tapered off corticosteroids within a few months, the observation of VTE events occurring throughout the follow-up period in this group cannot be attributed entirely to medication effects. Adding to this, some patients who received biologic monotherapy may have simply been refractory or intolerant to other maintenance agents or treated primarily for fistulizing or fibrostenotic complications of Crohn's disease, and may have had relatively milder inflammatory bowel activity at baseline. Conversely, patients treated with corticosteroids are more likely to have been experiencing a moderate to severe inflammatory disease flare.Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar proposed that the observed similarity in VTE risk with combination therapy and corticosteroid monotherapy further supports the notion of an increased prothrombotic effect of corticosteroid therapy. However, it is possible that some patients who received combination therapy had greater baseline disease activity that lead to the use of two agents. Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar were only able to control for surrogate measures of disease activity, including recent hospitalizations and IBD-related surgeries, which are unlikely to capture the full breadth of inflammatory activity in these patients. Indeed, many patients may have been hospitalized previously for reasons unrelated to an IBD flare. It also is possible that there was a significant lag in starting biologics in many patients who received combination therapy owing to requirements for pretreatment testing and vaccination and/or obtaining financial coverage, which could have lead to a delay in optimal disease control. Other patients may have received only corticosteroids because they failed to respond to biologics. In any of these scenarios, greater disease activity in the combination therapy group could be the main driver for the failure to show a similar benefit of biologic therapy as observed in the biologic monotherapy group.A number of studies have shown an association between IBD and VTE risk.6Murthy S.K. et al.Am J Gastroenterol. 2011; 106: 713-718Google Scholar A large population-based study from the United Kingdom also reported a substantially higher risk of VTE during periods of active disease as compared with periods of remission; here too, however, corticosteroid prescription was used as a surrogate marker for disease activity.7Grainge M.J. et al.Lancet. 2010; 375: 657-663Google Scholar No study directly implicated corticosteroids or other treatment as a causative factor in the development of VTE in IBD patients. Indeed, there is very little literature supporting a role for corticosteroids in the development of VTE, despite its widespread use. Still, the present study is provocative and prospective studies now are required to better define the role of corticosteroid treatment on VTE risk in IBD patients. We read with interest the article by Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar in which they studied the association between corticosteroid therapy and venous thromboembolism (VTE) in 15,100 patients with inflammatory bowel disease (IBD) using a large US Commercial Claims Database.1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar Compared with corticosteroid monotherapy, biologic monotherapy was associated with a lower odds (adjusted odds ratio, 0.21) of VTE, whereas combination therapy (corticosteroids + biologics) was associated with a similar odds (adjusted odds ratio, 1.01) of VTE over a 1-year follow-up period, after controlling for several demographic and clinical factors. VTE events were observed exclusively during the first 2 months of treatment in patients receiving biologic monotherapy, whereas they were observed throughout the follow-up period in corticosteroid-treated patients. Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar concluded that corticosteroid use is associated independently with the development of VTE in IBD patients. We praise the authors for undertaking a rigorous analysis of this important question in a large IBD cohort. However, there are several issues that limit inference of a causal association between corticosteroid use and VTE risk. First, it is impossible to separate the direct impact of IBD treatment on VTE events from its indirect impact on VTE through its effects on disease activity. Biologic therapy achieves better overall disease control than corticosteroid-based treatment in IBD,2Hanauer S.B. et al.Lancet. 2002; 359: 1541-1549Google Scholar, 3Colombel J.F. et al.Gastroenterology. 2007; 132: 52-65Google Scholar, 4D'haens G. et al.Lancet. 2008; 371: 660-667Google Scholar, 5Rutgeerts G. et al.N Engl J Med. 2005; 353: 2462-2476Google Scholar which may have largely dictated the observed associations. The observation that biologic monotherapy was associated with much faster resolution of VTE risk supports this notion because corticosteroid-treated patients are more likely to have had persistently active disease, disputing the argument by Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar that the period beyond the first few months should be less reflective of disease activity. Furthermore, because most patients likely would have tapered off corticosteroids within a few months, the observation of VTE events occurring throughout the follow-up period in this group cannot be attributed entirely to medication effects. Adding to this, some patients who received biologic monotherapy may have simply been refractory or intolerant to other maintenance agents or treated primarily for fistulizing or fibrostenotic complications of Crohn's disease, and may have had relatively milder inflammatory bowel activity at baseline. Conversely, patients treated with corticosteroids are more likely to have been experiencing a moderate to severe inflammatory disease flare. Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar proposed that the observed similarity in VTE risk with combination therapy and corticosteroid monotherapy further supports the notion of an increased prothrombotic effect of corticosteroid therapy. However, it is possible that some patients who received combination therapy had greater baseline disease activity that lead to the use of two agents. Higgins et al1Higgins P.D.R. et al.Clinical Gastroenterol Hepatol. 2015; 13: 316-321Google Scholar were only able to control for surrogate measures of disease activity, including recent hospitalizations and IBD-related surgeries, which are unlikely to capture the full breadth of inflammatory activity in these patients. Indeed, many patients may have been hospitalized previously for reasons unrelated to an IBD flare. It also is possible that there was a significant lag in starting biologics in many patients who received combination therapy owing to requirements for pretreatment testing and vaccination and/or obtaining financial coverage, which could have lead to a delay in optimal disease control. Other patients may have received only corticosteroids because they failed to respond to biologics. In any of these scenarios, greater disease activity in the combination therapy group could be the main driver for the failure to show a similar benefit of biologic therapy as observed in the biologic monotherapy group. A number of studies have shown an association between IBD and VTE risk.6Murthy S.K. et al.Am J Gastroenterol. 2011; 106: 713-718Google Scholar A large population-based study from the United Kingdom also reported a substantially higher risk of VTE during periods of active disease as compared with periods of remission; here too, however, corticosteroid prescription was used as a surrogate marker for disease activity.7Grainge M.J. et al.Lancet. 2010; 375: 657-663Google Scholar No study directly implicated corticosteroids or other treatment as a causative factor in the development of VTE in IBD patients. Indeed, there is very little literature supporting a role for corticosteroids in the development of VTE, despite its widespread use. Still, the present study is provocative and prospective studies now are required to better define the role of corticosteroid treatment on VTE risk in IBD patients. Increased Risk of Venous Thromboembolic Events With Corticosteroid vs Biologic Therapy for Inflammatory Bowel DiseaseClinical Gastroenterology and HepatologyVol. 13Issue 2PreviewWe investigated whether treatment of active inflammatory bowel disease with biologic agents is associated with a reduced risk of venous thromboembolic events (VTEs) compared with corticosteroid therapy. Full-Text PDF ReplyClinical Gastroenterology and HepatologyVol. 14Issue 1PreviewIn the letter by Murthy and Nguyen, 5 points are made about our study, as follows1: (1) it is very difficult to separate the effects of inflammatory bowel disease activity from the effects of inflammatory bowel disease therapy on venous thromboembolic event (VTE) risk; (2) they speculated that patients on steroids and biologics have more disease activity, even after controlling for hospitalizations and surgeries; (3) they speculated that patients would have tapered off of steroids (and therefore had less disease activity) after a few months, so that continued VTE events cannot be attributed to steroids; (4) they speculated that a lag in initiating biologic therapy may have worsened disease control; and (5) they claimed that no study has implicated corticosteroids as a causative factor in the development of VTE. Full-Text PDF