|Year : 2018 | Volume
| Issue : 1 | Page : 1-7
Colon and rectal surgery for inflammatory bowel disease patients on vedolizumab: Preliminary surgical outcomes
Sarah B Stringfield, Lisa A Parry, Sonia L Ramamoorthy, Samuel G Eisenstein
Department of Surgery, University of California, San Diego, California, USA
|Date of Web Publication||30-Aug-2018|
Sarah B Stringfield
University of California, San Diego, California
Source of Support: None, Conflict of Interest: None
Background and Objectives: Vedolizumab is an antagonist of leukocyte trafficking that targets gut α4β7 integrins and is efficacious in inflammatory bowel disease (IBD). Studies investigating postoperative complications in patients on this medication have not been performed. The objective of this study is to identify rates and types of postoperative complications experienced in patients with IBD who have undergone surgery following treatment with vedolizumab. Patients and Methods: This was a retrospective review of the electronic medical record of patients with IBD who underwent perianal or abdominal surgery, June 2014–March 2016, at the University of California San Diego Medical Center. Main outcome measures were rates and types of postoperative complications. Results: Patients were divided into three treatment groups: vedolizumab, other biologics, and no biologics. Twenty-nine patients on vedolizumab underwent forty operations that fit study criteria. Fifteen of 26 abdominal operations experienced a postoperative complication, for a complication rate of 57.7%. The most common complication was infectious (34.6%). Anastomotic leak rate was 16.7% and mortality rate was 7.7%. Complication rates in patients on vedolizumab were higher than rates in other patients with IBD. One of 14 perianal operations experienced an infectious complication (7%). Readmission rate in abdominal patients on vedolizumab was higher than the other categories (31% vs. 7% and 10%, P = 0.01). Conclusions: We observed high rates of postoperative complications in patients on vedolizumab who underwent abdominal surgery. Rates were higher than published outcomes as well as outcomes for other IBD patients at our institution. Studies including larger numbers of patients must be performed to further investigate this issue.
Keywords: Colon and rectal surgery, Crohn′s disease, inflammatory bowel disease, ulcerative colitis, vedolizumab
|How to cite this article:|
Stringfield SB, Parry LA, Ramamoorthy SL, Eisenstein SG. Colon and rectal surgery for inflammatory bowel disease patients on vedolizumab: Preliminary surgical outcomes. World J Colorectal Surg 2018;7:1-7
|How to cite this URL:|
Stringfield SB, Parry LA, Ramamoorthy SL, Eisenstein SG. Colon and rectal surgery for inflammatory bowel disease patients on vedolizumab: Preliminary surgical outcomes. World J Colorectal Surg [serial online] 2018 [cited 2019 Oct 14];7:1-7. Available from: http://www.wjcs.us.com/text.asp?2018/7/1/1/240252
| Introduction|| |
Inflammatory bowel diseases (IBDs) including Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions of the gastrointestinal tract. Uncontrolled inflammation can lead to disability, hospitalization, surgical resections, and increased risk of malignancy. Proposed mediators of inflammation in IBD include the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and α4-integrins., The α4-integrins are cell surface glycoproteins with a role in the migration of leukocytes across vascular endothelium, facilitating trafficking to areas of inflammation in the gut, where they initiate and maintain this inflammation. These cytokines and integrins are the targets of many drugs proven effective in patients with IBD.
Vedolizumab (Entyvio®, Millennium Pharmaceuticals Inc., Takeda, Cambridge, Mass, USA) is an antagonist of leukocyte trafficking that targets gut α4β7 integrins. It was approved by the Food and Drug Administration (FDA) for the use in moderate-to-severe UC and CD in May 2014. Multiple studies have looked at the efficacy and safety of vedolizumab in IBD. Vedolizumab shows benefit during induction and maintenance therapy, and a greater proportion of vedolizumab-treated patients compared with placebo-treated patients were in remission after 10 weeks in the group of patients who failed treatment with anti-TNF drugs. Statistically significant differences in adverse events between vedolizumab and placebo were only seen in nasopharyngitis. As vedolizumab selectively targets gut integrins, it is thought to have less systemic effects than other anti-TNF medications or nonselective anti-integrins.
Currently, at our institution, vedolizumab has primarily been used in patients who failed traditional medical management, including anti-TNF therapy. Many patients on vedolizumab will continue to have uncontrolled disease and may require surgical intervention. There have not been any studies regarding vedolizumab and postoperative complications. The goal of this study is to identify rates and types of postoperative complications in vedolizumab-treated IBD patients and to see whether any preoperative or operative demographics place the patients at increased risk.
| Patients and Methods|| |
We performed a retrospective study of postoperative complications in IBD patients between June 2014 and March 2016. After Institutional Review Board approval, the operative cases of the colorectal specialty surgeons at the University of California San Diego (UCSD) Medical Center were reviewed. All patients with a diagnosis of IBD, CD, or UC were identified. In addition, all patients treated with vedolizumab at our institution were identified through a search of the medication administration record within the electronic medical record.
Inclusion and exclusion criteria
All patients with a diagnosis of IBD who underwent surgery at UCSD with a colorectal surgeon between June 1, 2014, and March 1, 2016, were initially included in the study. Operations were included in the study if they were intra-abdominal and involving manipulation of the small or large intestine and/or if they were perianal in nature. Operations that included concurrent additional procedures were excluded from the study. All patients were over the age of 18. Medication history was reviewed and patients were categorized according to the IBD medication they most recently received. A drug was considered active in the patient if they had received it within five half-lives of surgery. The following time periods were used: vedolizumab = 125 days, infliximab = 48 days, adalimumab = 100 days, certolizumab = 70 days, golimumab = 70 days, and natalizumab = 75 days.
Medical records of patients who fit inclusion criteria were reviewed for clinical data. Preoperative labs and body mass index were obtained a maximum of 14 days before surgery. Preoperative weight loss was defined as a >10% total body weight lost within 12 months before surgery. Cases were considered emergent in nature if they were during a hospitalization that was the result of a visit to the emergency department (ED). Postoperative complications were defined as occurring within 30 days after surgery, and all patients had a minimum follow-up of 30 days. Complications were graded according to Clavien–Dindo classification and Grade II–V complications were considered clinically significant.
The primary outcome was the rate of postoperative complications following abdominal or perianal surgery.
Secondary outcomes included differences in patient demographics between patients on vedolizumab who experienced a complication and patients who did not experience a complication.
Categorical variables were analyzed using Fisher's test and Chi-squared test. Continuous variables were analyzed using a two-sided t-test. P < 0.05 was considered statistically significant.
| Results|| |
A total of 246 operations were performed on patients with IBD during the study period. Abdominal operations accounted for 153 cases. Fifteen operations included concurrent non-colorectal procedures, and were therefore excluded, for a total of 138 abdominal operations of interest. Eighty cases were perianal, and one was excluded. Thirteen operations were not perianal nor abdominal in nature and were excluded.
We identified 127 patients treated with vedolizumab at our institution during the study period. An additional nine patients received vedolizumab at an outside institution but underwent surgery at UCSD. Twenty-four of the 127 patients treated at UCSD underwent any operation within the period, for an operative rate of 19% (24/127). The 33 surgical patients underwent a total of 57 operations. After exclusion criteria were applied, we identified 29 patients who underwent 40 abdominal or perianal operations within 125 days of receiving vedolizumab. Average number of operations per patient was 1.38 (range: 1–4). One patient received a single dose of an experimental biologic medication and one patient received a single dose of certolizumab following vedolizumab therapy during the 125 days before surgery and was included in the vedolizumab group.
Abdominal surgery patients
The 138 abdominal operations were subdivided into three categories according to medication received: vedolizumab, other biologics, or no biologics.
We identified 22 patients who underwent 26 abdominal operations while on vedolizumab. Types of operations included total and subtotal colectomy (13), ileostomy takedown (4), laparotomy with lysis of adhesions and/or small bowel resection (3), hemicolectomy (2), completion proctectomy with J-pouch (2), and loop ileostomy creation (2). Sixteen (62%) of these patients were on corticosteroids at the time of surgery.
Thirty patients underwent thirty abdominal operations while treated with other biologic medications. Twelve patients received adalimumab, 13 patients received infliximab, 2 patients received certolizumab, 1 patient received golimumab, 1 patient received natalizumab, and 1 patient received both infliximab and adalimumab within 5 half-lives of surgery. Fifteen (50%) of these patients were on corticosteroids at the time of surgery.
Fifty-seven patients underwent 81 abdominal operations in the group of patients not on biologic medications. Twelve (15%) of the patients were on corticosteroids at the time of surgery.
We identified 15 operations in 12 patients who experienced a Clavien–Dindo Grade II or greater complication in the vedolizumab group. Eleven operations in 11 patients were uncomplicated, making the complication rate 57.7% (15/26) for abdominal operations. Of the 22 unique patients, 12 (54.5%) experienced a complication following at least one operation. Twenty-three complications were identified in the 15 operations, with infectious complications the most common (9/23, 39% of complications, occurred following 34.6% of operations), followed by bleeding or the requirement of blood transfusions (7/23, 30.4% of complications, 26.9% of operations) and small bowel obstruction (3/23, 13% of complications, 11.5% of operations) [Table 1]. Twelve anastomoses were performed, for an anastomotic leak rate of 16.7% (2/12). All anastomoses were stapled and no stricturoplasties were performed. One leak occurred at an ileal-sigmoid anastomosis despite the presence of a diverting loop ileostomy, and the other leak occurred following an ileostomy closure. Demographics were compared between the patients who had a complication and those who did not [Table 2]. The only statistically significant difference found between the two groups demonstrated a greater proportion of patients on corticosteroids in the group that did not have a complication. There were trends toward lower hemoglobin level, greater doses of vedolizumab and shorter time from the last dose until surgery, and greater blood loss in the complication group, but these were not statistically significant. Demographics and surgical information of the patients who experienced a complication are described in [Table 3].
Two patients on vedolizumab died within 30 days of surgery for a mortality rate of 7.7% (2/26) following an abdominal surgery and 9.1% (2/22) of abdominal patients. Both patients died from sepsis of unknown cause, out of proportion to the severity of their postoperative course.
The first patient was 39 years old with CD who received 7 doses of vedolizumab, most recently 26 days before surgery. The patient underwent elective laparotomy with lysis of adhesions for a history of recurrent small bowel obstructions. The patient also developed sepsis on postoperative day (POD) 2 and was brought back to the operating room, which demonstrated only a pinpoint enterotomy without any intra-abdominal contamination and did not correlate with the severity of the patient's sepsis. The patient worsened despite repair, resuscitation, and broad-spectrum antimicrobials. She developed multisystem organ failure, experienced cardiac arrest on POD 5, and died. One of four blood cultures grew Escherichia More Details coli. Autopsy did not provide any additional information into cause of death.
The second patient was 52 years old with CD. Vedolizumab therapy was initiated 2 months before surgery. The patient underwent elective laparotomy with creation of a loop ileostomy and incision and drainage of perianal fistulas. He did well initially and was discharged on POD 3. On POD 17, he presented to an outside hospital with fever and malaise, rapidly decompensated, and was transferred to our institution on POD 19 in septic shock requiring three vasopressors. Computed tomography was negative for an infectious intra-abdominal process, no perianal abscesses were identified, and blood cultures were negative. Despite maximal medical therapy, the patient worsened and died on POD 21. Autopsy was not performed.
We identified 12 operations in 12 patients on other biologic agents who experienced a Grade II or greater complication, for an overall complication rate of 40% (12/30). There were 16 unique complications. The most common was hematologic at an overall rate of 23.3% (7/30) and 44% of complications. This was followed by infectious complications at 20% overall (6/30) and 37.5% of complications. There were no anastomotic leaks or deaths [Table 1].
We identified 28 operations in 24 patients who were not on any biologic medications who experienced a Grade II or greater complication, for an overall complication rate of 34.6% (28/81). There were 50 unique complications. The most common complication was infectious, at an overall rate of 30.9% (25/81), accounting for 50% of complications. This was followed by hematologic complications, for a rate of 13.6% overall (11/81) and 22% of complications. There were no deaths. Anastomotic leaks occurred in 3 of the 63 anastomoses, for a rate of 4.8% [Table 1].
Clavien–Dindo class of complications varied between the three groups, with no deaths (Grade V complications) occurring in the other biologics or no biologics groups and no Grade IV complications occurring in the other biologics group. However, differences between the three groups only approached significance (P = 0.08) [Table 4].
|Table 4: Complication grades in patients who underwent abdominal surgery|
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There were a high number of ED encounters resulting in readmissions in the patients on vedolizumab who underwent abdominal surgery. In the vedolizumab group, 54% of patients returned to the ED. This was significantly higher than ED visits in those on other biologics or no biologics (20% in both groups, P = 0.0018). The number of readmissions in the vedolizumab group was also significantly higher (31% vs. 7% and 10%, P = 0.01) [Table 5].
Perianal surgery patients
We identified 9 patients who underwent 14 operations for perianal conditions related to CD. One patient experienced an infectious complication, specifically Clostridium difficile infection, for a complication rate of 7% (1/14) after a perianal operation and 11% of patients (1/9). These patients had a history of a greater number of failed biologic medications than the abdominal group [Table 2]. Of interest, the patient who experienced the complication received vedolizumab the day before surgery and also required a preoperative transfusion for anemia.
| Discussion|| |
Vedolizumab is a relatively new medication that has been proven effective in patients with severe IBD who have failed treatment with anti-TNF medications. Despite treatment with vedolizumab, there are patients who will fail medical therapy and require surgery. While the drug has been shown to be safe in the primary treatment of IBD, there have not been any studies looking at postoperative results in surgical patients on this medication. At our institution, 19% of patients on vedolizumab required surgery, and we observed several severe postoperative complications in these patients, including two deaths from unclear causes of sepsis. These events were the impetus for our study.
Vedolizumab is an antagonist of leukocyte trafficking that specifically targets gut α4β7 integrins. Leukocyte trafficking is the migration of activated leukocytes to sites of inflammation, regulated by interactions between proteins on the lymphocyte cell membrane and endothelial cells. These leukocytes participate in an amplified dysregulated immune response, which causes tissue damage. Selectively targeting gut inflammation through these integrins preserves systemic immune responses, minimizing the number of systemic complications. However, blocking lymphocyte trafficking to the bowel may impair the ability of anastomoses to heal, and if standard barriers to infection are compromised due to surgery, patients may be more susceptible to systemic sepsis.
The GEMINI trials demonstrated vedolizumab's efficacy in inducing and maintaining clinical remission in both UC and CD., Higher rates of mucosal healing and corticosteroid-free remission were observed in patients treated with vedolizumab compared to placebo. In GEMINI 3, efficacy was proven in both patients with previous anti-TNF exposure as well as the treatment naive. This suggests efficacy in the population of patients who are refractory to other medical therapies, which is the population that has been treated with vedolizumab at our institution. Despite efficacious new IBD medications, there are patients who will fail all medical therapy and require surgery. However, the FDA does not require studies examining outcomes in surgical patients before drug approval for new IBD medications.
Vedolizumab has a long half-life; therefore, it takes 125 days for the medication to be cleared from the body. We were not able to show statistical significance due to small sample sizes; however, we did see a trend toward increased complications after abdominal surgery with a shorter interval since the last dose of vedolizumab and a greater total number of doses preoperatively. The appropriate and safe time to operate on patients treated with vedolizumab remains to be established; however, it may be beneficial to delay surgery if possible in patients who recently received the medication. With the long half-life, it is unlikely feasible to delay surgery until the drug is completely out of the patient's system.
Our study found high rates of postoperative complications in patients who received the drug and required abdominal surgery. A meta-analysis of the literature on postoperative complications following abdominal surgery in IBD patients who failed medical therapy cites a 21% overall complication rate in CD, with a 16% infectious complication rate. Patients with UC experienced a 35% overall complication rate with a 17% rate of infectious complications. Our rates were similar among patients on other biologics; however, the patients receiving vedolizumab experienced a much higher rate of complications, with a 58% overall complication rate and a 35% rate of infectious complications. In addition, we experienced a 17% rate of anastomotic leak and an 8% mortality rate. Compared to IBD patients on other medications who underwent similar operations during the same period at our institution, complication rates in patients on vedolizumab were higher in all categories.
At our institution, patients treated with vedolizumab have failed medical treatment with at least one and many times up to four other biologic agents. This makes it difficult to truly tease out whether the negative outcomes are a result of receiving a medication which suppressed their immune system or whether they have a more severe phenotype of their disease, predisposing them to worse surgical outcomes. This is also demonstrated in the fact that a higher percentage of patients on vedolizumab were also concurrently receiving corticosteroids. Interestingly, in our patient population, the patients on corticosteroids actually had fewer complications, indicating that there is likely some element of poorly controlled disease contributing to the elevated complication rate. This may also explain the unexpectedly high rate of infectious complications in the group of patients not receiving biologic therapy. The expected rates of complications in patients who failed medical management are not known; however, we have shown that our complication rates are higher than those seen in other surgical patients with IBD.
Our study is limited by the small number of patients within each group. A larger study is needed to definitively determine whether there are other characteristics that predispose these patients to complications. It appears that many markers of disease severity, such as significant weight loss, albumin, and the American Society of Anesthesiologists class are very similar between the two groups. This makes it difficult to predict which patients are at risk and in which patients' surgeries should be delayed. The two patients who expired did not have any markers that would have given us cause to predict they would be at high risk.
This study is also limited by retrospective data analysis and the fact that vedolizumab was not used in a randomized study setting. The drug was likely used more often in patients with the most severe forms of IBD. The small size of the study limits our ability to make statistically significant conclusions. Based on our single-institution results, we feel it is important to further investigate outcomes in this patient population. Ultimately, a large-scale collaborative between several high-volume institutions may prove to be beneficial in truly evaluating the effect of this medication as well as a variety of new medications which may soon become available to treat IBD.
| Conclusion|| |
We found that the use of vedolizumab is associated with increased risk of 30-day postoperative complications in patients with IBD who underwent abdominal surgery compared to other patients with IBD who were not on the medication. In light of these results, it would be prudent to further investigate this patient population and exercise caution as well as mitigate potential complications which may develop in these very complicated patients. This may mean allowing the medication to wash out before surgery or to include diverting ostomies in surgeries where previously they may not have been considered.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]